Combined antiproliferative activity of 5-fluorouracil and mitomycin-C against primary human ovarian tumors and cell lines in a clonogenic assay

Abstract

Ovarian tumors from 389 patients were successfully grown in a human tumor clonogenic assay (HTCA). Specimens from patients with or without prior chemotherapy showed similar chemosensitivity patterns. Excluding drugs commonly used for first-line chemotherapy, 5-fluorouracil (5-FU) and mitomycin-C (MMC) are among the active second-line agents, based upon HCTA data. Using this in vitro information from primary tumor specimens, two human ovarian cancer cell lines were used to study in detail the interactions of combined 5-FU and MMC. Drug scheduling which maximized combined antitumor activity was studied. Combined 5-FU and MMC revealed positive drug interactions most consistently when both drugs were used simultaneously with long-term exposure. Pulse treatment with MMC (1 hr) followed by continuous 5-FU exposure resulted in slightly less additive interaction than simultaneous long-term exposure. Pretreatment with 5-FU followed by a continuous exposure to MMC was as effective as the simultaneous method, as long as MMC was added within an 8-hr interval. Drug schedule dependency was examined, revealing that MMC, as a single agent, is both dose and schedule dependent. The results of these in vitro studies suggest that: (1) exposure to prior chemotherapy does not induce demonstrable pleiotropic drug resistance in these ovarian cancers tested; and (2) combined 5-FU and MMC show positive interactions against ovarian cancer cell lines, with optimal scheduling seeming to be long-term simultaneous exposure to both MMC and 5-FU.