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 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'-fluoro, 3'-fluoro, 10-deaza, and 10-thia analogs as well as
5,10-dideazatetrahydrofolate, 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 spheroids treated with either
5-DACTHF or DMPDDF suggested that the reason for the difference is extensive cell kill throughout the spheroid in the presence of DMPDDF compared with little or no kill, over that found in controls, with
5-DACTHF. Treatment of spheroids with
5-DACTHF in the presence of 1 microM
hypoxanthine resulted in no significant reversal of growth inhibition; 50% reversal required 10 microM
hypoxanthine. The spheroid studies were extended to in vivo studies examining the effects of
5-DACTHF on established WiDr and colon 38
tumors. The results showed that, in contrast to
melphalan, which produced cures and
tumor regressions,
5-DACTHF produced reversible growth inhibition with no significant 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.