Skip to main content
SpringerLink
Log in

Drug resistance in ovarian cancer — the role of p53

  • Article
  • Published:
Pathology & Oncology Research

Abstract

The aims were to determine the importance of p53 and bcl-2 expression on the response to chemotherapy with alkylating agents in patients with ovarian cancer. We have followed the response to chemotherapy in a series of 59 patients with ovarian adenocarcinoma designated as p53 and bcl-2 positive or negative by immunocytochemistry. Of these cases, 50 received either cisplatin + treosulfan or treosulfan alone. Immunocytochemistry for p53 was positive in 28/59 tumors. Patients were grouped according to their response to chemotherapy (stable or progressive disease) assessed at 6, 12, and 18 months. There was increasing divergence of p53+ and p53- tumors over time. Of those which were p53+, 25% showed progression at 6 months, 80% at 12 months and 89% progression at 18 months. In contrast, 23%, 50%, and 67% of p53-tumors showed progression at 6, 12 and 18 months respectively. For bcl-2, in 23/55 positive tumors there was progression in 35%, 78% and 94% compared with 25%, 57% and 59% in bcl-2 negative tumors at 6, 12 and 18 months respectively. Those tumors which were bcl-2 and p53 negative were most likely to progress, while those which were bcl-2 and p53 positive had the best prognosis. These differences did not translate into increased overall survival with minimum follow-up of 12 months. This data lends support to our suggestion that despite initially increased susceptibility to alkylating agents, enhanced genomic instability due to p53 inactivation may render tumors more likely to develop resistance to chemotherapy over time. This effect may be altered by bcl-2 function, lack of which will lead to a good response to chemotherapy as the tumor’s ability to undergo apoptosis will not be compromised.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bosari S, Viale G, Radaelli U, et al: p53 accumulation in ovarian carcinoma and its prognostic implications. Hum Pathol 24:1175–1179, 1993.

    Article  PubMed  CAS  Google Scholar 

  2. Brown R, Clugston C, Burns R, et al: Increased accumulation of p53 protein in cisplatin-resistant cell lines. Int J Cancer 55:678–684, 1993.

    Article  PubMed  CAS  Google Scholar 

  3. Cree IA, Kurbacher CM: Individualising chemotherapy for solid tumors - is there any alternative? Anti-Cancer Drugs 8:541–548, 1997.

    Article  PubMed  CAS  Google Scholar 

  4. Clarke AR, Purdie CA, Harrison DJ, et al: Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362:849–852, 1993.

    Article  PubMed  CAS  Google Scholar 

  5. Diebold J, Baretton G, Felchner M, et al: bcl-2 expression, p53 accumulation, and apoptosis in ovarian carcinomas. Am J Clin Pathol 105:341–349, 1996.

    PubMed  CAS  Google Scholar 

  6. Dong Y, Walsh MD, McGuckin MA et al: Reduced expression of retinoblastoma gene product (pRB) and high expression of p53 are associated with poor prognosis in ovarian cancer. Int J Cancer 74:407–415 1997.

    Article  PubMed  CAS  Google Scholar 

  7. Dowell SP, Hall PA: The p53 tumor suppressor gene and tumor prognosis: is there a relationship? J Pathol 177:221–224, 1995.

    Article  PubMed  CAS  Google Scholar 

  8. el Rouhy S, Thomas A, Costin D, et al: p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 82:3452–3459, 1993.

    Google Scholar 

  9. Eliopoulos AG, Kerr DJ, Herod J, et al: The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. Oncogene 11:1217–1228, 1995.

    PubMed  CAS  Google Scholar 

  10. Eltabbakh GH, Belinson JL, Kennedy AW et al: p53 overex-pression is not an independent prognostic factor for patients with primary ovarian epithelial cancer. Cancer 80:892–898, 1997.

    Article  PubMed  CAS  Google Scholar 

  11. Fan S, Smith ML, Rivet DJ2nd,et al: Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxi-fylline. Cancer Res 55:1649–1654, 1995.

    PubMed  CAS  Google Scholar 

  12. Fan S, El-Diery WS, Bae I, et al: p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res 55:1649–1654, 1995.

    PubMed  CAS  Google Scholar 

  13. Gee JM, Robertson JF, Ellis IO, et al: Immunocytochemical localization of BCL-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy. Int J Cancer 59:619–628, 1994.

    Article  PubMed  CAS  Google Scholar 

  14. Geisler JP, Geisler HE, Wiemann MC, et al: Quantification of p53 in epithelial ovarian cancer. Gynecol Oncol 66:435–438, 1997.

    Article  PubMed  CAS  Google Scholar 

  15. Hartwell LH, Kastan MB: Cell cycle control and cancer. Science 266:1821–1828, 1994.

    Article  PubMed  CAS  Google Scholar 

  16. Havrilesky LJ, Elbendary A, Hurteau JA, et al: Chemotherapy-induced apoptosis in epithelial ovarian cancers. Obstet Gynecol 85:1007–1010, 1995.

    Article  PubMed  CAS  Google Scholar 

  17. Henriksen R, Wilander E, Oberg K: Expression and prognostic significance of Bcl-2 in ovarian tumours. Br J Cancer Nov 72:1324–1329, 1995.

    CAS  Google Scholar 

  18. Herod JJ, Eliopoulos AG, Warwick J, et al: The prognostic significance of Bcl-2 and p53 expression in ovarian carcinoma. Cancer Res 56:2178–2184, 1996.

