Combination of raltitrexed with other cytotoxic agents: Rationale and preclinical observations

Agents for use in combination therapy should be effective as monotherapy in the tumour type of interest, have different mechanisms of action or pharma cology, and preferably non-overlapping toxicity profiles. Raltitrexed is ef fective as monotherapy in a number of tumour types, but it is hoped that co mbining it with other cytotoxic agents will lead to enhanced efficacy. Ralt itrexed and 5-fluorouracil (5-FU) are specific and non-specific inhibitors, respectively, of thymidylate synthase, a critical enzyme in the de novo sy nthesis of DNA. Preclinical studies have indicated that raltitrexed and 5-F U have an incompletely overlapping spectrum of antitumour activity and may have additive or synergistic effects on colon carcinoma cells. These intera ctions are schedule-dependent (raltitrexed should precede 5-FU). Pre-treatm ent of colon carcinoma cells with raltitrexed has also been shown to increa se intracellular levels of phosphoribosyl pyrophosphate resulting in increa sed incorporation of 5-FU nucleotides into RNA. Raltitrexed has a different mechanism of action from two other new agents active in colorectal cancer, irinotecan and oxaliplatin, and tumours are therefore not necessarily cros s-resistant. Short pre-exposure of colon carcinoma cells to the irinotecan active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), prior to exposu re to raltitrexed has consistently resulted in synergistic cell kill, where as the reverse sequence is antagonistic. Preliminary results indicate that equitoxic doses of raltitrexed and cisplatin, or oxaliplatin, are antagonis tic in two colon carcinoma cell Lines. However, because there are major dif ficulties in translating preclinical drug combination results to the clinic al setting, these results should be interpreted with caution. (C) 1999 Else vier Science Ltd. All rights reserved.