Pharmacogenomics of Gemcitabine: Can Genetic Studies Lead to Tailor-made Therapy?

Overview

Journal Br J Cancer

Specialty Oncology

Date 2007 Jun 28

PMID 17595663

Citations 64

Authors

H Ueno

K Kiyosawa

N Kaniwa

Affiliations

Soon will be listed here.

Abstract

Gemcitabine is a deoxycytidine analogue that has a broad spectrum of antitumour activity in many solid tumours including pancreatic cancer. We have recently carried out a pharmacogenomic study in cancer patients treated with gemcitabine, and found that one genetic polymorphism of an enzyme involved in gemcitabine metabolism can cause interindividual variations in the pharmacokinetics and toxicity of this agent. In this paper, we review recent genetic studies of gemcitabine, and discuss the possibility of individualised cancer chemotherapy based on a pharmacogenomic approach.

Citing Articles

Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer.

Gu Y, Yang R, Zhang Y, Guo M, Takehiro K, Zhan M Mol Biomed. 2025; 6(1):2.

PMID: 39757310 PMC: 11700966. DOI: 10.1186/s43556-024-00239-2.

Gemcitabine as chemotherapy of head and neck cancer in Fanconi anemia patients.

van Harten A, Shah R, de Boer D, Buijze M, Kreft M, Song J Oncogenesis. 2024; 13(1):26.

PMID: 38992100 PMC: 11239817. DOI: 10.1038/s41389-024-00525-2.

Synthesis and anticancer evaluation of acetylated-lysine conjugated gemcitabine prodrugs.

Wang M, Qu K, Zhao P, Yin X, Meng Y, Herdewijn P RSC Med Chem. 2023; 14(8):1572-1580.

PMID: 37593582 PMC: 10429768. DOI: 10.1039/d3md00190c.

RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer.

Ono H, Murase Y, Yamashita H, Kato T, Asano D, Ishikawa Y Int J Oncol. 2023; 62(4).

PMID: 36866763 PMC: 10019754. DOI: 10.3892/ijo.2023.5499.

Development and Characterization of PEGDA Microneedles for Localized Drug Delivery of Gemcitabine to Treat Inflammatory Breast Cancer.

Alafnan A, Seetharam A, Hussain T, Gupta M, Danish Rizvi S, Moin A Materials (Basel). 2022; 15(21).

PMID: 36363283 PMC: 9658843. DOI: 10.3390/ma15217693.

References

Lord R, Brabender J, Gandara D, Alberola V, Camps C, Domine M . Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res. 2002; 8(7):2286-91. View

Mini E, Nobili S, Caciagli B, Landini I, Mazzei T . Cellular pharmacology of gemcitabine. Ann Oncol. 2006; 17 Suppl 5:v7-12. DOI: 10.1093/annonc/mdj941. View

Yue L, Saikawa Y, Ota K, Tanaka M, Nishimura R, Uehara T . A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. Pharmacogenetics. 2003; 13(1):29-38. DOI: 10.1097/00008571-200301000-00005. View

Osato D, Huang C, Kawamoto M, Johns S, Stryke D, Wang J . Functional characterization in yeast of genetic variants in the human equilibrative nucleoside transporter, ENT1. Pharmacogenetics. 2003; 13(5):297-301. DOI: 10.1097/00008571-200305000-00010. View

Rosell R, Danenberg K, Alberola V, Bepler G, Sanchez J, Camps C . Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res. 2004; 10(4):1318-25. DOI: 10.1158/1078-0432.ccr-03-0156. View

Rosell R, Felip E, Taron M, Majo J, Mendez P, Sanchez-Ronco M . Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin Cancer Res. 2004; 10(12 Pt 2):4215s-4219s. DOI: 10.1158/1078-0432.CCR-040006. View

Fukunaga A, Marsh S, Murry D, Hurley T, McLeod H . Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway. Pharmacogenomics J. 2004; 4(5):307-14. DOI: 10.1038/sj.tpj.6500259. View

Kim S, Saito Y, Maekawa K, Sugiyama E, Kaniwa N, Ueno H . Thirty novel genetic variations in the SLC29A1 gene encoding human equilibrative nucleoside transporter 1 (hENT1). Drug Metab Pharmacokinet. 2006; 21(3):248-56. DOI: 10.2133/dmpk.21.248. View

Joerger M, Bosch T, Doodeman V, Beijnen J, Smits P, Schellens J . Novel deoxycytidine kinase gene polymorphisms: a population screening study in Caucasian healthy volunteers. Eur J Clin Pharmacol. 2006; 62(8):681-4. DOI: 10.1007/s00228-006-0162-7. View

10.

Mey V, Giovannetti E, de Braud F, Nannizzi S, Curigliano G, Verweij F . In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients. Br J Cancer. 2006; 95(3):289-97. PMC: 2360654. DOI: 10.1038/sj.bjc.6603242. View

11.

Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A . RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol. 2006; 24(29):4731-7. DOI: 10.1200/JCO.2006.06.1101. View

12.

Sugiyama E, Kaniwa N, Kim S, Kikura-Hanajiri R, Hasegawa R, Maekawa K . Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol. 2006; 25(1):32-42. DOI: 10.1200/JCO.2006.06.7405. View

13.

Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young J, Dumontet C . The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 2004; 10(20):6956-61. DOI: 10.1158/1078-0432.CCR-04-0224. View

14.

Heinemann V, Xu Y, Chubb S, Sen A, Hertel L, GRINDEY G . Cellular elimination of 2',2'-difluorodeoxycytidine 5'-triphosphate: a mechanism of self-potentiation. Cancer Res. 1992; 52(3):533-9. View

15.

Neff T, Blau C . Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine. Exp Hematol. 1996; 24(11):1340-6. View

16.

Van Rompay A, Johansson M, Karlsson A . Phosphorylation of deoxycytidine analog monophosphates by UMP-CMP kinase: molecular characterization of the human enzyme. Mol Pharmacol. 1999; 56(3):562-9. DOI: 10.1124/mol.56.3.562. View

17.

Goan Y, Zhou B, Hu E, Mi S, Yen Y . Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res. 1999; 59(17):4204-7. View

18.

Shi J, Shi Z, Zhang S, Zhu Y, Gu B, Li G . Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients. Pharmacogenetics. 2004; 14(11):759-68. DOI: 10.1097/00008571-200411000-00007. View

19.

Bepler G, Zheng Z, Gautam A, Sharma S, Cantor A, Sharma A . Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. Lung Cancer. 2005; 47(2):183-92. DOI: 10.1016/j.lungcan.2004.07.043. View

20.

Yonemori K, Ueno H, Okusaka T, Yamamoto N, Ikeda M, Saijo N . Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin. Clin Cancer Res. 2005; 11(7):2620-4. DOI: 10.1158/1078-0432.CCR-04-1497. View