DNA repair mechanisms involved in gemcitabine cytotoxicity and in the interaction between gemcitabine and cisplatin - PubMed (original) (raw)
DNA repair mechanisms involved in gemcitabine cytotoxicity and in the interaction between gemcitabine and cisplatin
Mirjam Crul et al. Biochem Pharmacol. 2003.
Abstract
The influence of DNA repair mechanisms on the interaction between gemcitabine and cisplatin was studied using a panel of Chinese hamster ovary (CHO) cell lines deficient in one of the following repair pathways: base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ). NER and HR are known to be involved in platinum-DNA adduct repair. Single agent experiments demonstrated that each of the repair deficient cell lines had a similar sensitivity towards gemcitabine as the parental cell lines, whereas the NER- and HR-deficient lines showed increased sensitivity towards cisplatin. Furthermore, in the parental cell lines, the administration sequence cisplatin followed by gemcitabine was synergistic, whereas the reversed schedule showed additivity and simultaneous administration revealed antagonistic cytotoxicity. In the repair deficient cell lines, using this synergistic schedule of cisplatin followed by gemcitabine, loss of synergy was observed in the NER- and HR-deficient cell lines. However, the magnitude of the effect in the NER-deficient cells was small. The sensitivity to the combination of cisplatin and gemcitabine shown by the BER- and NHEJ-deficient cell lines did not differ significantly from that of the parental cell line. Cellular accumulation of platinum as well as the formation of GG- and AG-intrastrand adducts in the parental line and in the HR-deficient line were not affected by gemcitabine. In conclusion, our results indicate that BER, NER, HR, and NHEJ are most likely incapable of modulating the cytotoxicity of gemcitabine, and that HR is involved in the synergistic interaction between cisplatin and gemcitabine in our cell system.
Similar articles
- Gemcitabine potentiates cisplatin cytotoxicity and inhibits repair of cisplatin-DNA damage in ovarian cancer cell lines.
Moufarij MA, Phillips DR, Cullinane C. Moufarij MA, et al. Mol Pharmacol. 2003 Apr;63(4):862-9. doi: 10.1124/mol.63.4.862. Mol Pharmacol. 2003. PMID: 12644587 - Influence of genetic markers on survival in non-small cell lung cancer.
Rosell R, Taron M, Camps C, López-Vivanco G. Rosell R, et al. Drugs Today (Barc). 2003 Oct;39(10):775-86. doi: 10.1358/dot.2003.39.10.799471. Drugs Today (Barc). 2003. PMID: 14668933 Review. - Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids.
Besançon OG, Tytgat GA, Meinsma R, Leen R, Hoebink J, Kalayda GV, Jaehde U, Caron HN, van Kuilenburg AB. Besançon OG, et al. Cancer Lett. 2012 Jun 1;319(1):23-30. doi: 10.1016/j.canlet.2011.12.016. Epub 2011 Dec 17. Cancer Lett. 2012. PMID: 22182450 - Cellular response of X-ray sensitive hamster mutant cell lines to gemcitabine, cisplatin and 5-fluorouracil.
Haveman J, Castro Kreder N, Rodermond HM, van Bree C, Franken NA, Stalpers LJ, Zdzienicka MZ, Peters GJ. Haveman J, et al. Oncol Rep. 2004 Jul;12(1):187-92. doi: 10.3892/or.12.1.187. Oncol Rep. 2004. PMID: 15201982 - Preclinical perspectives on platinum resistance.
Kelland LR. Kelland LR. Drugs. 2000;59 Suppl 4:1-8; discussion 37-8. doi: 10.2165/00003495-200059004-00001. Drugs. 2000. PMID: 10864225 Review.
Cited by
- The plant-specific CDKB1-CYCB1 complex mediates homologous recombination repair in Arabidopsis.
Weimer AK, Biedermann S, Harashima H, Roodbarkelari F, Takahashi N, Foreman J, Guan Y, Pochon G, Heese M, Van Damme D, Sugimoto K, Koncz C, Doerner P, Umeda M, Schnittger A. Weimer AK, et al. EMBO J. 2016 Oct 4;35(19):2068-2086. doi: 10.15252/embj.201593083. Epub 2016 Aug 5. EMBO J. 2016. PMID: 27497297 Free PMC article. - Phase II study of gemcitabine and cisplatin in locally advanced/metastatic oesophageal cancer.
Millar J, Scullin P, Morrison A, McClory B, Wall L, Cameron D, Philips H, Price A, Dunlop D, Eatock M. Millar J, et al. Br J Cancer. 2005 Nov 14;93(10):1112-6. doi: 10.1038/sj.bjc.6602842. Br J Cancer. 2005. PMID: 16278660 Free PMC article. Clinical Trial. - BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine.
Jones RM, Kotsantis P, Stewart GS, Groth P, Petermann E. Jones RM, et al. Mol Cancer Ther. 2014 Oct;13(10):2412-21. doi: 10.1158/1535-7163.MCT-13-0862. Epub 2014 Jul 22. Mol Cancer Ther. 2014. PMID: 25053826 Free PMC article. - Synergistic Pharmacodynamic Effects of Gemcitabine and Fibroblast Growth Factor Receptor Inhibitors on Pancreatic Cancer Cell Cycle Kinetics and Proliferation.
Lin Q, Qian Z, Jusko WJ, Mager DE, Ma WW, Straubinger RM. Lin Q, et al. J Pharmacol Exp Ther. 2021 Jun;377(3):370-384. doi: 10.1124/jpet.120.000412. Epub 2021 Mar 22. J Pharmacol Exp Ther. 2021. PMID: 33753538 Free PMC article. - Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival.
Li D, Liu H, Jiao L, Chang DZ, Beinart G, Wolff RA, Evans DB, Hassan MM, Abbruzzese JL. Li D, et al. Cancer Res. 2006 Mar 15;66(6):3323-30. doi: 10.1158/0008-5472.CAN-05-3032. Cancer Res. 2006. PMID: 16540687 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources