Drug resistance in ovarian cancer and potential for its reversal

  • T. C. Hamilton
  • S. W. Johnson
  • A. K. Godwin
  • M. A. Bookman
  • P. J. O’Dwyer
  • K. Hamaguchi
  • K. Jackson
  • R. F. Ozols


Ovarian cancer is characterized as a disease responsive to chemotherapy and current medical treatment strategies are based on the use of a platinum containing anticancer drug, either cisplatin or carboplatin, as the cornerstone of post surgical treatment [1,2]. Unfortunately, the majority of patients with stage III or IV disease are not cured by platinum containing combination chemotherapy and when ovarian cancers recur, especially after short disease-free intervals, they are generally refractory to a variety of other unrelated chemotherapeutic agents [1,3]. It is clear that our understanding of this aspect of ovarian cancer biology could have substantial clinical impact if approaches to reverse the failure of therapy or prevent treatment failure could be discovered.


Ovarian Cancer Cell Line Gynecologic Oncology Group Human Ovarian Cancer Cell Line Buthionine Sulfoximine Develop Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ozols, R.F., O’Dwyer, P.J. and Hamilton, T.C. (1993) Drug resistance in ovarian cancer. In Cancer of the Ovary (eds M. Markman and W. Hoskins), W.B. Saunders, Philadelphia, pp. 261–76.Google Scholar
  2. 2.
    Ozols, R.F. (1992) Ovarian cancer. Part II: Treatment. Curr. Probl Cancer XVI, 67–126.CrossRefGoogle Scholar
  3. 3.
    Ozols, R.F. and Young, R.C. (1991) Chemotherapy of ovarian cancer. Semin. Oncol 18,222–32.PubMedGoogle Scholar
  4. 4.
    Perez, R.P., O’Dwyer, P.J., Handel, L.M. et al (1991) Comparative cytotoxicity of CI-973, cis- platin, carboplatin and tetraplatin in human ovarian cell lines. Int. J. Cancer 48,265–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Mistry, P., Kelland, L.R., Abel, G. et al (1991) The relationships between glutathione, glu- tathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines. Br. J. Cancer 64, 215–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Fojo, A., Hamilton, T.C., Young, R.C. et al (1987) Multidrug resistance in ovarian cancer. Cancer 60 2075–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Cowan, K.H., Goldsmith, M.E., Levine, R.M. et al (1982) Dihydrofolate reductase gene amplification and possible rearrangement in estrogen-responsive methotrexate-resistant human breast cancer cells, J. Biol. Chem. 257, 15079–84.PubMedGoogle Scholar
  8. 8.
    Hamaguchi, K., Godwin, A.K., Yakushiji, M. et al (1993) Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines. Cancer Res. 53, 5225–32.PubMedGoogle Scholar
  9. 9.
    Masuda, H., Ozols, R.F., Lai, G-M. et al (1988) Increased DNA repair as a mechanism of acquired resistance to cis-diamminedichloro- platinum (II) in human ovarian cancer cell lines. Cancer Res. 48,5713–16.PubMedGoogle Scholar
  10. 10.
    Lai, G-M., Ozols, R.F., Smyth, J.F. et al. (1988) Enhanced DNA repair and resistance to cisplatin in human ovarian cancer. Biochem. Pharmacol 37,4597–600.PubMedCrossRefGoogle Scholar
  11. 11.
    Lai, G-M., Ozols, R.F. and Hamilton, T.C. (1989) Role of glutathione on DNA repair in cisplatin resistant human ovarian cancer cell lines. J. Natl Cancer Inst. 81,535–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Johnson, S.W., Perez, R.P., Godwin, A.K. et al (1994) Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines. Biochem. Pharm. 47,689–97.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhen, W.P., Link, C.J., O’Connor, P.M. et al (1992) Increased gene-specific repair of cisplatin interStrand cross-links in cisplatin-resis- tant human ovarian cancer cell lines. Mol Cell Biol 12,3689–98.PubMedGoogle Scholar
  14. 14.
    Van Houten, B. (1990) Nucleotide excision repair in Escherichia coli. Microbiol Rev. 54, 18–51.Google Scholar
