MODULATION OF THE ANTITUMOR-ACTIVITY OF 5-FLUOROURACIL AND CISPLATINUM BY N-PHOSPHONACETYL-L-ASPARTATE IN THE MURINE COLON-CARCINOMA NUMBER-26

Modulation of the antitumor activity of cisplatinum (CDDP) alone or in combination with 5-fluorouracil (FUra) by N-phosphonacetyl-L-aspartate (PALA) was investigated in Balb/c mice bearing colon 26 adenocarcinoma, using weekly i.v. push schedule (days 1, 7 and 14) with PALA (100 mg/kg) been administered 24 h prior to each drug treatment. Antitumor activity was assessed at the maximum tolerated dose (MTD) of treatment by determining tumor doubling time (TD), ratio of tumor size in drug treated to control values (T/C) and by kinetic of tumor regression, being partial (PR) or complete (CR) tumor regression. In this model system, FUra and CDDP alone and in combination did not produce significant antitumor activity. Although tumor reduction by these agents was primarily in the form of PR, regrowth of tumor was apparent following termination of treatment. In contrast, pretreatment with a nontoxic dose of PALA produced significant increase in CR rates, ranged from 6% of treated animals with CDDP to 19% of animals treated with FUra. Furthermore, the greatest therapeutic efficacy was achieved when PALA was used to modulate the antitumor activity of the combination of FUra and CDDP. Under these conditions 70% and 30% of treated animals achieved PR and CR, respectively. With the weekly schedule use herein, PALA did not potentiate significantly the toxicity of either FUra or CDDP. Potentiation of CDDP toxicity by PALA was observed when the drug was used in combination with FUra, requiring approximately 6 fold reduction in CDDP dose. In brief, using the optimal doses of FUra and CDDP in combination, PALA potentiated significantly the antitumor activity of the combination in mice bearing a tumor relatively resistant to FUra and CDDP when used as a single agent and in combination.