Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1994 Jan;69(1):1–7. doi: 10.1038/bjc.1994.1

Mechanism of action of an orally administered platinum complex [ammine bis butyrato cyclohexylamine dichloroplatinum (IV) (JM221)] in intrinsically cisplatin-resistant human ovarian carcinoma in vitro.

M J McKeage 1, G Abel 1, L R Kelland 1, K R Harrap 1
PMCID: PMC1968778  PMID: 8286188

Abstract

Intrinsic resistance to existing clinical platinum drugs is a major cause of treatment failure; moreover, these agents have the drawbacks of cross-resistance and intravenous administration. The mechanism of intrinsic cisplatin resistance and the mechanism of circumvention of intrinsic resistance by a member (JM221) of the ammine/amine platinum (IV) dicarboxylate class of platinum complex was studied in intrinsically resistant (SKOV-3) and sensitive (41M) human ovarian carcinoma cell lines. JM221 reduced the cisplatin resistance factor nine- to 2.7-fold, was more potent than cisplatin and showed marked time-dependent cytotoxicity. Cellular platinum accumulation was 20- to 40-fold greater (P < 0.001), and DNA platination was fourfold greater (P < 0.02), immediately following 2 h equimolar exposure to JM221, compared with cisplatin. DNA platinum levels decreased following cisplatin exposure with a half-life approximating 48 h in both lines, while no net removal of DNA-bound platinum was recorded following JM221 exposure. JM221 caused DNA interstrand cross-linking, but this was 10-20% less frequent with JM221 than with cisplatin when expressed as a proportion of total DNA platinum lesions. Cisplatin DNA interstrand cross-linking was twofold greater in the intrinsically sensitive line (41M) than in the resistant line (SKOV-3) over a range of concentrations and time-points. Neither cellular platinum accumulation, levels of DNA platination nor the rate of removal of DNA-bound platinum in the two cell lines related to their ninefold difference in cisplatin sensitivity. Intrinsic cisplatin resistance appears to be attributable to the inhibition of formation of bifunctional DNA lesions, while the circumvention of intrinsic resistance by JM221 seems to be the result of both improved transport properties and circumvention of DNA repair mechanisms.

Full text

PDF
1

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alberts D. S., Green S., Hannigan E. V., O'Toole R., Stock-Novack D., Anderson P., Surwit E. A., Malvlya V. K., Nahhas W. A., Jolles C. J. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol. 1992 May;10(5):706–717. doi: 10.1200/JCO.1992.10.5.706. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. A., Howell S. B. Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. Cancer Cells. 1990 Feb;2(2):35–43. [PubMed] [Google Scholar]
  3. BURTON K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J. 1956 Feb;62(2):315–323. doi: 10.1042/bj0620315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dabholkar M., Bostick-Bruton F., Weber C., Bohr V. A., Egwuagu C., Reed E. ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst. 1992 Oct 7;84(19):1512–1517. doi: 10.1093/jnci/84.19.1512. [DOI] [PubMed] [Google Scholar]
  5. Extra J. M., Espie M., Calvo F., Ferme C., Mignot L., Marty M. Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol. 1990;25(4):299–303. doi: 10.1007/BF00684890. [DOI] [PubMed] [Google Scholar]
  6. Gore M. E., Fryatt I., Wiltshaw E., Dawson T., Robinson B. A., Calvert A. H. Cisplatin/carboplatin cross-resistance in ovarian cancer. Br J Cancer. 1989 Nov;60(5):767–769. doi: 10.1038/bjc.1989.356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hills C. A., Kelland L. R., Abel G., Siracky J., Wilson A. P., Harrap K. R. Biological properties of ten human ovarian carcinoma cell lines: calibration in vitro against four platinum complexes. Br J Cancer. 1989 Apr;59(4):527–534. doi: 10.1038/bjc.1989.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kelland L. R., Murrer B. A., Abel G., Giandomenico C. M., Mistry P., Harrap K. R. Ammine/amine platinum(IV) dicarboxylates: a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin-resistant human ovarian carcinoma cell lines. Cancer Res. 1992 Feb 15;52(4):822–828. [PubMed] [Google Scholar]
  9. Kirby K. S., Cook E. A. Isolation of deoxyribonucleic acid from mammalian tissues. Biochem J. 1967 Jul;104(1):254–257. doi: 10.1042/bj1040254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Knox R. J., Friedlos F., Lydall D. A., Roberts J. J. Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res. 1986 Apr;46(4 Pt 2):1972–1979. [PubMed] [Google Scholar]
  11. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  12. Mistry P., Kelland L. R., Abel G., Sidhar S., Harrap K. R. The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines. Br J Cancer. 1991 Aug;64(2):215–220. doi: 10.1038/bjc.1991.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Neijt J. P., ten Bokkel Huinink W. W., van der Burg M. E., van Oosterom A. T., Willemse P. H., Vermorken J. B., van Lindert A. C., Heintz A. P., Aartsen E., van Lent M. Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer. 1991;27(11):1367–1372. doi: 10.1016/0277-5379(91)90011-2. [DOI] [PubMed] [Google Scholar]
  14. Parker R. J., Eastman A., Bostick-Bruton F., Reed E. Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest. 1991 Mar;87(3):772–777. doi: 10.1172/JCI115080. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES