THYMIDYLATE SYNTHASE QUANTITATION IN HUMAN COLON CANCER

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Tumors of the large bowel will affect approximately one in twenty persons in the United States. In 1992, approximately 60,000 patients in the U.S. will die of disseminated large bowel cancer. 5-Fluorouracil (5-FU), the most active and widely used systemic agent against colorectal cancer, forms the basis of almost all systemic therapy for this disease. The best understood mechanism of 5-FU action is its ability to block the incorporation of thymidine into DNA by inhibition of the enzyme thymidylate synthase (TS). Quantitations of intratumoral TS by protein assays have suggested a consistent inverse relationship between the intratumoral amount of this enzyme and the likelihood of tumor response to 5-FU. Recently, adaptation of PCR technology has provided an ultra-sensitive method for quantitatively measuring the genetic expression of TS using as little as 10 mg of human tumor tissue. Preliminary data obtained with this technology confirms the inverse relationship mentioned above. By incorporating the data management and statistical resources of the Southwest Oncology Group, this project will employ PCR technology to ascertain the genetic expression of TS in disseminated large bowel tumors, as well as in those tumors which have been resected for cure. Prospective measurements of TS expression in disseminated large bowel cancer will be utilized to confirm that the level of TS expression predicts response and/or resistance to 5-FU. Upon noting clinical resistance (progression) for those patients initially exhibiting a clinical response, tumors will be biopsied again to assess for a change in TS expression. It is anticipated that TS expression, as determined by PCR technology, will define a "marker" of innate and acquired resistance to 5-FU in patients with large bowel cancer. Intratumoral TS expression could then be used to determine whether a patient with disseminated large bowel cancer should receive 5-FU or an experimental agent as first line treatment. Through measurement of TS expression within normal mucosa, primary tumor and lymph nodes (with and without tumor), the range of genetic variability among tissues from the same patient will be ascertained and correlated with the natural history of these tumors. By comparing the quantitation of TS expression with recurrence and survival for patients registered on Southwest Oncology Group postoperative large bowel cancer trials, its role as an independent prognostic variable will be determined.