Yearly Archives: 2005

Curcumin, An Atoxic Antioxidant and Natural NFB, Cyclooxygenase-2, Lipooxygenase, and Inducible Nitric Oxide Synthase Inhibitor: A Shield Against Acute and Chronic Diseases

  • 12/30/2005
  • London, UK
  • Stig Bengmark, MD, Ph. D.
  • Journal of Parenteral and Enteral Nutrition, Vol. 30, No. 1, 2006 45-51

Background:
The world suffers a tsunami of chronic diseases, and a typhoon of acute illnesses, many of which are associated with the inappropriate or exaggerated activation of genes involved in inflammation. Finding therapeutic agents which can modulate the inflammatory reaction is the highest priority in medical research today. Drugs developed by the pharmaceutical industry have thus far been associated with toxicity and side effects, which is why natural substances are of increasing interest.

Methods:
A literature search (PubMed) showed almost 1500 papers dealing with curcumin, most from recent years. All available abstracts were read. Approximately 300 full papers were reviewed. Results: Curcumin, a component of turmeric, has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NFB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS). Significant preventive and/or curative effects have been observed in experimental animal models of a number of diseases, including arteriosclerosis, cancer, diabetes, respiratory, hepatic, pancreatic, intestinal and gastric diseases, neurodegenerative and eye diseases.

Conclusions:
Turmeric, an approved food additive, or its component curcumin, has shown surprisingly beneficial effects in experimental studies of acute and chronic diseases characterized by an exaggerated inflammatory reaction. There is ample evidence to support its clinical use, both as a prevention and a treatment. Several natural substances have greater antioxidant effects than conventional vitamins, including various polyphenols, flavonoids and curcumenoids. Natural substances are worth further exploration both experimentally and clinically

December, 2005|Archive|

Slowly, Cancer Genes Tender Their Secrets

  • 12/27/2005
  • New York, NY
  • Gina Kolata
  • New York Times (www.nytimes.com)

Jay Weinstein found out that he had chronic myelogenous leukemia in 1996, two weeks before his marriage. He was a New York City firefighter, and he thought his health was great.

He learned that there was little hope for a cure. The one treatment that could save him was a bone marrow transplant, but that required a donor, and he did not have one. By 1999, his disease was nearing its final, fatal phase. He might have just weeks to live.

Then, Mr. Weinstein had a stroke of luck. He managed to become one of the last patients to enroll in a preliminary study at the Oregon Health & Science University, testing an experimental drug.

Mr. Weinstein is alive today and still taking the drug, now on the market as Gleevec. Its maker, Novartis, supplies it to him free because he participated in the clinical trial.

Dr. Brian Druker, a Howard Hughes investigator at the university’s Cancer Institute, who led the Gleevec study, sees Mr. Weinstein as a pioneer in a new frontier of science. His treatment was based not on blasting cancer cells with harsh chemotherapy or radiation but instead on using a sort of molecular razor to cut them out.

That, Dr. Druker and others say, is the first fruit of a new understanding of cancer as a genetic disease. But if cancer is a genetic disease, it is like no other in medicine.

With cancer, a person may inherit a predisposition that helps set the process off, but it can take decades – even a lifetime – to accumulate the additional mutations needed to establish a tumor. That is why, scientists say, cancer usually strikes older people and requires an element of bad luck.

“You have to get mutations in the wrong place at the wrong time,” Dr. Druker says.

Other genetic diseases may involve one or two genetic changes. In cancer, scores of genes are mutated or duplicated and huge chunks of genetic material are rearranged. With cancer cells, said Dr. William Hahn, an assistant professor of medicine at Harvard Medical School, “it looks like someone has thrown a bomb in the nucleus.”

In other genetic diseases, gene alterations disable cells. In cancer, genetic changes give cells a sort of superpower.

At first, as scientists grew to appreciate the complexity of cancer genetics, they despaired. “If there are 100 genetic abnormalities, that’s 100 things you need to fix to cure cancer,” said Dr. Todd Golub, the director of the Cancer Program at the Broad Institute of Harvard and M.I.T. in Cambridge, Mass., and an oncologist at the Dana-Farber Cancer Institute in Boston. “That’s a horrifying thought.”

Making matters more complicated, scientists discovered that the genetic changes in one patient’s tumor were different from those in another patient with the same type of cancer. That led to new questioning. Was every patient going to be a unique case? Would researchers need to discover new drugs for every single patient?

“People said, ‘It’s hopelessly intractable and too complicated a problem to ever figure out,’ ” Dr. Golub recalled.

But to their own amazement, scientists are now finding that untangling the genetics of cancer is not impossible. In fact, they say, what looked like an impenetrable shield protecting cancer cells turns out to be flimsy. And those seemingly impervious cancer cells, Dr. Golub said, “are very much poised to die.”

The story of genes and cancer, like most in science, involves many discoveries over many years. But in a sense, it has its roots in the 1980’s, with a bold decision by Dr. Bert Vogelstein of Johns Hopkins University to piece together the molecular pathways that lead to cancer.

It was a time when the problem looked utterly complicated. Scientists thought that cancer cells were so abnormal that they were, as Dr. Vogelstein put it, “a total black box.”

But Dr. Vogelstein had an idea: what if he started with colon cancer, which had some unusual features that made it more approachable?

Colon cancer progresses through recognizable phases. It changes from a tiny polyp, or adenoma – a benign overgrowth of cells on the wall of the colon – to a larger polyp, a pre-cancerous growth that, Dr. Vogelstein said, looks “mean,” and then to a cancer that pushes through the wall of the colon. The final stage is metastasis, when the cancer travels through the body.

“This series of changes is thought to occur in most cancers, but there aren’t many cancers where you can get specimens that represent all these stages,” Dr. Vogelstein said.

With colon cancer, pathologists could get tissue by removing polyps and adenomas in colonoscopies and taking cancerous tumors in surgery.

Colon cancer was even more appealing for such a study because there are families with strong inherited predispositions to develop the disease, indicating that they have cancer genes that may be discovered.

So Dr. Vogelstein and his colleagues set out to search for genes “any way we could,” Dr. Vogelstein said. Other labs found genes, too, and by the mid-1990’s, scientists had a rough outline of what was going on.

Although there were scores of mutations and widespread gene deletions and rearrangements, it turned out that the crucial changes that turned a colon cell cancerous involved just five pathways. There were dozens of ways of disabling those pathways, but they were merely multiple means to the same end.

People with inherited predispositions to colon cancer started out with a gene mutation that put their cells on one of those pathways. A few more random mutations and the cells could become cancerous.

The colon cancer story, Dr. Druker said, “is exactly the paradigm we need for every single cancer at every single stage.”

But scientists were stymied. Where should they go from there? How did what happens in colon cancer apply to other cancers? If they had to repeat the colon cancer story every time, discovering genetic alterations in each case, it would take decades to make any progress.

The turning point came only recently, with the advent of new technology. Using microarrays, or gene chips – small slivers of glass or nylon that can be coated with all known human genes – scientists can now discover every gene that is active in a cancer cell and learn what portions of the genes are amplified or deleted.

With another method, called RNA interference, investigators can turn off any gene and see what happens to a cell. And new methods of DNA sequencing make it feasible to start asking what changes have taken place in what gene.

The National Cancer Institute and the National Human Genome Research Institute recently announced a three-year pilot project to map genetic aberrations in cancer cells.

The project, Dr. Druker said, is “the first step to identifying all the Achilles’ heels in cancers.”

Solving the problem of cancer will not be trivial, Dr. Golub said. But, he added, “For the first time, we have the tools needed to attack the problem, and if we as a research community come together to work out the genetic basis of cancer, I think it will forever change how we think about the disease.”

Already, the principles are in place, scientists say. What is left are the specifics: the gene alterations that could be targets for drugs.

