CLINICAL AND PHARMACOLOGICAL STUDIES OF INTERFERON AND CHEMOTHERAPY IN GASTROINTESTINAL AND BREAST-CANCER

The interferons enhance the cytotoxicity of antimetabolites, alkylatin g agents, and plant antibiotics against cultured human tumours in vitr o and in vivo. Five clinical trials in humans with advanced colorectal carcinoma have demonstrated responses ranging from 26 to 63% in patie nts treated with 5-fluorouracil (5-FU) plus interferon-alpha (IFN-alph a), suggesting improved response with the combination as compared with 5-FU alone. In addition, responses have been observed in patients wit h adenocarcinomas of the lung, pancreas, breast, and kidney, squamous cell carcinoma of the oesophagus, and urothelial carcinoma treated wit h 5-FU/IFN-alpha. However, enhanced 5-FU-related toxicity was observed in these studies, as has been observed when 5-FU is combined with oth er modulating agents, such as leucovorin. While some studies suggested that enhanced 5-FU-related toxicity was associated with an IFN-alpha- induced reduction in 5-FU clearance when 5-FU was given as an intraven ous (i.v.) bolus (750 mg/m2 IV weekly) or as a high-dose five-day cont inuous infusion (CI) (750 mg/m2/day x 5 days), another study found enh anced 5-FU toxicity in the absence of pharmacokinetic perturbation whe n 5-FU was given as a low-dose prolonged CI (300 mg/m2/day x 28 or mor e days). IFN-alpha-induced reduction in 5-FU clearance was observed at higher (5 - 10 x 10(6) units/m2) but not lower (3 x 10(6) units/m2) d oses of IFN-alpha in two studies when used concomitantly with 5-FU giv en as an i.v. bolus, but was also observed at low doses of IFN-alpha ( 0.5, 1.0, 3.0 x 10(6) units/m2) when administered in conjunction with 5-FU given as a high dose five-day CI. Furthermore, the IFN-alpha-indu ced reduction in 5-FU clearance is abrogated by the concomitant admini stration of leucovorin, and conversely leucovorin clearance is also im paired by IFN-alpha, potentially confounding the interpretation of tri als investigating the addition of leucovorin to the 5-FU/IFN-alpha com bination. The interaction between 5-FU and IFN-alpha, therefore, appea rs to be quite complex. Further research is required to determine the optimal dose and schedule of 5-FU and IFN-alpha administration, the bi ochemical basis for their interaction, the effectiveness of the combin ation relative to 5-FU used either alone or in combination with other modulating agents, and the potential for combining IFN-alpha with othe r cytotoxic agents in the treatment of carcinomas arising at other sit es.