  15. 15.
    Thompson, L.H. (1991) Properties and applications of human DNA repair genes. Mutation Res 247,213–19.PubMedCrossRefGoogle Scholar
  16. 16.
    Dabholkar, M., Bostick-Bruton, F., Weber, C. et al (1992) ERCCl and ERCC2 expression in mahgnant tissues from ovarian cancer patients. J. Natl Cancer Inst. 84,1512–17.PubMedCrossRefGoogle Scholar
  17. 17.
    O’Dwyer, P.J., Moyer, J.D., Suffness, M. et al (1994) Antitumor activity and biochemical effects of aphidicolin glycinate (NSC 303812) alone and in combination with cisplatin in vivo. Cancer Res. 54, 724–9.Google Scholar
  18. 18.
    Sessa, C., Zucchetti, M., Davoli, E. et al (1991) Phase I and clinical pharmacological evaluation of aphidicolin glycinate. J. Natl Cancer Inst. 83,1160–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Godwin, A.K., Meister, A., O’Dwyer, P.J. et al (1992) High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase in glutathione synthesis. Proc. Natl Acad. Sci USA 89,3070–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Hosking, L.K., Whelan, R.D.H., Shellard, S.A. e t al (1990) An evaluation of the role of glutathione and its associated enzymes in the expression of differential sensitivities to antitumor agents shown by a range of human tumor cell lines. Biochem. Pharmacol 40,1833–42.Google Scholar
  21. 21.
    Meijer, C., Mulder, N.H., Timmer-Bosscha, H. et al (1992) Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds. Cancer Res 52, 6885–9.PubMedGoogle Scholar
  22. 22.
    Meister, A. and Anderson, M.E. (1993) Glutathione. Ann. Rev. Biochem. 52, 711–60.CrossRefGoogle Scholar
  23. 23.
    Hamilton, T.C., Winker, M.A., Louie, K.G. et al (1985) Augmentation of adriamycin, melphalan and cisplatin cytotoxicity in drug- resistant and -sensitive human ovarian cancer cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem. Pharmacol 34, 2583–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Ozols, R.F., Louie, K.G., Plowman, J. et al (1987) Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor bearing nude mice by buthionine sulfoximine depletion of glutathione.Biochem. Pharmacol 36,147–53.PubMedCrossRefGoogle Scholar
  25. 25.
    O’Dwyer, P.J., Hamilton, T.C., Young, R.C. et al (1992) Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: clinical and biochemical results, J. Natl Cancer Inst. 84,264–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Smith, J.W., Longo, D. L., Alvord, W. G. et al (1993) The effects of treatment with interleukin- a on platelet recovery after high-dose carbo- platin. N. Engl J. Med. 328, 756–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Bookman, M. A, Caron, D. A., Hogan, W. M. et al (1993) Phase-1 evaluation of dose-intense chemotherapy with interleukin-1α: (ILl-α) for gynecologic mahgnancies. Proc. ASCO 12, A868.Google Scholar
  28. 28.
    Calvert, A.H., Newell, D.R., Gumbrell, L.A. et al (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J. Clin. Oncol 11748–56.Google Scholar
  29. 29.
    McGuire, W.P., Hoskins, W.J., Brady, M.F. et al (1993) A Phase III trial comparing cisplatin/Cytoxan (PC) and cisplatin/taxol (PT) in advanced ovarian cancer (AOC). Proc. ASCO 12, A808.Google Scholar
  30. 30.
    Ozols, R. F., Kilpatrick, D., O’Dwyer, P. et al (1993) Phase I and pharmacokinetic study of taxol (T) and carboplatin (C) in previously untreated patients (PTS) with advanced epithelial ovarian cancer (OC): a pilot study of the Gynecologic Oncology Group.Proc. ASCO 12, A824.Google Scholar

Copyright information

© Chapman & Hall 1995

Authors and Affiliations

  • T. C. Hamilton
  • S. W. Johnson
  • A. K. Godwin
  • M. A. Bookman
  • P. J. O’Dwyer
  • K. Hamaguchi
  • K. Jackson
  • R. F. Ozols

There are no affiliations available

Personalised recommendations