“We’re close to being able to put our arms around the whole cancer problem,” said Robert Weinberg, a biology professor at the Massachusetts Institute of Technology and a member of the Whitehead Institute. “We’ve completed the list of all cancer cells needed to create a malignancy,” Dr. Weinberg said. “And I wouldn’t have said that five years ago.”

The list includes roughly 10 pathways that cells use to become cancerous and that involve a variety of crucial genetic alterations. There are genetic changes that end up spurring cell growth and others that result in the jettisoning of genes that normally slow growth. There are changes that allow cells to keep dividing, immortalizing them, and ones that allow cells to live on when they are deranged; ordinarily, a deranged cell kills itself.

Still other changes let cancer cells recruit normal tissue to support and to nourish them. And with some changes, Dr. Weinberg said, cancer cells block the immune system from destroying them.

In metastasis, he added, when cancers spread, the cells activate genes that normally are used only in embryo development, when cells migrate, and in wound healing.

But so many genetic changes give rise to a question: how does a cell acquire them?

In any cell division, there is a one-in-a-million chance that a mutation will accidentally occur, Dr. Weinberg notes. The chance of two mutations is one in a million million and the chance of three is one in a million million million million.

This slow mutation rate results from the fact that healthy cells quickly repair damage to their DNA.

“DNA repair stands as the dike between us and the inundation of mutations,” Dr. Weinberg said.

But one of the first things a cell does when it starts down a road to cancer is to disable repair mechanisms. In fact, BRCA1 and 2, the gene mutations that predispose people to breast and ovarian cancer, as well as some other inherited cancer genes, disable these repair systems.

Once the mutations start, there is “a kind of snowball effect, like a chain reaction,” Dr. Vogelstein said.

With the first mutations, cells multiply, producing clusters of cells with genetic changes. As some randomly acquire additional mutations, they grow even more.

In the end, all those altered genes may end up being the downfall of cancer cells, researchers say.

“Cancer cells have many Achilles’ heels,” Dr. Golub says. “It may take a couple of dozen mutations to cause a cancer, all of which are required for the maintenance and survival of the cancer cell.”

Gleevec, researchers say, was the first test of this idea. The drug knocks out a gene product, abl kinase, that is overly abundant in chronic myelogenous leukemia. The first clinical trial, which began seven years ago, seemed like a long shot.

“The idea that this would lead to therapy was something you wrote in your grant application,” said Dr. Charles Sawyers, a Howard Hughes investigator at the University of California, Los Angeles. “It wasn’t anything you believed would happen soon.”

But the clinical trial of Gleevec, conducted at the Oregon Health & Science University, U.C.L.A. and M. D. Anderson Cancer Center in Houston, was a spectacular success. Patients’ cancer cells were beaten back to such an extent that the old tests to look for them in bone marrow were too insensitive, Dr. Sawyers said.

Gleevec is not perfect. It is expensive, costing about $25,000 a year. It is not a cure: some cancer cells remain lurking, quiescent and ready to spring if the drug is stopped, so patients must take it every day for the rest of their lives. And some patients are now developing resistance to Gleevec.

Still, Dr. Sawyers says, “Seven years later, most of our patients are still doing well.” Without Gleevec, he added, most would be dead.

As for the future of cancer therapy, Dr. Golub and others say that Gleevec offers a taste of the possible.

Dr. Golub said he expected that new drugs would strike the Achilles’ heels of particular cancers. The treatment will not depend on where the cancer started – breast, colon, lung – but rather which pathway is deranged.

“It’s starting to come into focus how one might target the problem,” Dr. Golub said. “Individual cancers are going to fall one by one by targeting the molecular abnormalities that underlie them.”

And some cancer therapies may have to be taken for a lifetime, turning cancer into a chronic disease.

“Seeing cancer become more like what has happened with AIDS would not be shocking,” Dr. Golub says. “Does that mean cure? Not necessarily. We may see patients treated until they die of something else.”

That is what Mr. Weinstein hopes will happen with him. The cancer is still there: new, exquisitely sensitive tests still find a few cells lurking in his bone marrow. And Gleevec has caused side effects. Mr. Weinstein says his fingers and toes sometimes freeze for a few seconds, and sometimes he gets diarrhea.

But, he said, “Certain things you put out of your mind because life is so good.”

December, 2005|Archive|

First approval for Erbitux in head and neck cancer

  • 12/27/2005
  • Switzerland
  • staff
  • PharmaTimes (www.pharmatimes.com)

Merck & Co has been granted approval in Switzerland to expand the uses of its Erbitux (cetuximab) product to include the treatment of patients with head and neck cancer.

The approval by Swissmedic is the first in the world for this indication and means that Erbitux can be used alongside radiotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) which has not yet spread to other parts of the body. The drug is already approved to treat metastatic colorectal cancer.

The market for head and neck cancer treatments is underserved at present, with radiotherapy and older, more toxic chemotherapy drugs the only treatment options available. Analysts at Credit Suisse First Boston said earlier this year that adding the head and neck cancer indication to Erbitux could boost peak sales of the drug into the $1.5 billion dollar range.

In Europe alone, around 100,800 people are diagnosed with head and neck cancer and almost 40,000 die from the disease every year, according to Merck.

The registration is based upon results from a Phase III study which showed that Erbitux combined with radiotherapy improved median survival by 19.7 months compared with radiation alone.

Erbitux was originated by biotechnology firm ImClone Systems and is sold in the USA by Bristol-Myers Squibb. ImClone filed for approval of Erbitux in head and neck cancer in the USA in August, and an application in the European Union is also under review.

December, 2005|Archive|

Introgen Updates Regulatory Guidance for ADVEXIN Therapy of Head and Neck Cancer

  • 12/27/2005
  • Austin, TX
  • press release
  • Chron.com (www.chron.com)

Introgen Therapeutics, Inc. today announced its proposal to the U.S. Food and Drug Administration (FDA) to request permission to accelerate the initiation of an interim analysis of its randomized, controlled phase 3 ADVEXIN clinical trial data ahead of schedule. Introgen plans to begin the safety analysis of its randomized, controlled phase 3 clinical trial investigating ADVEXIN monotherapy for the control of recurrent, squamous cell carcinoma of the head and neck (SCCHN). The analysis of the phase 3 trial data is being initiated before the protocol-specified number of survival events has occurred.

As part of Introgen’s ongoing interactions with the FDA, the company also plans to submit additional information regarding the characteristics of patients most likely to benefit from ADVEXIN therapy based upon the drug’s known molecular mechanisms of action and further analyses of ADVEXIN’s phase 2 clinical trial data in head and neck cancer. Correlating the mechanisms of drug action with disease and patient characteristics facilitates selection of appropriate clinical trial endpoints and defines target patient populations most likely to obtain medical benefit.

Introgen’s senior vice president of Worldwide Commercialization, Dr. Max Talbott stated, “FDA has suggested that Introgen consider performing interim efficacy analyses of the Phase 3 clinical trial data in head and neck cancer. We are developing a plan for these analyses that is consistent with the FDA initiatives to expedite drug approvals based upon the identification of target patient populations most likely to benefit from therapy. We have compiled significant data regarding ADVEXIN’s molecular mechanisms of action, prognostic factors and the disease characteristics that define the patients most likely to benefit from ADVEXIN treatment. We plan to submit this information and the phase 3 interim analyses to the FDA to advance ADVEXIN’s regulatory submissions.”

Information correlating a drug’s mechanisms of action with patients’ disease characteristics complies with the FDA’s Selective Approval and Critical Path Initiative designed to expedite drug approvals by defining the target patient populations most likely to benefit from treatment. The phase 3 clinical study protocol calls for an independent data safety monitoring board (DSMB) to analyze the interim safety data and report its findings to Introgen and the FDA.

