• 11/16/2005
  • Philadelphia, PA
  • press release
  • EurekAlert (www.eurekalert.org)

A second look at compounds and drugs, some previously used to treat illness and conditions ranging from malaria to contraception, is giving new life to several abandoned therapies and new applications for existing drugs.

From drugs such as the cottonseed extract gossypol, once tested as a male contraceptive in China, to arsenic, which can be made less toxic in an organic form, new applications are being investigated for effectiveness against solid tumors of various types.

A press briefing features at the “Molecular Targets and Cancer Therapeutics” International Conference here is spotlighting a few of these compounds and drugs that are undergoing recycling as possible cancer treatments.

These include:

Thalidomide, a notorious drug once linked to birth defects that is undergoing patient testing in combination with a growth factor against prostate cancer.

A drug developed as an insecticide now helping scientists to understand the microtubule assembly process that is important for pancreatic cancer cell growth.

Gossypol, once touted as a potential male contraceptive, may find a new use — helping certain head and neck cancers overcome their resistance to cisplatin.

An organic form of arsenic that is showing some potential as a treatment for solid tumors.

Drugs currently used around the globe to treat people infected with malaria may address a critical cell nutrition issue with proliferating cancer cells.

Overcoming Cisplatin Resistance in Head and Neck Cancer by Targeting Bcl-xL Using a Novel Small Molecule (Abstract 3256)

In nature, cotton seed produces two forms of gossypol – a ‘left handed’ and a ‘right handed’ form of the molecule.

Cancer researchers from the University of Michigan have discovered that gossypol made as a left handed isomer – and only the left handed form – inhibits head and neck squamous cell carcinoma (HNSCC) cell growth that has become resistant to cisplatin, a front line chemotherapeutic drug. That active anti-tumor cottonseed polyphenol is designated (-)-gossypol.

“(-)-Gossypol restores the activity of cisplatin in HNSCC cells that have become resistant to chemotherapy,” said Joshua Bauer, a graduate student in pharmacology at the University of Michigan Comprehensive Cancer Center.

“Outright resistance to cisplatin in HNSCC patients develops in about a third of head and neck tumors,” Bauer said. HNSCC cells that become cisplatin-resistant often overexpress copious amounts of a molecule called Bcl-xL, which in some capacity interferes with the ability of cisplatin to bind to tumor cell DNA, thwart repair mechanism activity, and induce cell death. Bcl-xL enables HNSCC cells to survive when they should die.

Bauer and his colleagues postulate that (-)-gossypol binds to Bcl-xL at a site that inactivates the cancer promoting protein.

Furthermore, “the timing and sequence of treatment with the chemotherapeutic drug combination of (-)-gossypol and cisplatin is critical in reaching maximum synergistic response in HNSCC tumors that are cisplatin resistant,” said Bauer.

In HNSCC cell lines resistant to cisplatin, treatment first with cisplatin, and then with (-)-gossypol resulted in a synergistic cell death rate of approximately 70 percent. Treatment with cisplatin alone resulted in only 5-7 percent cell death; treatment with (-)-gossypol yielded 30-40 percent cell death. A similar pattern of response to the drug combination was also observed in cell lines engineered to produce high levels of Bcl-xL.

Cells that were not resistant to cisplatin were additively responsive to the chemo combination. While cisplatin alone caused 70 percent cell death among non-resistant HNSCC cells, and (-)-gossypol induced 25 percent cell death when applied alone, the combination administered sequentially resulted in approximately 90 percent cell death regardless of which drug was introduced first.

Head and neck cancer is the sixth most common cancer world wide and in the United States there are approximately 40,000 new cases diagnosed annually and 10,000 people die annually of this disease. Head and neck cancer is endemic in India, so worldwide it is a major cause of cancer incidence and mortality.

“This is a disease that is very debilitating since it affects structures of the body that are visible, necessary for communications, and for eating, drinking, and breathing.” Bauer said. “Most tumors present at an advanced stage and thus the survival rate is poor.”

A Novel Organic Arsenic Molecule: ZIO-101 (S-dimethylarsin-gluthathione): Molecular Biology and Results of a Phase-1 Study