Paclitaxel alters the expression and specific activity of deoxycytidine kinase and cytidine deaminase in non-small cell lung cancer cell lines
Tóm tắt
We observed that paclitaxel altered the pharmacokinetic properties of gemcitabine in patients with non-small cell lung cancer (NSCLC) and limited the accumulation of gemcitabine and its metabolites in various primary and immortalized human cells. Therefore, we classified the drug-drug interaction and the effects of paclitaxel on deoxycytidine kinase (dCK) and cytidine deaminase (CDA) in three NSCLC cell lines. These enzymes are responsible for the metabolism of gemcitabine to its deaminated metabolite dFdU (80% of the parent drug) and the phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP. These metabolites appear to relate to sensitivity and tolerability of gemcitabine based on previous animal and laboratory studies. Three immortalized human cells representative of the most common histological subtypes identified in patients with advanced NSCLC were exposed to the individual drugs or combinations to complete a multiple drug effect analysis. These same cell lines were exposed to vehicle-control or paclitaxel and the mRNA levels, protein expression and specific activity of dCK and CDA were compared. Comparisons were made using a two-tailed paired t-test or analysis of variance with a P value of < 0.05 considered significant. The multiple drug effect analysis indicated synergy for H460, H520 and H838 cells independent of sequence. As anticipated, paclitaxel-gemcitabine increased the number of G2/M cells, whereas gemcitabine-paclitaxel increased the number of G0/G1 or S cells. Paclitaxel significantly decreased dCK and CDA mRNA levels in H460 and H520 cells (40% to 60%, P < 0.05) and lowered dCK protein (24% to 56%, P < 0.05) without affecting CDA protein. However, paclitaxel increased both dCK (10% to 50%) and CDA (75% to 153%) activity (P < 0.05). Paclitaxel caused substantial declines in the accumulation of the deaminated and phosphorylated metabolites in H520 cells (P < 0.05); the metabolites were not measurable in the remaining two cell lines. The ratio of dCK to CDA mRNA levels corresponded to the combination index (CI) estimated for sequential paclitaxel-gemcitabine. In summary, paclitaxel altered the mRNA levels and specific activity of dCK and CDA and these effects could be dependent on histological subtype. More cell and animal studies are needed to further characterize the relationship between mRNA levels and the overall drug-drug interaction and the potential to use histological subtype as a predictive factor in the selection of an appropriate anticancer drug regimen.
Tài liệu tham khảo
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002, 346: 92-98. 10.1056/NEJMoa011954.
Scagliotti G, Kaiser C, Bisesma B, Manegold C, Gatzemeiser U, Serwatowski P, Syrigos K, Balint B, Smit HJ, Vansteenkiste J: Correlation of biomarker expression and clinical outcome in a large phase III trial of pemetrexed plus cisplatin or gemcitabine plus cisplatin in chemonaive patients with lcoally advanced or nmetastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2007, 2: S375-10.1097/01.JTO.0000283223.48520.7c.
Baggstrom MQ, Stinchcombe TE, Fried DB, Poole C, Hensing TA, Socinski MA: Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis. J Thorac Oncol. 2007, 2: 845-853. 10.1097/JTO.0b013e31814617a2.
Smorenburg CH, Sparreboom A, Bontenbal M, Verweij J: Combination chemotherapy of the taxanes and antimetabolites: its use and limitations. Eur J Cancer. 2001, 37: 2310-2323. 10.1016/S0959-8049(01)00309-4.
Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V: Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995, 22: 3-10.
Bergman AM, Eijk PP, Ruiz van Haperen VW, Smid K, Veerman G, Hubeek I, Ijssel van den P, Ylstra B, Peters GJ: In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Cancer Res. 2005, 65: 9510-9516. 10.1158/0008-5472.CAN-05-0989.
Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA: An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 2004, 64: 3761-3766. 10.1158/0008-5472.CAN-03-3363.
Kroep JR, Loves WJ, Wilt van der CL, Alvarez E, Talianidis L, Boven E, Braakhuis BJ, van Groeningen CJ, Pinedo HM, Peters GJ: Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther. 2002, 1: 371-376.
Kwon WS, Rha SY, Choi YH, Lee JO, Park KH, Jung JJ, Kim TS, Jeung HC, Chung HC: Ribonucleotide reductase M1 (RRM1) 2464G>A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines. Pharmacogenet Genomics. 2006, 16: 429-438. 10.1097/01.fpc.0000204999.29924.da.
Ruiz van Haperen VW, Veerman G, Eriksson S, Stegmann AP, Peters GJ: Induction of resistance to 2',2'-difluorodeoxycytidine in the human ovarian cancer cell line A2780. Semin Oncol. 1995, 22: 35-41.
Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991, 9: 491-498.
Andre N, Ortiz A, Mercier C, Giacometti S, Feuerstein J-M, Camin-Jau L, BVernar J-L, Ciccolini J: Phenotypic determination of CDA status: animal study and application in pediatric oncology. 2008, Philadelphia AACR
Kuhn JG: Pharmacology and pharmacokinetics of paclitaxel. Ann Pharmacother. 1994, 28: S15-17.
Anderson H, Hopwood P, Stephens RJ, Thatcher N, Cottier B, Nicholson M, Milroy R, Maughan TS, Falk SJ, Bond MG, et al: Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer–a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer. 2000, 83: 447-453. 10.1054/bjoc.2000.1307.
Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, Anderson H, Gustafson N, Jeynes A, Gallant G, et al: Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 2000, 92: 1074-1080. 10.1093/jnci/92.13.1074.
Shord SS, Camp JR, Young LA: Paclitaxel decreases the accumulation of gemcitabine and its metabolites in human leukemia cells and primary cell cultures. Anticancer Res. 2005, 25: 4165-4171.
Shord SS, Faucette SR, Gillenwater HH, Pescatore SL, Hawke RL, Socinski MA, Lindley C: Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2003, 51: 328-336.
Martin A, Clynes M: Comparison of 5 microplate colorimetric assays for in vitro cytotoxicity testing and cell proliferation assays. Cytotechnology. 1993, 11: 49-58. 10.1007/BF00749057.
Chou TC, Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984, 22: 27-55. 10.1016/0065-2571(84)90007-4.
Kroep JR, Giaccone G, Tolis C, Voorn DA, Loves WJ, Groeningen CJ, Pinedo HM, Peters GJ: Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines. Br J Cancer. 2000, 83: 1069-1076. 10.1054/bjoc.2000.1399.
Vindelov LL, Christensen IJ, Nissen NI: A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry. 1983, 3: 323-327. 10.1002/cyto.990030503.
Lamba JK, Crews K, Pounds S, Schuetz EG, Gresham J, Gandhi V, Plunkett W, Rubnitz J, Ribeiro R: Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants. J Pharmacol Exp Ther. 2007, 323: 935-945. 10.1124/jpet.107.128595.
Wilt van der CL, Kroep JR, Loves WJ, Rots MG, Van Groeningen CJ, Kaspers GJ, Peters GJ: Expression of deoxycytidine kinase in leukaemic cells compared with solid tumour cell lines, liver metastases and normal liver. Eur J Cancer. 2003, 39: 691-697. 10.1016/S0959-8049(02)00813-4.
Vincenzetti S, Cambi A, Neuhard J, Garattini E, Vita A: Recombinant human cytidine deaminase: expression, purification, and characterization. Protein Expr Purif. 1996, 8: 247-253. 10.1006/prep.1996.0097.
Hatzis P, Al-Madhoon AS, Jullig M, Petrakis TG, Eriksson S, Talianidis I: The intracellular localization of deoxycytidine kinase. J Biol Chem. 1998, 273: 30239-30243. 10.1074/jbc.273.46.30239.
Somasekaram A, Jarmuz A, How A, Scott J, Navaratnam N: Intracellular localization of human cytidine deaminase. Identification of a functional nuclear localization signal. J Biol Chem. 1999, 274: 28405-28412. 10.1074/jbc.274.40.28405.
Shord SS, Camp JR: Paclitaxel alters the metabolism of gemcitabine to its active metabolite diflourodeoxycytidine triphosphate. Proc Am Soc Clin Oncol. 2004, 23: 149-
Theodossiou C, Cook JA, Fisher J, Teague D, Liebmann JE, Russo A, Mitchell JB: Interaction of gemcitabine with paclitaxel and cisplatin in human tumor cell lines. Int J Oncol. 1998, 12: 825-832.
Cascallo M, Calbo J, Capella G, Fillat C, Pastor-Anglada M, Mazo A: Enhancement of gemcitabine-induced apoptosis by restoration of p53 function in human pancreatic tumors. Oncology. 2005, 68: 179-189. 10.1159/000086772.
Shord SS, Patel SR: Gene expression ratio of deoxycytidine kinase (dCK) to cytidine deaminase (CDA) corresponds with cytotoxicity in solid tumors in vitro. Proceedings of the 99th Annual Meeting of the American Association for Cancer Research; 2008 Apr 12–16. 2008, San Diego, CA Philadelphia (PA): AACR
Gandhi V, Plunkett W: Modulatory activity of 2',2'-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res. 1990, 50: 3675-3680.