Dr. Robert E. Sobol, Introgen’s senior vice president of Medical and Scientific Affairs stated: “We have enrolled adequately for the number of survival events to have occurred. We believe it is appropriate to proceed with the interim analysis to advance ADVEXIN’s regulatory submissions. It is timely to provide FDA with interim data from our Phase 3 clinical studies to complement the Phase 2 data previously submitted to the agency that supports the safety and selective anti-cancer activity of ADVEXIN. Introgen continues to advance the development of selective molecular agents. These agents can control and manage cancer without the significant side effects associated with conventional cancer treatments.”

About ADVEXIN
There are two multi-national, multi-site Phase 3 trials of ADVEXIN therapy, currently underway in recurrent squamous cell cancer of the head and neck. Introgen has received FDA Fast Track designation for ADVEXIN therapy and ADVEXIN has been designated as an Orphan Drug for the treatment of head and neck cancer under the Orphan Drug Act. In December of 2004, Introgen initiated the registration process for ADVEXIN by submitting to the US Food and Drug Administration a Request for a rolling Biologic License Application.
ADVEXIN has been evaluated in a variety of cancer types and in combination with several standard cancer therapies, including radiation and chemotherapy. Data from several published preclinical and clinical studies have demonstrated the ability of ADVEXIN to safely enhance the anti-cancer effects of radiation and chemotherapy treatment.

ADVEXIN supplies p53 protein in very high concentrations in cancer tissue and selectively kills cancer cells. p53, known as the “Guardian of the Genome”, is a normal constituent of cells and is known as a tumor suppressor because it inhibits the growth of tumor cells. One of the major roles of this protein is to eliminate cancerous cells by recognizing when the cell has been damaged by mutations and stopping cell growth to initiate repair. If the cell is damaged beyond repair, p53 initiates the cell death pathway to prevent the cell from growing out of control.

About Introgen
Introgen Therapeutics, Inc. is a biopharmaceutical company focused on the discovery, development and commercialization of targeted molecular therapies for the treatment of cancer and other diseases. Introgen is developing molecular therapeutics, immunotherapies, vaccines and nano-particle tumor suppressor therapies to treat a wide range of cancers using tumor suppressors, cytokines and genes. Introgen maintains integrated research, development, manufacturing, clinical and regulatory departments and operates multiple manufacturing facilities including a commercial scale cGMP manufacturing facility.

December, 2005|Archive|

ImClone Systems Issues Statement Regarding Swissmedic Approval of ERBITUX for the Treatment of Head and Neck Cancer

  • 12/27/2005
  • New York, NY
  • press release
  • BusinessWire.com (home.businesswire.com)

ImClone Systems Incorporated today issued the following statement regarding the approval by Swissmedic, the Swiss agency for therapeutic products, of ERBITUX(R) (Cetuximab), an IgG1 monoclonal antibody, in combination with radiation in the treatment of patients with previously untreated, advanced squamous cell carcinoma of the head and neck:

“This approval gives doctors in Switzerland a first-of-its-kind treatment option in a tumor type that has seen no new modalities of treatment in thirty years. Swissmedic’s decision is further validation of ERBITUX’s role in neutralizing the EGF receptor, an important mediator of a tumor’s survival and a receptor overexpressed in virtually all head and neck cancers. ImClone Systems and Merck KGaA will continue to study ERBITUX in head and neck cancer, including in combination with chemoradiation, and are optimistic about ERBITUX’s future promise.”

Merck KGaA of Darmstadt, Germany, received the approval for ERBITUX from Swissmedic based on a phase III trial (IMCL-9815) that included 424 patients with advanced squamous cell carcinoma of the oropharynx (area of the throat at the back of the mouth), larynx (voice box) or hypopharynx (cavity at the back of the mouth that opens into the esophagus) that had spread through the head and neck region. Patients were randomized to receive radiation plus weekly ERBITUX therapy (n=211) or radiation alone (n=213) for six to seven weeks.

This study and other ERBITUX study data are included in regulatory applications in various countries, including a supplemental Biologics License Application (sBLA) that was recently accepted for filing by the U.S. Food and Drug Administration (FDA). The U.S. application, which also seeks approval for ERBITUX as monotherapy in patients with recurrent and/or metastatic disease where prior platinum-based chemotherapy has failed or where platinum-based therapy would not be appropriate, was granted priority review, a designation given to drugs that potentially offer a significant therapeutic advance over existing therapies for serious or life-threatening diseases.

About Head and Neck Cancer

According to the American Cancer Society, approximately 40,000 Americans will be diagnosed with head and neck cancer this year, including cancers of the tongue, mouth, pharynx, and larynx. In addition, it is estimated that more than 11,000 Americans will die from the disease in 2005. In Europe, approximately 100,000 new cases of head and neck cancer are diagnosed each year, including cancers of the tongue, mouth, pharynx, and larynx, and more than 39,000 deaths occur.

About ERBITUX(R) (Cetuximab)

On February 12, 2004, the FDA approved ERBITUX for use in the United States in combination with irinotecan in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy and for use as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy. The effectiveness of ERBITUX for the treatment of colorectal cancer is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in metastatic colorectal cancer patients.

ERBITUX has already obtained market authorization in 47 countries: Switzerland, the U.S., Mexico, Argentina, Chile, Iceland, Norway, the European Union, Peru, Australia, Croatia, Israel, Bulgaria, Panama, Guatemala, Colombia, Singapore, Hong Kong, South Korea, Canada, Ecuador, Malaysia and the Philippines for the use in combination with irinotecan in patients with EGFR-expressing mCRC who have failed prior irinotecan therapy. In the U.S., Argentina, Chile, Mexico, Peru, Singapore, Australia, Panama, Colombia, Guatemala, Hong Kong, Canada, Ecuador, and the Philippines ERBITUX is also approved for single agent use.

ImClone Systems Incorporated and Bristol-Myers Squibb Company are collaborating on the development of ERBITUX in North America. Merck KGaA is ImClone Systems’ global development and marketing partner for ERBITUX.

ERBITUX binds specifically to epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is also detected in many human cancers including those of the colon and rectum.

Important Safety Information

Severe infusion reactions, rarely fatal and characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension, have occurred in approximately 3% (20/774) of patients with the administration of ERBITUX. Most reactions (90%) were associated with the first infusion of ERBITUX despite the use of prophylactic antihistamines. Severe infusion reactions require immediate and permanent discontinuation of ERBITUX therapy. Caution must be exercised with every ERBITUX infusion as there were patients who experienced their first severe infusion reaction during later infusions. A 1-hour observation period is recommended following the ERBITUX infusion. Longer observation periods may be required in patients who experience infusion reactions.

Severe cases of interstitial lung disease (ILD), which was fatal in one case, occurred in less than 0.5% of 774 patients receiving ERBITUX.

Dermatologic toxicities, including acneform rash (11% of 774 patients, grade 3/4), skin drying and fissuring, inflammatory or infectious sequelae (e.g., blepharitis, cheilitis, cellulitis, cyst) and paronychial inflammation (0.4% of 774 patients, grade 3) were reported. Sun exposure may exacerbate any skin reactions.

Hypomagnesemia has been reported with ERBITUX when administered as a single agent and in combination with multiple different chemotherapeutic regimens. The incidence of hypomagnesemia (both overall and severe (NCI CTC grades 3 & 4)) was increased in patients receiving ERBITUX alone or in combination with chemotherapy as compared to those receiving best supportive care or chemotherapy alone based on ongoing, controlled clinical trials in 244 patients. Approximately one-half of these patients receiving ERBITUX experienced hypomagnesemia and 10-15% experienced severe hypomagnesemia. Electrolyte repletion was necessary in some patients, and in severe cases, intravenous replacement was required. Patients receiving ERBITUX therapy should be periodically monitored for hypomagnesemia, and accompanying hypocalcemia and hypokalemia during, and up to 8 weeks following the completion of, ERBITUX therapy.

