Critical factors for the reversal of methotrexate cytotoxicity by folinic acid
- PMID: 1997110
- PMCID: PMC1971778
- DOI: 10.1038/bjc.1991.70
Critical factors for the reversal of methotrexate cytotoxicity by folinic acid
Abstract
The cytotoxicity of methotrexate (MTX) on representative human tumour cell lines (two cell lines from head and neck carcinomas, two from breast carcinomas, two from osteosarcomas and one lymphoblastoid cell line) was evaluated to: (1) examine the optimal time interval between MTX and folinic acid (FA) administration; (2) determine the critical FA/MTX concentration ratios; and (3) compare the relative effects of the equimolar mixture d,I-FA and I-FA. The cytotoxic effects of MTX were assessed by the MTT semi-automated test. For all of the cell lines tested, a significant inverse relationship was noted between the degree of MTX cytotoxicity reversal and the duration of the time interval between MTX and FA administration. Overall an 18-24 h interval between MTX and FA represented a time-threshold after which MTX effects could not efficiently be reversed by FA in most cell lines. With shorter time intervals between MTX and FA, MTX cytotoxicity could be partially on even totally reversed by FA; the intensity of reversal varied among the cell lines tested, and depended on the FA/MTX ratio. Regardless of the interval between MTX and FA, analysis of the various FA/MTX ratios revealed a significant direct relationship between this ratio and the percentage of recovery. Presence of the d-form had no influence on the MTX rescue capacity of the I-form; this suggests that the presence of the d-FA is unlikely to have any significant clinical consequences.
Similar articles
-
Leucovorin rescue of human cancer and bone marrow cells following edatrexate or methotrexate.Biochem Pharmacol. 1994 Feb 11;47(4):659-65. doi: 10.1016/0006-2952(94)90128-7. Biochem Pharmacol. 1994. PMID: 7510479
-
l-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children.J Natl Cancer Inst. 1992 Aug 5;84(15):1190-5. doi: 10.1093/jnci/84.15.1190. J Natl Cancer Inst. 1992. PMID: 1635087
-
Mechanism of leucovorin reversal of methotrexate cytotoxicity in human MCF-7 breast cancer cells.Biochem Pharmacol. 1990 Dec 15;40(12):2651-60. doi: 10.1016/0006-2952(90)90583-7. Biochem Pharmacol. 1990. PMID: 2260989
-
Challenging the clinical relevance of folinic acid over rescue after high dose methotrexate (HDMTX).Med Hypotheses. 2013 Nov;81(5):942-7. doi: 10.1016/j.mehy.2013.08.027. Epub 2013 Sep 3. Med Hypotheses. 2013. PMID: 24035689 Review.
-
Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates.NCI Monogr. 1987;(5):17-26. NCI Monogr. 1987. PMID: 2448654 Review.
Cited by
-
Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma.Blood Res. 2016 Mar;51(1):50-7. doi: 10.5045/br.2016.51.1.50. Epub 2016 Mar 25. Blood Res. 2016. PMID: 27104192 Free PMC article.
-
Mechanism of Action of Methotrexate Against Zika Virus.Viruses. 2019 Apr 10;11(4):338. doi: 10.3390/v11040338. Viruses. 2019. PMID: 30974762 Free PMC article.
-
Glucarpidase to combat toxic levels of methotrexate in patients.Ther Clin Risk Manag. 2012;8:403-13. doi: 10.2147/TCRM.S30135. Epub 2012 Nov 22. Ther Clin Risk Manag. 2012. PMID: 23209370 Free PMC article.
References
MeSH terms
Substances
LinkOut - more resources
Full Text Sources