Rational basis for the metabolic modulation of 5-fluorouracil by leucovorin and interferon alpha

Although 5-fluorouracil (FUra) has been the drug of choice for the treatment of patients with advanced colorectal carcinoma, the response rates are in the range of 15% and the median survival times do not exceed 9 months. Interferon alpha (IFN alpha) has limited antitumour activity in this disease. Recent clinical trials have demonstrated that both the response rate and the survival time of patients with advanced colorectal cancer can be significantly improved by the addition of leucovorin (CF) to FUra. In a randomized phase III trial, the median response to FUra and CF was about 30% with a range of 20-55%, dependent on the dose and schedule of administration of CF. Due to multiplicity of mechanisms of action postulated for IFN alpha, the role of IFN alpha in the modulation of the cytotoxicity and therapeutic efficacy of FUra alone and in combination with CF has been evaluated in patients with advanced colorectal cancer and also in a variety of human cell lines in culture, including human colorectal cell lines, HCT-8, human bladder cell line RT-4 and leukaemia CEM cells. The results obtained in patients demonstrated that indeed the antitumour activity of FUra can be improved by the addition of IFN alpha with a response range from 26% to 76%. The initial clinical use of this combination, however, has been limited in some cases by the severe host toxicity. In vitro results demonstrated that: (1) in vitro cytotoxicity potentiation by IFN alpha is cell-type dependent; (2) in these cells where modulation was possible, alpha IFN was used as a low and noncytotoxic doses (10-50 micrograms/ml for 3-5 d exposure), and (3) the cytotoxicity of IFN alpha was dose dependent, indicating a direct antiproliferative cellular effect.