Other serious adverse events associated with ERBITUX in clinical trials (n=774) were fever (5%), sepsis (3%), kidney failure (2%), pulmonary embolus (1%), dehydration (5% in patients receiving ERBITUX plus irinotecan, 2% receiving ERBITUX as a single agent) and diarrhea (6% in patients receiving ERBITUX plus irinotecan, 0.2% with ERBITUX as a single agent).

Additional common adverse events seen in patients receiving ERBITUX plus irinotecan (n=354) or ERBITUX as a single agent (n=420) were acneform rash (88%/90%), asthenia/malaise (73%/48%), diarrhea (72%/25%), nausea (55%/29%), abdominal pain (45%/26%), vomiting (41%/25%), fever (34%/27%), constipation (30%/26%) and headache (14%/26%).

Full prescribing information, including boxed WARNING regarding infusion reactions, is available upon request or by visiting www.ERBITUX.com.

About ImClone Systems Incorporated

ImClone Systems Incorporated is committed to advancing oncology care by developing and commercializing a portfolio of targeted biologic treatments designed to address the medical needs of patients with a variety of cancers. The Company’s research and development programs include growth factor blockers and angiogenesis inhibitors. ImClone Systems’ strategy is to become a fully integrated biopharmaceutical company, taking its development programs from the research stage to the market. ImClone Systems’ headquarters and research operations are located in New York City, with additional administration and manufacturing facilities in Branchburg, New Jersey.

December, 2005|Archive|

Tobacco firms use tricks to beat deal

  • 12/26/2005
  • Australia
  • Elizabeth Gosch
  • The Australian (www.theaustralian.news.com.au)

Tobacco companies are side-stepping a recent agreement with the consumer watchdog by replacing the banned words “light” and “mild” with suggestive colours and numbers on cigarette packs.

Anti-smoking groups accused tobacco companies yesterday of using dirty tricks to get around their agreement with the Australian Competition and Consumer Commission to remove the words “light” and “mild” from cigarette packets.

A $9million television, print and radio advertising campaign warning consumers that low-tar cigarettes are not a healthier alternative began yesterday.

The campaign is funded by fines levied on three of the country’s major tobacco companies by the ACCC.

“The television advertisements are very effective. They make it clear that any cigarette pack which is coloured differently or has numbers on it should not create the impression that those cigarettes are less harmful or less toxic,” ACCC chairman Graeme Samuel said.

From March, smokers will get another strong disincentive with graphic images of mouth cancer, gangrene and open heart surgery replacing written warnings on cigarette packs.

The series of 14 colour photos includes images of a stroke-damaged brain, a blind eye and cancerous lungs.

Earlier this year, the ACCC found Philip Morris, British American Tobacco and Imperial had been using misleading advertising.

The companies agreed to remove the “light”, “mild” and related descriptions and numbers from packaging, stop making health representations relating to those terms and contribute $9million in funding for a consumer education campaign.

Action on Smoking and Health Australia chief executive Anne Jones said that while the ads were welcome, the tobacco companies had already broken the agreement.

“The message is a strong one – that is, that all tobacco products are toxic regardless of the colour of the pack, the name or the number,” she said.

“But the tobacco companies are side-stepping the agreement by using replacement terms and pack colouring.

“They have a long history of misleading advertising and will always work in the grey area of the law.”

More than 90 per cent of Australian smokers – about 2.7million people – smoke low-tar brands. But studies show they are more likely to inhale more deeply, hold the smoke for longer and take more puffs.

Quit executive director Todd Harper yesterday renewed the call for generic tobacco packaging and said the colouring of packs was a particular concern.

“Tobacco industry documents themselves state that red packs connote strong flavour, green packs connote coolness or menthol and white packs are suggestive of a low-tar cigarette that is sanitary and safe,” Mr Harper said.

“New words like ‘smooth’, ‘fresh’ and ‘fine’ have already started appearing and together with pack colours and imagery they continue to build on the deception that some cigarettes are safer than others.”

Efforts to contact tobacco companies yesterday were unsuccessful.

Since warnings on cigarette packs were introduced in the early 1990s, and the anti-smoking campaign took hold in the form of smoke-free zones, smoking rates in Australia have dropped 10 per cent.

Last year, 17.4per cent of people aged 14 and over smoked regularly, compared with 19.5per cent in 2001 and 29per cent in the late 80s.

December, 2005|Archive|

Can Most Types Of Cancers Be Prevented?

  • 12/24/2005
  • Houston, TX
  • Renee Twombly
  • Medical News Today (www.medicalnewstoday.com)

It’s a question that has emerged in the past 20 years, given advances in screening and early diagnosis, rapid developments in genetics and molecular biology, and progress in the treatment of early disease and in next-generation targeted therapies.

And finding answers is one of the top goals of The University of Texas M. D. Anderson Cancer Center, which has one of the largest cancer prevention research programs in the world.

M. D. Anderson was among the first to begin dedicated prevention research efforts in the late 1970s. A decade ago, nine faculty were working on 23 projects – a pursuit that was regarded as trend-setting at the time. The cancer center’s focus on prevention has grown so much in recent years that the 48 faculty, involved in 140-plus research projects and clinical programs valued at more than $20 million in 2005 alone, just moved into the new Cancer Prevention Building.

In addition to housing faculty offices, the building’s Cancer Prevention Center and new Behavioral Research and Treatment Center provide advanced early detection and risk-reduction services and state-of-the-art biobehavioral and psychosocial research venues.

These two centers involve only a sliver of the basic and applied research under way. In short, the researchers, physicians, nurses, employees and volunteers that staff this building aim to bring about a future that may some day be free of cancer.

They also are the first to say that attaining this goal will not be easy; that prevention will require developing a wide variety of strategies and associated tactics to curtail the variety of different diseases, all called cancer, that have now emerged as the number one killer of Americans under age 85.

“Prevention is very broad,” says Bernard Levin, M.D., vice president and head of the Division of Cancer Prevention and Population Sciences. “It is not just prevention of cancer development, but includes advances in diagnosis and treatment that reduce suffering and mortality from the disease.”

In short, “prevention,” as oncologists use the term spans the gamut from stopping cancer from ever developing to improving cure rates through earlier detection, thereby preventing recurrence and death. Prevention also encompasses preventing suffering from cancer by controlling pain and meeting psychosocial needs.

Because we see prevention as so inclusive, the task we have set for ourselves is very difficult and won’t likely be accomplished for decades,” Levin says. “But if we can lessen the odds that even one person will develop cancer, or suffer or die from it, we have moved one step closer to our goal. It is that march of progress over time that will make a difference in the future.”

Developing a model of cancer prevention

Debate exists on how many cancer deaths are preventable in principle – estimates range from 50 percent to 80 percent – but most researchers agree that tobacco use (mostly smoking) accounts for the majority. Today, cigarette smoking claims about 438,000 premature deaths in the U.S. annually. It is responsible for up to one-third of all cancer deaths and accounts for 20 percent of annual U.S. mortality due to all causes, according to the federal Centers for Disease Control and Prevention.

And while lung cancer is tobacco’s primary killer, smoking also is responsible for many other types of tumors. Since the same carcinogens that cause lung cancer also affect the lining of the entire respiratory tract and are absorbed by the blood and then excreted as waste, smoking is a major cause in cancers of the oral cavity, pharynx, larynx, esophagus, pancreas, stomach, kidney and bladder, among others. The American Cancer Society states that smoking damages almost every organ in the body.

The cumulative consequence of other lifestyle factors on cancer risk such as obesity, physical activity, diet/nutrition and alcohol use, as well as infectious agents and occupational exposures, is not fully known, although some experts say it may approach that of tobacco use.

