The combination of 5FU and leucovorin (LV) has resulted in significant increases in response rates and modest improvements in survival for patients with metastatic colorectal cancer. However, many patients are resistant to treatment at presentation and others acquire resistance during therapy. Resistance may be the result of provision of thymidylate via the alternate salvage pathway from intracellular or extracellular breakdown products of DNA. Persantine inhibits nucleoside transport at the cell membrane thereby blocking salvage of preformed nucleosides. Thus, extracellular nucleosides will be unable to enter the cell while lipid- soluble AZT can diffuse into the cell and compete with any thymidine generated by escape of TS inhibition by 5FU and LV or the intracellular salvage of nucleosides. The combination of these agents should lead to effective thymidine starvation and cell death. A phase I study using fixed doses of 5FU, LV and persantine with increasing doses of AZT (50 mg, 100 mg and 200 mg) has been completed. Dose-limiting toxicity was not observed and a phase II study is being conducted at the 200 mg dose of AZT. Six patients received AZT at 50 mg, 5 at 100 mg and 5 at 200 mg during the phase I portion of the study. Grade 4 anemia and grade 4 thrombocytopenia were observed in one patient each at 50 and 100 mg dose levels, respectively. No grade 4 toxicity was observed at 200 mg AZT. There was one minor response at 100 mg of AZT in a patient with renal cell carcinoma. Four of the five patients at 200 mg of AZT are not evaluable for response. Thus far, 13 patients have been enrolled on the phase II portion of the study; renal (6), melanoma (4) and colorectal (3).
