The stereospecific cytotoxic potency of (6R) and (6S)-5,10- dideazatetrahydrofolate correlates with cellular folylpolyglutamate synthetase levels.
The de novo purine synthesis inhibitor 5,10-dideazatetrahydrofolate (DDATHF) has previously been shown to inhibit the growth of mouse L1210 and human CCRF-CEM leukemia cells. The present study demonstrates that both the 6R and 6S diastereomers of DDATHF are also cytotoxic to mammalian cells in a stereospecific manner. The cytotoxic potency of (6R)-DDATHF (also known as Lometrexol) towards different cell lines varied by approximately 14-fold and that of (6S)-DDATHF by as much as 156-fold. Compared to (6R)-DDATHF, (6S)-DDATHF was 6.0- and 7.2-fold more cytotoxic to human WiDr colon adenocarcinoma and Chinese hamster ovary (CHO) cells, respectively, and only 1.5- and 2.0-fold more cytotoxic to human T24 bladder carcinoma and mouse L1210 leukemia cells, respectively. However, compared to (6S)-DDATHF, (6R)-DDATHF was 8.7- and 6.9-fold more cytotoxic to C3H/10T1/2 clone 8 and clone 16 mouse fibroblasts, respectively. Weak inhibition of aminoimidazolecarboximide ribonucleotide formyltransferase (AICARFT, EC 2.1.2.3) appeared to have little role in the cytotoxicity of DDATHF diastereomers to WiDr cells during a 24-h exposure. Although glycinamide ribonucleotide formyltransferase (GARFT, EC 2.1.21) is the main biochemical target of DDATHF, DDATHF stereoisomers' cytotoxic potency showed no clear negative correlation with cellular GARFT levels. However, cellular folylpolyglutamate synthetase (FPGS, EC 6.3.2.17) levels correlated with cytotoxic potency in a positive manner. Surprisingly, two enzyme-dose/DDATHF LD90-response curves were observed for FPGS corresponding to differences in (6R) and (6S)-DDATHF cytotoxic potency among the six cell lines studied.
Lehman
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NL
University of Southern California Cancer Research Laboratory, Los Angeles 90033, USA.
D000217:Acyltransferases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016466:CHO Cells / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D006224:Cricetinae; D003593:Cytoplasm / Q000737:chemistry / Q000201:enzymology; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D010453:Peptide Synthases / Q000187:drug effects* / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism; D013237:Stereoisomerism; D013763:Tetrahydrofolates / Q000633:toxicity*; D013997:Time Factors
D000970:Antineoplastic Agents; D007042:Hypoxanthines; D012265:Ribonucleotides; D013763:Tetrahydrofolates; D019271:Hypoxanthine; C045894:lometrexol; D000217:Acyltransferases; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase