Abstract
The ability of two supposed DNA-repair inhibitors to modulate cisplatin-induced cytotoxicity in a human ovarian cancer cell line (CAOV-3) and a human cervical cancer cell line (Me-180) was investigated using a short-term chemosensitivity assay based on bioluminescence of cellular adenosine triphosphate (ATP). Cisplatin concentrations bracketing the reported peak plasma concentration (2.5 μg/ml) were used and the 50% inhibitory concentrations were determined by linear regression of log-transformed survival data. At 2.5 mM, the methylxanthine caffeine enhanced cisplatin sensitivity 2.9-fold in CAOV−3 cells and 2.7-fold in Me−180 cells. At 2.5 mM, pentoxifylline, a closely related methylxanthine, increased cisplatin sensitivity 2.9-fold in CAOV−3 cells and 3.4-fold in Me−180 cells. Chemical modification of cisplatin-induced cytotoxicity by assumed inhibition of DNA-repair mechanisms may hold promise for clinical application in the treatment of gynecological cancer.
Key words: Pentoxifylline, Caffeine, DNA-repair inhibition, Ovarian cancer, Cervical cancer
Abbreviation
- PTX
pentoxifylline
References
- Alberts D, Chen G (1980) Tabular summary of pharmacokinetic parameters relevant to in vitro drug assay. In: Salmon S (ed) Cloning of human tumor stem cells. Liss, New York, pp 351–359 [PubMed] [Google Scholar]
- Beermann B, Ings R, Mansby J, Chamberlain J, McDonald A (1985) Kinetics of intravenous and oral pentoxifylline in healthy subjects. Clin Pharmacol Ther 37:25–28 [DOI] [PubMed] [Google Scholar]
- Biddle W, Ambrus C, Gastpar H, Ambrus J (1984) Antineoplastic effect of the xanthine derivative trental. J Med 15:355–366 [PubMed] [Google Scholar]
- Chou T, Talaly P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55 [DOI] [PubMed] [Google Scholar]
- Collins A (1987) Cellular responses to ionizing radiation: effects of interrupting DNA repair with chemical agents. Int J Radiat Biol 51:971–983 [DOI] [PubMed] [Google Scholar]
- Dixon W (ed) (1988) BMDP statistical software manual. University of California, Berkeley, Calif. [Google Scholar]
- Dobmeyer D, Stine R, Leier C, Greenberg R, Schaal S (1983) The arrhymogenic effects of caffeine in human beings. N Engl J Med 308:814–816 [DOI] [PubMed] [Google Scholar]
- Fingert H, Chang J, Pardee A (1986) Cytotoxic, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents. Cancer Res 46:2463–2467 [PubMed] [Google Scholar]
- Fingert H, Pu A, Chen Z, Googe P, Alley M, Pardee A (1988) In vivo and in vitro enhanced antitumor effects by pentoxifylline in human cancer cells treated with thiotepa. Cancer Res 48:4375–4381 [PubMed] [Google Scholar]
- Fojo A, Hamilton T, Young R, Ozols R (1987) Multidrug resistance in ovarian cancer. Cancer 60:2075–2080 [DOI] [PubMed] [Google Scholar]
- Hamilton T, Young R, Ozols R (1984) Experimental model systems of ovarian cancer; applications to the design and evaluation of new treatment approaches. Semin Oncol 11:285–298 [PubMed] [Google Scholar]
- Kelland L, Steel G (1988) Modification of radiation dose-rate sparing effects in a human carcinoma of the cervix cell line by inhibitors of DNA repair. Int J Radiat Biol 54:229–244 [DOI] [PubMed] [Google Scholar]
- Masuda H, Ozols R, Lai G, Fojo A, Rothenberg M, Hamilton T (1988) Increased DNA repair as a mechanism of acquired resistance to cis-diamminedichloroplatinum in human ovarian cancer cell lines. Cancer Res 48:5713–5716 [PubMed] [Google Scholar]
- Moscow J, Cowan K (1988) Multidrug resistance. J Natl Cancer Inst 80:14–20 [DOI] [PubMed] [Google Scholar]
- Mouelatos D, Dozi-Vassiliades J, Kotsis A, Gourtsas C (1988) Enhancement of cytogenetic damage and of antineoplastic effect by caffeine in Ehrlich ascites tumor cells treated with cyclophosphamide in vivo. Cancer Res 48:1129–1131 [PubMed] [Google Scholar]
- SAS User's Guide (1985) Statistics. 5th edn, Carey, N. C.
- Scanlon K, Kashani-Sabet M, Sowers L (1989) Overexpression of DNA replication and repair enzymes in cisplatin-resistant human colon carcinoma HTC8 cells and circumvention by azidothymidine. Cancer Commun 1:269–275 [PubMed] [Google Scholar]
- Schneider J, Martin M, Erasun F, Matia J, Rodriguez-Escudero F (1990) Cisplatin-containing versus cisplatin-free adjuvant chemotherapy in ovarian carcinoma. Oncology 47:109–111 [DOI] [PubMed] [Google Scholar]
- Sevin BU, Peng Z, Perras J, Ganjei P, Penalver M, Averette H (1988) Application of an ATP-bioluminescence assay in human tumor chemosensitivity testing. Gynecol Oncol 31:191–204 [DOI] [PubMed] [Google Scholar]
- Tomita K, Tsuchiya H, Sasaki T (1989) DNA repair and drug resistance: Enhancement of the effects of anticancer agents by DNA repair inhibitors. Gan To Kagaku Ryoho 16:576–584 [PubMed] [Google Scholar]