• 5/10/2003
  • New York
  • Karla Gale
  • Reuters Health News

British researchers report that positron emission tomography (PET) can measure levels of thymidine in tumors, an indicator of patient response to chemotherapy with agents that inhibit thymidylate synthase.

Their findings, published in the May 7th issue of the Journal of the National Cancer Institute, show that PET can be used broadly to “track cancer treatment efficacy without the need for repeated tissue biopsies,” coauthor Dr. Pat M. Price told Reuters Health. Not only will individual treatment assessment permit early recognition of treatment failure, such strategies should accelerate the rate at which clinical trials can be completed, she added.

Thymidylate synthase inhibitors such as 5-fluorouracil, 5-fluorodeoxyuridine and nolatrexed dihydrochloride (AG337; Agouron Pharmaceuticals, San Diego) target a key enzyme in the biosynthetic pathway of thymidine nucleotides used in the synthesis of DNA, Dr. Price and colleagues explain. Resistance to these agents involves a salvage pathway by which depleted thymidine levels are reversed by increasing exogenous thymidine uptake, which makes thymidine a valuable marker of tumor proliferation. Plasma levels of deoxyuridine, which increase following thymidylate synthase inhibition, do not reflect thymidylate synthase inhibition in specific tissues.

Dr. Price, of Christie Hospital NHS Trust in Manchester, UK, and her associates set out to evaluate PET scanning with radiolabeled thymidine as a means of measuring tumor thymidine incorporation, an indicator of thymidylate synthase inhibition. They conducted PET scanning in patients with advanced gastrointestinal cancer. Five patients enrolled in a phase I trial of AG337 were scanned 4 days before beginning treatment and then 1 hour after taking an oral dose. Radiolabeled thymidine was administered intravenously beginning 30 seconds after the start of PET scanning. Seven control patients were similarly evaluated.

The researchers observed an increase in tumor fractional retention of thymidine of 38% in the treated patients and a 3% increase in control patients, a significant difference (p = 0.028). Values for normal liver tissue did not differ significantly between groups. They also observed a strong correlation between tumor fractional retention of thymidine and plasma levels of deoxyuridine (p = 0.028).

Dr. Price told Reuters Health that PET technology has the potential for broad applicability apart from thymidylate synthase inhibitors and gastric cancers. Her group’s findings provide proof of principle that “this noninvasive strategy can also be used to evaluate cell apoptosis and drug transport, in addition to antiproliferative effects.”

“Now that the human genome is being mapped, we know far more about the specific molecules,” she added. “The challenge now is to know what happens when they are used to treat disease.”

J Natl Cancer Inst 2003;95:675-682.