Abstract
Vinca alkaloids are important chemotherapeutic agents, and their pharmacokinetic properties display significant interindividual variations, possibly due to CYP3A4-mediated metabolism. We have evaluated the relevance of this metabolism for the chemotherapeutic and the toxicological properties of these drugs. Analysis was performed using Chinese hamster ovary cell lines that expressed either CYP2D6 or CYP3A4. The latter cells metabolized vinblastine with a turnover number of 0.4 min−1, resulting in a decreased cytotoxicity of this compound. Whereas vincristine and vinblastine at a concentration of 100 nM killed more than 90% of the parental cells, more than 50 and 35%, respectively, of cells that coexpressed CYP3A4 and cytochrome P450 (P450) reductase survived these treatments. No additional increase in cytotoxicity was noted above 100 nM. Similarly, preincubation of vinblastine with bacterial membranes that contained recombinant CYP3A4 and P450 reductase decreased the cytotoxicity of vinblastine for parental Chinese hamster ovary cells. We also demonstrate that the presence of vinblastine in a coculture of cells that expressed β-galactosidase together with cells that expressed CYP3A4 strongly selected for the latter cells, resulting in an increased level of CYP3A4 in the surviving cell population. Similarly, treatment of the human colon adenocarcinoma cell line LS174T with vinblastine selected for a cell population with higher levels of endogenous CYP3A4 as revealed by immunohistochemistry without simultaneous increase of multidrug resistance protein 1 (MDR1). This is the first evidence that tumor P450s have the potential to contribute to the development of drug resistance during chemotherapy.
Footnotes
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Send reprint requests to: T. Friedberg, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. E-mail:t.h.friedberg{at}dundee.ac.uk
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↵1 The consortium of pharmaceutical companies supporting this work were: Astra, Glaxo-Wellcome, Janssen Pharmaceutica, Lilly, Novo-Nordisk, Park-Davis, Pfizer, Roche Products, Sanofi-Winthrop, Servier, Smith-Kline Beecham, Wyeth-Ayerst, and Zeneca.
- Abbreviations:
- P450
- cytochrome P450
- CHO
- Chinese hamster ovary
- hOR
- NADPH-P450 reductase
- MDR1
- multidrug resistance protein 1
- DMEM
- Dulbecco's modified Eagle's medium
- DMSO
- dimethyl sulfoxide
- Received December 17, 1999.
- Accepted March 14, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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