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dc.contributor.authorvan der Wilt, CLen_US
dc.contributor.authorBackus, HHJen_US
dc.contributor.authorSmid, Ken_US
dc.contributor.authorComijn, Len_US
dc.contributor.authorVeerman, Gen_US
dc.contributor.authorWouters, Den_US
dc.contributor.authorVoorn, DAen_US
dc.contributor.authorPriest, DGen_US
dc.contributor.authorBunni, MAen_US
dc.contributor.authorMitchell, Fen_US
dc.contributor.authorJackman, ALen_US
dc.contributor.authorJansen, Gen_US
dc.contributor.authorPeters, GJen_US
dc.identifier.citationCANCER RESEARCH, 2001, 61 pp. 3675 - 3681en_US
dc.description.abstractPlasma levels of folates and thymidine in mice are about 10-fold higher than in humans and may influence the therapeutic efficacy of thymidylate synthase (TS) Inhibitors, such as 5-fluorouracil (5FU) and the antifolates pemetrexed (MTA) and raltitrexed (RTX). Therefore, we tested their therapeutic efficacy in various murine tumor models, grown in mice on a normal and a folate-depleted diet, with high and low thymidine kinase (TK) levels. MTA and RTX were inactive against Colon-26-10 [doubling times gained by treatment; growth delay factor (GDF), 0.5 and 0.3, respectively], whereas 5FU was very active (GDF, >10; complete cures). Colon-26-10/F, grown In mice on a folate-depleted diet, was more sensitive to RTX and MTA (GDF, 2.1 and 1.3, respectively) but not to 5FU (GDF, 1.2); however, leucovorin reversed the effect leading to cures. Folate depiction did not reverse resistance of Colon-26A and Colon-26G (low TK) to MTA and RTX, whereas leucovorin only enhanced the 5FU effect in Colon-26A and Colon-26A/F. Folic acid at 15 mg/kg did not improve the therapeutic efficacy of MTA in folate-deficient mice. The folate-depleted diet decreased the reduced folates in Colon-26A/F and Colon-26-G/F tumors less (4-5-fold; P < 0.01) than in Colon-26-10/F tumors (8-fold; P < 0.001). Folate depletion increased TS levels 2-3-fold in all of the models and TK levels 6-fold (P < 0.01) in Colon-26G/F, explaining the lark of activity of MTA and RTX in Colon-26G/F. In contrast, TK-deficient FM3A/TK tumors were much more sensitive to RTX, MTA, and 5FU than parent FM3A tumors, which have comparable TS levels. The rate of thymidine phosphorylysis varied considerably in all of the tumors without a clear relation to antitumor activity. In conclusion, tumor folates may potentiate (5FU) or protect (antifolates). Murine tumor models should combine low folates and low thymidine rescue to optimize preclinical testing of antifolates.en_US
dc.format.extent3675 - 3681en_US
dc.titleModulation of both endogenous folates and thymidine enhance the therapeutic efficacy of thymidylate synthase inhibitorsen_US
dc.typeJournal Article
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCANCER RESEARCHen_US
pubs.notesaffiliation: Peters, GJ (Reprint Author), Univ Hosp Vrije Univ, Dept Med Oncol, POB 7057, NL-1007 MB Amsterdam, Netherlands. Univ Hosp Vrije Univ, Dept Med Oncol, NL-1007 MB Amsterdam, Netherlands. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Inst Canc Res, CRC, Ctr Canc Therapeut, Sutton SM2 5N9, Surrey, England. keywords-plus: DIETARY FOLIC-ACID; ANTITUMOR-ACTIVITY; MULTITARGETED ANTIFOLATE; ANTICANCER DRUGS; COLON TUMORS; 5-FLUOROURACIL; RESISTANCE; LEUCOVORIN; PLASMA; CELLS research-areas: Oncology web-of-science-categories: Oncology number-of-cited-references: 45 times-cited: 46 usage-count-last-180-days: 0 usage-count-since-2013: 2 journal-iso: Cancer Res. doc-delivery-number: 428WV unique-id: ISI:000168485400026 da: 2018-09-25en_US
pubs.notesNot knownen_US
pubs.embargo.termsNot knownen_US
dc.contributor.icrauthorJackman, Annen_US

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