Effect of purine synthesis inhibition on WiDr spheroids in vitro or on WiDr or colon 38 tumors in vivo: Complete growth inhibition but not regression

摘要: Clinical responses for anticancer agents are based upon tumor regression. We have investigated the potential of glycineamide ribonucleotide transformylase (GAR TFase) inhibitors to produce regressions in multiple preclinical models colon carcinoma. The growth multicellular spheroids WiDr human carcinoma was inhibited by GAR TFase 5-deazaacyclotetrahydrofolate (5-DACTHF), its 2'-fluoro, 3'-fluoro, 10-deaza, and 10-thia analogs as well 5,10-dideazatetrahydrofolate, but none compounds caused spheroid regressions. By contrast, complete disruption observed with exposure etoposide, m-AMSA (amsacrine), piritrexim, or 2-desamino-2-methyl-10-propargyl-5,8-dideazafolate (DMPDDF). Light microscopy treated either 5-DACTHF DMPDDF suggested that reason difference is extensive cell kill throughout presence compared little no kill, over found controls, 5-DACTHF. Treatment 1 microM hypoxanthine resulted significant reversal inhibition; 50% required 10 hypoxanthine. studies were extended vivo examining effects on established 38 tumors. results showed that, contrast melphalan, which produced cures regressions, reversible inhibition regression predict clinical response, typically measured regression, may be rare following single agent therapy de novo purine biosynthesis.