Characterization of an Ovarian Carcinoma Cell Line Resistant to Cisplatin and Flavopiridol

Flavopiridol, the first inhibitor of cyclin-dependent kinases to enter clinical trials, has shown promising antineoplastic activity and is currently undergoing Phase II testing. Little is known about mechanisms of resistance to this agent. In the present study, we have characterized an ovarian carci...

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Bibliographic Details
Published in:Clinical cancer research 2000-02, Vol.6 (2), p.661-670
Main Authors: Keith C. Bible, Scott A. Boerner, Kathryn Kirkland, Kari L. Anderl, Duane Bartelt, Jr, Phyllis A. Svingen, Timothy J. Kottke, Yean K. Lee, Steven Eckdahl, Paul G. Stalboerger, Robert B. Jenkins, Scott H. Kaufmann
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - toxicity
Biological and medical sciences
Carmustine - toxicity
Chromosome Aberrations
Chromosome Mapping
Cisplatin - pharmacokinetics
Cisplatin - toxicity
DNA Adducts - analysis
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Female
Flavonoids - toxicity
General aspects
Humans
Karyotyping
Medical sciences
Organoplatinum Compounds - pharmacokinetics
Organoplatinum Compounds - toxicity
Ovarian Neoplasms - genetics
Ovarian Neoplasms - pathology
Pharmacology. Drug treatments
Piperidines - toxicity
Tumor Cells, Cultured
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Summary:Flavopiridol, the first inhibitor of cyclin-dependent kinases to enter clinical trials, has shown promising antineoplastic activity and is currently undergoing Phase II testing. Little is known about mechanisms of resistance to this agent. In the present study, we have characterized an ovarian carcinoma cell line [OV202 high passage (hp)] that spontaneously developed drug resistance upon prolonged passage in tissue culture. Standard cytogenetic analysis and spectral karyotyping revealed that OV202 hp and the parental low passage line OV202 shared several marker chromosomes, confirming the relatedness of these cell lines. Immunoblotting demonstrated that OV202 and OV202 hp contained similar levels of a variety of polypeptides involved in cell cycle regulation, including cyclin-dependent kinases 2 and 4; cyclins A, D 1 , and E; and proliferating cell nuclear antigen. Despite these similarities, OV202 hp was resistant to flavopiridol and cisplatin, with increases of 5- and 3-fold, respectively, in the mean drug concentrations required to inhibit colony formation by 90%. In contrast, OV202 hp and OV202 displayed indistinguishable sensitivities to oxaliplatin, paclitaxel, topotecan, 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, doxorubicin, vincristine, and 5-fluorouracil, suggesting that the spontaneously acquired resistance was not attributable to altered P-glycoprotein levels or a general failure to engage the cell death machinery. After incubation with cisplatin, whole cell platinum and platinum-DNA adducts measured using mass spectrometry were lower in OV202 hp cells than OV202 cells. Similarly, after flavopiridol exposure, whole cell flavopiridol concentrations measured by a newly developed high performance liquid chromatography assay were lower in OV202 hp cells. These data are consistent with the hypothesis that acquisition of spontaneous resistance to flavopiridol and cisplatin in OV202 hp cells is due, at least in part, to reduced accumulation of the respective drugs. These observations not only provide the first characterization of a flavopiridol-resistant cell line but also raise the possibility that alterations in drug accumulation might be important in determining sensitivity to this agent.
ISSN:1078-0432
1557-3265