Given the certainty that the number one cause of cancer illness and death is also the most preventable, scientists to date have aimed much of cancer prevention science on smoking. “Because tobacco is responsible for an impressive one-third of cancers, prevention efforts naturally begin with it,” Levin says.

But he and colleagues in the Division of Cancer Prevention and Population Sciences have moved beyond solely delivering advice to stop smoking.

They are developing a comprehensive program that not only devises innovative behavioral and pharmacological approaches to smoking prevention and cessation, but burrows down to the molecular level on every aspect related to prevention.

For example, researchers at M. D. Anderson are looking at brain physiology; variations in genes that “favor” smoking and other addictive behaviors; genes that either protect people from developing cancer or put them at greater risk; and genes that either aid or thwart cancer treatment.

The goals of such research, Levin says, are to be able to:
-Predict those people who might be most susceptible to smoking and to help them resist smoking initiation;
-Provide more effective cessation assistance to those who are already smoking;
-Help prevent development of cancer by use of chemoprevention strategies;
-Understand the biological processes that make some smokers more susceptible to different cancers; and
-Offer tailored treatments based on tumor and genetic profiles in each patient to help prevent further disease.

If such a global program can reduce tobacco-related cancers, then the same approach might work for cancers influenced by poor nutrition, lack of exercise and excess body weight, and other such factors, Levin says. Add in prevention screening and it makes sense why Levin says “the future of cancer prevention is an integrated approach.”

Biobehavior in the cancer formula

Two facts about smokers rivet cancer researchers: the notion that not everyone who tries cigarettes becomes addicted, and the knowledge that only a fraction of long-term smokers (about 15 percent) will develop lung cancer, although tobacco also is responsible for one-third of all cardiovascular deaths under age 85.

Innate differences exist between non-smokers and smokers in terms of “biobehavior,” such as a need for nicotine, the way different societal cultures view smoking and how they respond to clinical treatment. Within the division’s three groups – the Department of Health Disparities Research, the Department of Behavioral Science and the Department of Epidemiology – are investigating aspects of these topics, often in collaboration.

Differences also are likely between smokers in their physiological responses – how their bodies vary in susceptibility to the cancer-causing compounds in cigarettes – which implies that agents might be designed that help prevent cancer from developing or treat it more effectively if it does. To explore these topics, other teams of researchers in the Department of Epidemiology and the Department of Clinical Cancer Prevention are working together.

The Department of Behavioral Science is unique in the United States, says its chair clinical psychologist Ellen R. Gritz, Ph.D. “It is a fully established department, with resources and faculty, as opposed to a program, which many cancer centers have.”

This department “focuses on the human side of cancer – the continuum from risk behaviors that cause or contribute to cancer to the psychosocial factors that affect treatment outcome, adjustment and survival,” Gritz says.

“Our goal in smoking-related research is to detect those who are susceptible to nicotine, identify the best ways to prevent these persons from beginning to smoke and, if they do, determine how best to break the nicotine addiction that can result,” Gritz says.

The Department’s longstanding efforts in this field have helped the institution enroll thousands of smokers in numerous smoking cessation studies. Among their notable achievements to date are:

-Development of a “scheduled smoking” approach to quitting, in which a smoker is prompted by a hand-held computer to smoke on a schedule with increasing intervals between prompts;
-Creation of a teen-savvy computerized classroom program (ASPIRE – A Smoking Prevention Interactive Experience) that has resulted in lower rates of smoking in high school; and
-Increased smoking cessation among junior high school students using computerized, personal health status feedback techniques.
Work is ongoing on several dozen other tobacco-related studies. Among them are:

-A randomized, controlled trial in 16 Texas rural and urban communities, which aims to design and test an intervention protocol for training physicians and pharmacists to effectively counsel their patients for smoking cessation;
-A project which tests a motivational intervention protocol for smoking cessation among students at the University of Houston. Individual smoking cessation treatment sessions are combined with internet “cyber-support” available 24/7;
-Research to derive factors that predict onset of smoking in white, Hispanic and African-American youth;
-Multiple studies on the role of depression in smoking behavior and smoking cessation. For example, one involves tracking depression in pregnant smokers, based on earlier findings that depression makes it harder for smokers to quit;
-Research on special populations of smokers, including low income, multi-ethnic HIV-positive persons;
-Research that examines the cognitive processes underlying addiction, such as the physical response in the brain to drugs used to treat nicotine dependence; and
-An investigation of why some cancer patients continue to smoke, and how they can be helped to stop during treatment and throughout survival.

The risk-related and behavioral research methods used to study smoking have been adapted by researchers in the department to look at other preventable cancers, such as skin cancer, melanoma and colon cancer, Gritz says. Among these current projects are studies that develop “interventions” that reduce sun exposure in preschool children, as well as in high-risk melanoma patients and their first degree relatives. Another project is examining the psychosocial aspects of genetic testing and counseling for people with a genetic risk of developing colon cancer.

Prevention also means addressing the psychosocial needs of patients with cancer, with the goal of providing the best opportunities for regaining health. “About 15 percent to 20 percent of patients have emotional or psychological needs that have not been adequately dealt with,” Gritz says. “We have been so focused on disease treatment that those important elements have traditionally been given lower priority.”

In the Behavioral Research and Treatment Center, studies are carried out on tobacco prevention and cessation and a range of other behavioral and psychosocial research topics. These include social interaction, exercise and sleep patterns. Other clinical research projects in Behavioral Science focus on addressing sexuality following various cancers, discussing parenting post-cancer treatment and studying the role of acupuncture, yoga and Chinese medicine in the integrative medical treatment of cancer.

Finally, Gritz plans to tackle ways to prevent cancers associated with obesity. Excess body weight is said to be responsible for about 10 percent of breast and colorectal cancers, and up to 40 percent of kidney, esophageal and endometrial cancers. “Finding ways to thwart the obesity epidemic that is arising in this country will not only help prevent these cancers, but other health issues such as heart disease and diabetes,” she says.

Defining genes of risk and benefit

More than 80 percent of all lung cancer cases occur in people who have smoked cigarettes, but what accounts for the fact that only a small percentage of tobacco users will develop the disease? Why are some people more at risk?

That’s one of the central issues being researched at the Department of Epidemiology, along with its corollary: why do some people with lung cancer fare better with treatment than others?

Now expand these questions into other tobacco-associated cancers such as those that occur in the bladder, kidney and esophagus, and to other non-smoking related cancers such as melanoma, brain, prostate and lymphoma, and that gives you an idea of the mission that Department Chair Margaret Spitz, M.D., has undertaken since 1995. “Although an element of chance is likely to play a role in the complex, multi-step process leading to cancer development, there is mounting evidence that genetic factors also influence susceptibility to cancer-causing exposures,” she says.

Finding those genetic factors that determine risk of developing cancer, as well as those that confer benefit from treatment, is the focus of the 213 employees in the department – the largest in the division.

“The diversity of human beings is remarkable,” Spitz says. “The fact that some smokers develop lung cancer while others don’t suggests that there are differences among smokers in susceptibility to the cancer-causing compounds in cigarettes.

“Individuals respond differently to environmental exposures,” she says. “They process chemicals differently, and they have a wide range of susceptibility to the undesirable side effects of treatments. Such differences could be explained by variation in our genes.”

Humans have a series of overlapping mechanisms to deal with the consequences of harmful environmental exposure, and these molecular pathways are all under genetic control, she says. “In our genes are thousands of small variations that may mean more – or less – production of an enzyme or protein that contribute to our diversity and explain our different risks of developing disease,” Spitz says.

For example, her research has revealed a possible hereditary component to nicotine addiction and an inability to quit, showing some smokers receive more pleasure from nicotine than others because of genetic differences in the brain’s dopamine reward pathway.

Another process under genetic control that could explain susceptibility is DNA repair capacity. These systems help maintain the integrity of genes by continually fixing the damage that occurs to DNA from exposure to harmful chemicals as well as to the daily assault of cosmic X-rays and UV light. If errors in this repair system occur, DNA damage can result in unstable genes and an increased cancer risk.

“Some people just have better DNA repair function than others,” Spitz says. “If we can find out why, it may enable us to identify those at risk for cancer at an earlier age and to tailor intervention therapies for each individual.”

Researchers in the department have studied variations in many DNA repair genes to see how they affect lung cancer risk. In these published studies, they report that patients with a variety of different cancers have significantly poorer capacity to repair DNA damage compared to those who do not develop the cancer.

Specifically:

-One finding demonstrated that individuals who don’t eat enough dietary folate (a vitamin found in some fruits and vegetables), and who had genetic instability, are at much greater risk of developing bladder cancer. Folate is crucial to DNA synthesis and repair, and cigarette smoking (the major cause of the disease) puts this system under stress, the researchers say.

The same genes that are implicated in cancer risk also may be involved in prediction of patient outcome, Spitz says. Among recent discoveries are that:

-Patients with esophageal cancer who had the best treatment outcomes were those that had gene variants that were less effective at neutralizing the killing power of cancer treatments. For example, patients treated with radiation treatment, who inherited less-effective variants of a gene (XRCC1) that repairs DNA damage from radiation, exhibited longer survival.

-People with more efficient DNA repair function who were given chemotherapy, particularly platinum-based drugs like cisplatin, had a lower overall survival rate than those with less efficient DNA repair.

While faulty DNA repair genes may put a person at risk for developing cancer, they also may benefit them when that cancer is being treated, Spitz says. “Such detailed genetic information can help us develop targeted interventions depending upon individual risk, which will promote cancer prevention and earlier detection as well as improve patient treatment and outcome.”

Currently, researchers in the Department of Epidemiology are studying more than 3,000 patients diagnosed with lung, head and neck, bladder, kidney or esophageal cancer. Similar approaches are ongoing for other cancers including melanoma, glioma, lymphoma, and breast and prostate cancer. They ask these patients questions relating to their smoking status, diet, occupation, exposure to chemicals and family history, and then collect urine, blood and tissue cells.

From these samples, they are applying novel molecular “assays,” or tests that gauge the biological importance of various genes or proteins.

Among the molecules being investigated in these assays are:

-Nicotine addiction genes;
-Gene variants involved in metabolism of chemicals, hormones and folic acid;
-DNA repair genes;
-Agents that push cells to mutate, or change;
-Length of telomeres (protein caps that stabilize chromosomes);
-Genes that control the cell cycle;
-Genes involved in inflammation;
-Methylation (addition of methyl groups that destroy gene function); and
-Genes that control a cell’s “microenvironment.”

The combined findings eventually will provide a molecular road map to risk of cancer development as well as optimal cancer treatment. If oncologists knew who would be most susceptible to cancer development, it may be possible to use agents or behavior modifications as preventatives. If cancer does develop, oncologists may be able to tailor treatment to an individual’s own genetic profile.

The department also has launched the first long-term effort to study health outcomes and risk factors in the Mexican-American population in the Houston metropolitan area, research paid for by philanthropy and tobacco industry settlement funds. Over many years, the study aims to enroll more than 100,000 Mexican-Americans in Texas, and to date more than 10,000 have joined. The study will follow the residents and collect biological samples to relate mortality and disease incidence to genetic, environmental and occupational exposures, diet, other lifestyle factors and health behaviors. A smaller five-year investigation, funded for $2.9 million by the National Cancer Institute, will specifically look at patterns of smoking experimentation and initiation in Mexican-American adolescents – why they begin smoking, how addiction sets in, what may help prevent their smoking and how to help these young smokers quit.

“We may one day be able to answer the ‘why me’ question – ‘why did I get cancer’ – or perhaps we might be able to prevent cancer from occurring at all,” Spitz says. “It won’t happen overnight, or even in my lifetime, but we’re definitely moving in the right direction.”

A daily dose of prevention

Will the patient of tomorrow be given a cocktail of daily drugs that will help prevent or reduce the chance of cancer developing?

This cocktail might include refined forms of anti-inflammatory drugs to prevent colon cancer, trace minerals to protect against prostate cancer, or proven versions of ancient remedies, such as turmeric spice for breast cancer and cups of green tea daily to repress oral cancer.

M. D. Anderson is devoted to finding preemptive strikes – ways to block cancer from ever starting or from becoming clinically apparent. These efforts are being spearheaded by Scott Lippman, M. D., chair of the Division’s Department of Clinical Cancer Prevention, Levin and other researchers campus-wide.

M. D. Anderson was among the first to look for agents that may help prevent cancer – some three decades ago, beginning with the innovative work of Waun Ki Hong, M.D. – and now is seen as a national leader in the field of chemoprevention, Levin says.

Four of five classes of chemopreventive agents the National Cancer Institute has said are promising and are “considered priority substances for study” are being investigated here. Some of the efforts involve national trials being led by M. D. Anderson researchers. Those compounds are retinoids, nonsteroidal anti-inflammatory drugs (NSAIDs), calcium compounds and selective estrogen receptor modulators (SERMs).

The research represents a completely new way of thinking about cancer, says Hong, head of the Division of Cancer Medicine at M. D. Anderson and a pioneer in the field. “Cancer doesn’t begin with the appearance of a tumor, just as cardiac disease doesn’t start with a heart attack,” he says. “And just as we can control the risk of a heart attack with medication, we want to control the process of cancer development with drugs and supplements.”

Hong launched the first chemoprevention clinical trial of its kind when he and a team of researchers demonstrated that smoking impaired the ability of vitamin A and its chemical cousin, retinoids, to keep cells healthy. In the early 1990s, they demonstrated that daily doses of retinoids could stop precancerous growths in the mouth and oral cavity from turning into cancer. They proved, for the first time, that cancer could be reversed. That work has led to examining other formulas of retinoic acids and other, unrelated agents.

Current strategies of “chemoprevention” – the use of natural or synthetic substances to reduce the risk of developing cancer – are less geared toward preventing all cancer than toward preventing specific major cancers, Lippman says.

“Great clinical strides have been made in breast, colorectal and prostate cancer prevention,” Lippman says. For example, he says that tamoxifen (Nolvadex®) reduced breast cancer risk by 50 percent in the Breast Cancer Prevention Trial, and finasteride (Propecia®, Proscar®) reduced prostate cancer risk by 25 percent in the Prostate Cancer Prevention Trial.

But men and women haven’t flocked to get prescriptions for either agent because, as Lippman points out, these two large-scale trials indicated that some serious side effects came along with preventive benefits. “This stand-off between agent risks and benefits has raised a major focus of cancer prevention – tailoring interventions to specific groups of people.

“Efforts to identify people at a very high cancer risk and likely to benefit from and not be harmed by particular agents will be crucial to the future of cancer prevention,” Lippman says. He leads an effort at M. D. Anderson and several other cancer centers to understand prostate cancer risk and how finasteride changed this risk in the Prostate Cancer Prevention Trial.

Other chemopreventive agents have proven to be effective. M. D. Anderson researchers have found that:

-A low-dose baby aspirin proved effective as a modest colon cancer chemopreventive. A randomized clinical trial of more than 1,000 participants found it reduced the number of precancerous polyps by 19 percent. Robert Bresalier, M.D., chair of the Department of Gastrointestinal Medicine and Nutrition, helped lead this national effort.

-Celecoxib, a non-steroidal anti-inflammatory drug (NSAID) known by the trade name Celebrex®, reduced the number of colon polyps in people who have familial adenomatous polyposis (FAP), in which hundreds of precancerous polyps form in the colon and rectum. The study, led by researchers at M. D. Anderson and St. Mark’s Hospital, London, in collaboration with the National Cancer Institute, led to federal approval of Celebrex for FAP patients.

