Phase II trial of oral methotrexate and dipyridamole in colorectal carcinoma.
We have employed a rationally designed combination attempting to biochemically modulate the cytotoxicity of methotrexate (MTX), an inhibitor of de novo purine and pyrimidine synthesis, by dipyridamole (DP), a noncytotoxic modulator which blocks cellular transport of preformed nucleosides, in the treatment of 27 patients with advanced colorectal carcinoma. Doses and schedule determined from a previous phase I pharmacokinetic study were MTX at 2.5 mg orally twice a day for 4 days to begin concurrently with DP, at 75 mg orally four times daily for 8 days. One partial response was achieved in a patient who had progressed on a previous regimen of leucovorin and 5-fluorouracil. The major toxic effects observed were myelosuppression and stomatitis. Lack of efficacy could be interpreted to reflect incomplete modulation. Therefore, studies employing continuous iv infusion of DP concurrent with or a loading schedule of DP prior to administration of MTX may be required to provide adequate evaluation of such biochemically directed strategies.
D000230:Adenocarcinoma / Q000188:drug therapy*; D000284:Administration, Oral; D000368:Aged; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004176:Dipyridamole / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000188:drug therapy*
D004176:Dipyridamole; D008727:Methotrexate