SYNERGISTIC CYTOTOXIC EFFECTS OF CHEMOTHE RAPEUTIC DRUGS ON COLON-TUMOR CELLS BY SIMULTANEOUS INHIBITION OF DE-NOVO AND SALVAGE METABOLIC PATHWAYS

The success of chemotherapy of colon tumours is currently limited. We have therefore used the human colon tumour cell line HT-29 to evaluate the cytotoxic effects of various drug combinations. Trimidox (3,4,5-t rihydroxybenzamidoxime), a recently patented inhibitor of ribonucleoti de reductase was combined with cytosinearabinoside (Ara-C) or 2',2'-di fluorodeoxycytidine (DFDC) in order to inhibit both pyrimidine de novo and salvage pathways. Synergistic cytotoxic effects were observed. Wh en HT-29 cells were sequentially treated with trimidox (20 muM for 24 h) and Ara-C (2 muM for 2 h), colony numbers decreased to 71% of the v alue calculated for additive cytotoxicity. When cells were simultaneou sly treated with trimidox (10 muM and 15 muM) and DFDC (0.2 nM), syner gistic inhibition of colony formation was likewise noted (colony numbe rs decreased to values as low as 73% or 71% of the values calculated f or additive cytotoxicity). On the other hand, we combined tiazofurin, an inhibitor of the guanylate de novo pathway, with allopurinol, which inhibits the guanylate salvage pathway by increasing intracellular hy poxanthine concentrations, leading to inhibition of the enzyme hypoxan thine-guanine phosphoribosyltransferase (HGPRT). Synergistic cytotoxic effects were observed under these conditions too. When cells were tre ated with 10 muM tiazofurin and 400 muM or 800 muM allopurinol the num ber of colonies decreased to 69% and 27%, respectively, of the values calculated for additive effects. Our data suggest these drug combinati ons to be promising options in the treatment of human colon cancer.