title: In vivo antitumor activity and metabolism of a series of 5-deazaacyclotetrahydrofolate (5-DACTHF) analogues.
abstract: This study compares the antitumor activity and metabolism of the purine de novo biosynthesis inhibitor 5-deazaacyclotetrahydrofolate and a series of analogues. All compounds have similar IC50 values for inhibition of MCF-7 cell growth, activity of glycineamide ribonucleotide transformylase, and methotrexate uptake by MOLT-4 cells, the latter a measure of cellular uptake potential. Only 5-deazaacyclotetrahydrofolate and the 2'-fluoro and 3'-fluoro analogues demonstrated significant inhibition of colon 38 adenocarcinoma or HCT-116 colon carcinoma growth in vivo. This correlated with the Km of these compounds for folylpolyglutamate synthetase. 5-Deazaacyclotetrahydrofolate and 2'-fluoro-5-deazaacyclotetrahydrofolate which displayed the strongest antitumor activity were detectable in colon 38 tumor tissue 24 hr after dosing and were present nearly exclusively as the polyglutamated species. These results indicate that polyglutamation represents a critical step in the in vivo antitumor activity of these compounds.
authors.affiliation: Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC 27709.
authors.forename: R J
authors.initials: RJ
authors.lastname: Mullin
authors.forename: B R
authors.initials: BR
authors.lastname: Keith
authors.forename: E C
authors.initials: EC
authors.lastname: Bigham
authors.forename: D S
authors.initials: DS
authors.lastname: Duch
authors.forename: R
authors.initials: R
authors.lastname: Ferone
authors.forename: L S
authors.initials: LS
authors.lastname: Heath
authors.forename: S
authors.initials: S
authors.lastname: Singer
authors.forename: K A
authors.initials: KA
authors.lastname: Waters
authors.forename: H R
authors.initials: HR
authors.lastname: Wilson
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases; D007700:Kinetics; D008727:Methotrexate / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010453:Peptide Synthases / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase; D013763:Tetrahydrofolates / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C062810:N-(4-((3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl)amino)benzoyl)glutamic acid; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D000217:Acyltransferases; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate