THYMIDYLATE SYNTHASE EXPRESSION IN COLORECTAL CANCER

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This project focuses on the application of the monoclonal antibody (TS 106) to human thymidylate synthetase (TS) for the detection and quantitation of TS in patent samples. Preliminary investigations using samples of tissue from patients with rectal cancer enrolled on a NSABP adjuvant clinical trial suggest that TS expression is predictive for both disease-free and overall survival. There are limited data which suggest that TS protein and gene expression are highly correlated and predict for response to 5-FU plus leucovorin based chemotherapy in patients with metastatic colorectal cancer. Using immunological techniques, our aim is to support a study team with the Eastern Cooperative Oncology Group (ECOG) to define the clinical significance of the level of TS expression as a predictor of survival and response to fluoropyrimidine containing regimens in patients with colorectal cancer. This antibody also provides the means for quantitating the regulation of TS expression in response to drugs such as 5-fluorouracil, leucovorin and levamisole. The proposal contains the following two specific aims: 1. Determine the clinical relevance of thymidylate synthase expression as a means for prognosticating survival in patients with colorectal cancer. We will assess thymidylate synthase expression by immunohistochemical technique using sections of formalin-fixed paraffin-embedded colon carcinoma tissue obtained from patients entered on ECOG protocol EST 2284 (INT 0035, a Phase Ill evaluation of levamisole alone or levamisole plus 5-FU as surgical adjuvant treatment for resected colon cancer), and EST 2288 (INT 0089, a Phase Ill trial of low-dose leucovorin plus 5-FU, high-dose leucovorin plus 5-FU, levamisole plus 5-FU or low-dose leucovorin plus 5- FU plus levamisole following curative resection of colon cancer). 2. Determine the clinical relevance of thymidylate synthase expression as a means for determining responsiveness to fluoropyrimidine-based regimens. We will assess thymidylate synthase expression using sections of formalin- fixed paraffin-embedded colorectal carcinoma tissue specimens obtained from patients who have entered ECOG protocol EST 2290 (a Phase Ill evaluation of 5-Fu vs 5-FU plus PALA or 5-FU plus oral leucovorin or 5-FU plus IV leucovorin or 5-FU plus interferon alpha in patients with advanced colorectal cancer).