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.
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.
Jansen
M
M
Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Dykstra
M
M
Lee
J I
JI
Stables
J
J
Topley
P
P
Knick
V C
VC
Mullin
R J
RJ
Duch
D S
DS
Smith
G K
GK
D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D005492:Folic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases; D051379:Mice; D008810:Mice, Inbred C57BL; D051026:Phosphoribosylglycinamide Formyltransferase; D011687:Purines / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D011687:Purines; D013763:Tetrahydrofolates; C062810:N-(4-((3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl)amino)benzoyl)glutamic acid; D005492:Folic Acid; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D000217:Acyltransferases; C059966:ICI 198583