Colorectal cancer has proven refractory to most chemotherapeutic agents; the best available therapy is 5-fluorouracil (5-FU) modulated with leucovorin. A composite analysis of nine randomized trials indicates that the addition of leucovorin to 5-FU approximately doubles the response rate from 13% to 25%. The majority of responses are partial and not durable. Thus, although biochemical modulation of 5-FU with leucovorin has met with some success, innovative strategies are crucially needed to improve the prognosis of patients with colorectal cancer. Our current investigations focus on two areas. The first is the identification of new agents with potential activity against adenocarcinomas of the gastrointestinal tract. Of particular interest are new drugs which display potent in vitro activity (IC50 for a 24 hour exposure equal to or less than 10 micromoles) and/or in vivo efficacy against human colorectal carcinoma cell lines. Studies designed to elucidate the optimal schedule of administration and mechanism of action of such agents are vital to facilitate their rational clinical use. The second line of investigation includes the interaction of other agents with 5-FU in an attempt to define optimal doses and sequences of drug combinations for potential clinical use. Finally, we are implementing Phase I clinical trials which incorporate biochemical or molecular endpoints in addition to clinical endpoints as a reflection of the biologic activity of the particular agent. The ultimate goal is to develop new agents and drug combinations which may be useful in the treatment of patients with gastrointestinal and breast malignancies.