-Supplements of selenium and vitamin E unexpectedly reduced the incidence of prostate cancer by up to two-thirds in trials testing them for different cancers. These observations led to the ongoing international Selenium and Vitamin E Cancer Prevention Trial (SELECT) in more than 32,000 patients. M. D. Anderson leaders of SELECT include Lippman and Elise D. Cook, M.D., who led the national effort to recruit minority men, especially African-Americans, who have the highest risk of prostate cancer in the world. Cook’s successful campaign resulted in the highest percentage of African-Americans ever recruited to a large-scale cancer prevention trial.

-The spice curcumin (found in turmeric and curry powders) has shown dramatic results in preventing cancer in animal studies, and has led to clinical studies at M. D. Anderson with patients that have pancreatic cancer or multiple myeloma. A trial with breast cancer patients is expected to begin in 2005. Patients in these trials take curcumin capsules daily.

A number of ongoing chemoprevention trials at M. D. Anderson are focusing on reducing chronic inflammation, which has lately been associated with cancer development. An agent of current interest in these investigations is Celebrex, given its proven ability to prevent inherited colon cancer. Celebrex works by blocking cycloxygenase-2, or “COX-2,” an enzyme that is over-produced when cells become inflamed. Studies have shown, however, that many tumors, including those for small-cell lung cancer, also contain a lot of COX-2, possibly because of the body’s natural immune reaction to the cancer.

The precise way Celebrex, or any preventive agent, works is never simple, however. Novel laboratory studies of Imad Shureiqi, M.D., at M. D. Anderson show that 15-lipoxygenase-1 and related signaling pathways are at least as important as COX-2 to the workings of Celebrex and other NSAIDs. “M. D. Anderson is a world leader in research to better understand agent mechanisms,” Lippman says. “And this research will hasten the arrival of safe and effective preventive drugs into the hands of the people who need them.”

Some of M. D. Anderson’s studies with Celebrex were halted after news that the agent’s sister drug, Vioxx®, was associated with an increase in cardiovascular problems. Later, a slightly increased risk of cardiovascular disease was also found in one of the polyp prevention trials using Celebrex. Another multi-center international trial of Celebrex was also halted; this one evaluated the role of the agent in preventing recurrence of precancerous colon polyps and Levin is co-principal investigator.

After consultation with the National Cancer Institute, the following M. D. Anderson studies investigating use of Celebrex as a chemopreventive have been re-opened:

-An international trial in FAP looking at use of Celebrex combined with eflornithine (DFMO), a drug used to treat African sleeping sickness, but which is suspected of having anti-cancer properties. This study is led by Patrick Lynch, M.D., in the Department of Gastrointestinal Medicine and Nutrition.

-A clinical trial testing whether Celebrex can repair precancerous lung damage in current and former smokers. Jonathan Kurie, M.D., in the Department of Thoracic/Head and Neck Medical Oncology, is the principal investigator.

=An international trial testing use of Celebrex in children who are carriers of the mutated FAP gene, and who have little or no evidence yet of polyps.

Hong’s work also has led to a major international program of M. D. Anderson in collaboration with Nordic investigators to prevent oral cancer with two molecular-targeted drugs (Celebrex and erlotinib, also known as Tarceva®) in people at extremely high risk of coming down with and dying from this disease. A molecular marker, aneuploidy (an abnormal amount of chromosomes in a cell), signals the risk of these people, “highlighting how important accurate risk detection is for effective chemoprevention,” Lippman says.

As promising as some of the research has been, none of M. D. Anderson’s chemoprevention experts, including Lippman and Levin, suggest that people take a little Celebrex here, a dose of aspirin there, or swallow tablets of curcumin with a dash of vitamin E as a way to “self medicate” against cancer.

They all stress most chemoprevention studies now test people who are at higher risk of developing cancer, such as former smokers, as a way to predict whether they will help those who are not at risk. It will take decades, they say, to prove that any substance can substantially reduce the risk of a disease in the average person without producing side effects. These studies will require giving young and healthy volunteers a drug for many years and then waiting until they have aged to see whether volunteers who used the agent developed fewer diseases compared to those who didn’t. “First, we must do no harm,” Lippman says.

Levin emphasizes that chemoprevention must not be substituted for other important lifestyle habits such as avoiding tobacco, eating a nutritious diet, exercising and managing body weight: “If you do these things and make sure you are adequately screened, you may be able to reduce your odds of developing cancer by 50 percent – and that is a conservative estimate,” he says.

“While we should be modest in claiming our work will lead to new chemoprevention advances in the coming years, we have promising leads from the laboratory that will enable us to conduct even better and more informative trials in the future,” Levin says.

Offering cancer prevention to all

Preventing cancer with a pill is a nice idea that will likely take years to achieve, but there is much that can be done now to help many Americans, says David Wetter, Ph.D., chair of the fourth “arm” of the prevention division, the Department of Health Disparities Research.

Wetter is referring to the fact that “underserved” populations in the United States shoulder a disproportionate burden of cancer, and the researchers he leads are finding ways to reduce those inequities.

Wetter’s new department, up and running only since April, builds on the pioneering work of the Center for Research on Minority Health, and reflects M. D. Anderson’s dedication to addressing cancer in those who are disadvantaged. It is the only department of its kind in the country and the current staff of three faculty members is expected to triple within four years.

Underserved populations today bear an unequal burden of cancer, with higher rates of incidence, severity and death, says Wetter, who has long researched smoking behavior in underserved and minority populations, as well the effects of gender on the ability to break the habit. Wetter has spent much of his career investigating new treatment approaches for smoking cessation, including palm top computer-delivered treatments, innovative telephone and face-to-face therapies, and meditation.

An example of such disparity is the fact that African-Americans have much higher rates of prostate cancer and Hispanic women have a greater incidence of cervical cancer, compared to other ethnic/racial groups. While biological differences may explain some of this increased burden, most is due to social inequities, such as lack of cancer screening and access to primary care, increased poverty and lower educational levels.

“We know that poor neighborhoods often do not have grocery stores with fresh vegetables and fruit, but only convenience stores that primarily sell snack food, cigarettes and alcohol,” Wetter says. “There are often no sidewalks, so it is not safe to walk. These factors set up conditions that promote the development of cancer and other diseases.

“This is just a simple illustration of the pervasive problems that exist, and it is critical that we address health disparities in all its forms, from the molecular to the societal,” he says.

Examples of the kind of work that is already under way within the department are:

-The African-American Nutrition for Life Project, or “A NU-LIFE,” designed to address the fact that breast cancer occurs more frequently in African-American women who have not experienced menopause than women of any other racial ethnic population. This four-year, $1.8 million study is following 200 Houston-area African-American women between the ages of 25 and 45 to determine if a low-fat, high-fiber diet affects breast cancer risk. According to Lovell Jones, Ph.D., principal investigator of the study and director of M. D. Anderson’s Center for Research on Minority Health, the study will determine how levels of total body fat, dietary fat and fiber intake, circulating triglycerides and free fatty acids impact estrogen levels. Previous studies have shown that a high-fiber, low-fat diet can reduce estrogen levels in women and that women with lower estrogen levels have a lower risk of breast cancer.

-A research center focused on how environmental contaminants affect health and cancer risk. The largest study in this project, known as “EXPORT,” examines biomarkers of genetic susceptibility to pesticide exposure in Mexican-American migrant and seasonal farm workers women and their children. Another aspect of the center is to look at the town of Fresno, Texas, and its almost 7,000 residents, of which 50 percent are Latino and 27 percent African-American. Fresno is located near two Superfund clean-up sites and a landfill, so researchers will try to determine the effect of environmental exposure on the health of these residents.

