EFFECT OF PURINE SYNTHESIS INHIBITION ON WIDR SPHEROIDS IN-VITRO OR ON WIDR OR COLON-38 TUMORS IN-VIVO - COMPLETE GROWTH-INHIBITION BUT NOTREGRESSION

Clinical responses for anticancer agents are based upon tumor regressi on. We have investigated the potential of glycineamide ribonucleotide transformylase (GAR TFase) inhibitors to produce regressions in multip le preclinical models of colon carcinoma. The growth of multicellular tumor spheroids of WiDr human colon carcinoma was inhibited by the GAR TFase inhibitors 5-deazaacyclotetrahydrofolate (5-DACTHF), its 2'-flu oro, 3'-fluoro, 10-deaza, and 10-thia analogs as well as 5,10-dideazat etrahydrofolate, but none of the compounds caused spheroid regressions . By contrast, complete spheroid disruption was observed with exposure to etoposide, m-AMSA (amsacrine), piritrexim, or 2-desamino-2-methyl- 10-propargyl-5,8-dideazafolate (DMPDDF). Light microscopy of the spher oids treated with either 5-DACTHF or DMPDDF suggested that the reason for the difference is extensive cell kill throughout the spheroid in t he presence of DMPDDF compared with little or no kill, over that found in controls, with 5-DACTHF. Treatment of spheroids with 5-DACTHF in t he presence of 1 muM hypoxanthine resulted in no significant reversal of growth inhibition; 50% reversal required 10 muM hypoxanthine. The s pheroid studies were extended to in vivo studies examining the effects of 5-DACTHF on established WiDr and colon 38 tumors. The results show ed that, in contrast to melphalan, which produced cures and tumor regr essions, 5-DACTHF produced reversible growth inhibition with no signif icant regression of tumors. The results predict that clinical response , typically measured by tumor regression, may be rare following single agent therapy with inhibitors of de novo purine biosynthesis.