-A low cost intervention that uses a palm top computer to help smokers in the African-American community resist the urge to use cigarettes. The tiny computer delivers messages, personalized to the individual, to bolster the motivation to quit in the face of “real world stressors,” according to Wetter, who leads the study. While the impact of socioeconomic disparities on cancer risk has long been recognized, the conditions are only getting worse, Wetter says. The underserved population is growing nationwide, and is especially prevalent in Texas and some other states, says Wetter. The Hispanic population is expected to become the largest ethnic group in the state soon, and this group is often not insured, he says. “Lack of insurance is a tremendous risk factor for cancer development because there is a lack of access to primary prevention, screening and care.”

Research can parse out factors that may lead to improved population health, according to Wetter. “It must have a real world impact and will likely have policy implications and be community based,” he says. “It is critical that we create an environment in which differences in health due to race, ethnicity, socioeconomic status, gender and other factors cease to exist.”

December, 2005|Archive|

Sabinsa’s Curcumin C3 Complex Ingredient Preferred by M.D. Anderson Cancer Center

  • 12/22/2005
  • Piscataway, NJ
  • press release
  • NPI Center (www.npicenter.com)

Sabinsa Corporation’s Curcumin C3 Complex(R) was named as the curcumin ingredient of choice by M.D. Anderson Cancer Center at the University of Texas. M.D. Anderson Cancer Center is currently conducting numerous studies to determine the effects of curcumin, an extract of turmeric root, in fighting against several types of cancers.

“Although there are numerous companies that supply curcumin, consumers need to be careful that they are buying the genuine product, which is why we recommend Sabinsa Corporation,” stated Dr. Bharat Aggarwal, professor of cancer research, M.D. Anderson Cancer Center. “A ‘supercurcumin’ is also available from Sabinsa that contains Bioperine(R), a standardized pepper extract, which enhances curcumin’s effectiveness.”

According to researchers at M.D. Anderson Cancer Center, curcumin blocks a key biological pathway needed for development of melanoma and other cancers. Curcumin shuts down nuclear factor-kappa B (NF-kB), a powerful master switch known to regulate expression of more than 300 genes that promote an abnormal inflammatory response that leads to a variety of disorders, including arthritis and cancer.

“We strive to provide safe and effective standardized ingredients of the highest quality to our customers around the world. It is gratifying to see the growing interest in research involving our patented Curcumin C3 Complex,” stated Todd Norton, president, Sabinsa Corporation.

Curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin are collectively known as curcuminoids, and are recognized as one of the most promising food derived compounds in fighting cancer. Sabinsa Corporation provides an extract of turmeric standardized to 95 percent curcuminoids, Curcumin C3 Complex(R). Over the past several years, numerous studies have been funded by the National Institutes of Health to investigate the role of curcumin and its derivatives in treatment of patients with cancer.
Additionally, M.D. Anderson Cancer Center is involved in pre-clinical and clinical research of the anti-cancer mechanism and application of curcuminoids in conditions including lung, breast, multiple myeloma, pancreatic, myelodysplatic syndrome, colon, prostate and head and neck cancers. For more information visit www.curcuminoids.com.

Sabinsa Corporation, founded in 1988, is a manufacturer and supplier of herbal extracts, cosmeceuticals, minerals and specialty fine chemicals. Sabinsa’s mission is to provide alternative and complementary natural products for human nutrition and well-being. Over the past nine years, Sabinsa has brought to market more than 50 standardized botanical extracts and privately funded several clinical studies in conjunction with prestigious institutions in support of these products. With more than 100 scientists working full time conducting ongoing research both in India and the United States, Sabinsa continues to develop and patent phytonutrients for the world market.

December, 2005|Archive|

Sentinel lymph node biopsy in oral cancer: validation of technique and clinical implications of added oblique planar lymphoscintigraphy and/or tomography

  • 12/20/2005
  • Denmark
  • JB Thomsen et al.
  • Acta Radiol, October 1, 2005; 46(6): 569-75

Purpose:
To validate lymphatic mapping combined with sentinel lymph node biopsy as a staging procedure, and to evaluate the possible clinical implications of added oblique lymphoscintigraphy and/or tomography and test the intra- and interobserver reproducibility of lymphoscintigraphy.

Material and Methods:
Forty patients (17 F and 23 M, aged 32-90) with 24 T1 and 16 T2 squamous cell carcinoma of the oral cavity. Planar lymphoscintigraphy, emission and transmission tomography were performed. Detection and excision of the sentinel nodes were guided by a gamma probe. The sentinel nodes were step-sectioning and stained with hematoxylin and eosin and cytokeratin (CK 1). Histology and follow-up were used as “gold standard”. Tumor location, number of sentinel lymph nodes, metastasis, and recurrences were registered. Two observers evaluated the lymphoscintigraphic images to assess the inter-rater agreement.

Results:
Eleven (28%) patients were upstaged. The sentinel lymph node identification rate was 97.5%. Sentinel lymph node biopsy significantly differentiated between patients with or without lymph node metastasis (P = 0.001). Lymphatic mapping revealed 124 hotspots and 144 hot lymph nodes were removed by sentinel lymph node biopsy. Three patients developed a lymph node recurrence close to the primary tumor site during follow-up. Added oblique lymphoscintigraphic images and/or tomography revealed extra hotspots in 15/40 (38%) patients. In 4/40 (10%), extra contralateral hotspots were detected.

Conclusion:
Sentinel lymph node biopsy upstaged 28% of the patients. Sentinel lymph nodes close to the primary tumor were difficult to find. Added oblique planar images and/or tomographic images revealed extra clinical relevant hotspots in 38% of patients. Reproducibility proved excellent.

Authors:
JB Thomsen, JA Sorensen, P Grupe, and A Krogdahl

Authors’ affiliations:
Department of Plastic and Reconstructive Surgery, Department of Nuclear Medicine, Department of Pathology, Odense University Hospital, Denmark.

December, 2005|Archive|

Imaging in head and neck cancer

  • 12/20/2005
  • Charleston, SC
  • Z. Rumboldt et al.
  • Curr Treat Options Oncol, January 1, 2006; 7(1): 23-34

The goals of imaging in head and neck cancer are to establish tumor extent and size, to assess nodal disease, to evaluate for perineural tumor spread, and to distinguish recurrent tumor from post-treatment changes.

MRI is the preferred modality for assessment of nasopharyngeal, sinonasal, and parotid tumors, because of better contrast resolution, high frequency of perineural spread, and less prominent motion artifacts. MRI is the best modality to delineate the extent of intraorbital and intracranial extension of malignant tumors. Tumors of the oropharynx, larynx, and hypopharynx are frequently primarily imaged with CT, which is less affected by breathing and swallowing artifacts.

MRI is also the initial study of choice for tumors confined to the oral tongue, and possibly also for other oral cavity locations because MRI is superior in detection of tumor spread into the bone marrow. There is no clear advantage of CT or MRI for evaluation of nodal disease.

Positron emission tomography (PET) is very sensitive for metastatic lymph nodes that are at least 8 mm in size and is the technique of choice in dubious cases. Imaging-guided biopsies are performed whenever needed. For imaging of treated head and neck cancer, PET scans have been found to generally offer higher sensitivity than MRI or CT.

Combined PET/CT may be the modality of choice because it almost completely eliminates the false-positive and false-negative PET findings. Patients with head and neck cancer who are referred to tertiary care centers commonly arrive with cross-sectional images obtained at other institutions. Reinterpretation of these studies by dedicated radiologists frequently leads to changes in findings, which alter treatment and affect prognosis.

Authors:
Z Rumboldt, L Gordon, L Gordon, R Bonsall, R Bonsall, S Ackermann, and S Ackermann

Authors affiliations:
Medical University of South Carolina, Department of Radiology, 169 Ashley Avenue, PO Box 250322, Charleston, SC 29425, USA

December, 2005|Archive|