    PubMed  CAS  Google Scholar 

  19. Jansen J, Schlagbauer-Wadl H, Brown BD: bcl-2 antisense therapy chemosensitises human melanoma in SCID mice. Nature Med 4:232–234, 1998.

    Article  PubMed  CAS  Google Scholar 

  20. Joensuu H, Pylkkanen L, Toikkanen S: Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198, 1994.

    PubMed  CAS  Google Scholar 

  21. Lane DP: p53, guardian of the genome. Nature 358: 15–16, 1992.

    Article  PubMed  CAS  Google Scholar 

  22. Levesque MA, Katsaros D, Yu H, et al: Mutant p53 protein over-expression is associated with poor outcome in patients with well or moderately differentiated ovarian carcinoma. Cancer 75:1327–1338, 1995.

    Article  PubMed  CAS  Google Scholar 

  23. Livingstone LR, White A, Sprouse J, et al: Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70:923–935, 1992.

    Article  PubMed  CAS  Google Scholar 

  24. Lowe SW, Schmitt EM, Smith Sw, et al: p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362; 847–857,1993.

    Article  PubMed  CAS  Google Scholar 

  25. Lowe SW, Bodis S, McClatchey A, et al: p53 status and the efficacy of cancer therapy in vivo. Science 266:807–813, 1994.

    Article  PubMed  CAS  Google Scholar 

  26. Makris A, Powles TJ, Dowsett M, Allred C: p53 protein over-expression and chemoresistance in breast cancer. Lancet 345; 1181–1182,1995.

    Article  PubMed  CAS  Google Scholar 

  27. Marx D, Binder C, Meden H, et al: Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer. Anticancer Res 17:2233–2240, 1997.

    PubMed  CAS  Google Scholar 

  28. Mattieu M-C, Koscielny S, Le Bihan M-L, et al: p53 protein overexpression and chemoresistance in breast cancer. Lancet 345;1182,1995.

    Article  Google Scholar 

  29. Nathan B, Gusterson B, Jadayal D, et al: Expression of bcl2 in primary breast cancer and its correlation with tumour pheno- type. For the International (Ludwig) Breast Cancer Study Group. Ann Oncol 5:409–414, 1994.

    PubMed  CAS  Google Scholar 

  30. Niwa N, Itoh M, Murase T, et al: Alteration of p53 gene in ovarian carcinoma: clinicopathological correlation and prognostic significance. Br J Cancer 70:1191–1197, 1994.

    PubMed  CAS  Google Scholar 

  31. Petty RD, Sutherland LA, Hunter EM, et al: Expression of the p53 tumour suppressor gene product is a determinant of chemo-sensitivity. Biophys Biochem Res Comm 199:264–270, 1994.

    Article  CAS  Google Scholar 

  32. Pietilainen T, Lipponen P, Aaltomaa S, et al: Expression of p53 protein has no independent prognostic value in breast cancer. J Pathol 177:225–232, 1995.

    Article  PubMed  CAS  Google Scholar 

  33. Rohlke P, Milde-Langosch K, Weyland C, et al: p53 is a persistent and predictive marker in advanced ovarian carcinomas: multivariate analysis including comparison with Ki67 immuno-reactivity. J Cancer Res Clin Oncol 123:496–501, 1997.

    Article  PubMed  CAS  Google Scholar 

  34. Shelling AN: Role of p53 in drug resistance in ovarian cancer.Lancet 349:744–745, 1997.

    Article  PubMed  CAS  Google Scholar 

  35. Silber R, Degar B, Costin D, et al: Chemosensitivity of lymphocytes from patients with B-cell chronic lymphocytic leukemia to chlorambucil, fludarabine, and camptothecin analogs. Blood 4:3440–3446, 1994.

    Google Scholar 

  36. Skuse GR, Ludlow JW: Tumour suppressor genes in disease and therapy. Lancet 345:902–906, 1995.

    Article  PubMed  CAS  Google Scholar 

  37. Smith PJ, Soues S, Gottlieb T, et al: Etoposide-induced cell cycle delay and arrest-dependent modulation of DNA topoiso-merase II in small-cell lung cancer cells. Br J Cancer 70:914–921,1994.

    PubMed  CAS  Google Scholar 

  38. van der ZeeAG, Hollema H, Suurmeijer AJ, et al: Value of P-gly-coprotein, glutathione S-transferase pi, c-erbB-2, and p53 as prognostic factors in ovarian carcinomas. J Clin Oncol 13:70–78, 1995.

    PubMed  Google Scholar 

  39. Viale G, Maisonneuve P, Bonoldi E, et al: The combined evaluation of p53 accumulation and of Ki-67 (MIB1) labelling index provides independent information on overall survival of ovarian carcinoma patients. Ann Oncol 8:469–476, 1997.

    Article  PubMed  CAS  Google Scholar 

  40. Wattel E, Preudhomme C, Hecquet B, et al: p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84:3148–3157, 1994.

    PubMed  CAS  Google Scholar 

  41. Yamasaki E, Tokunaga O, Sugimori H: Apoptotic index in ovarian carcinoma: correlation with clinicopathologic factors and prognosis. Gynecol Oncol 66:439–448, 1997.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Dundee, Scotland

    Russel Petty & Iain Duncan

  2. Department of Pathology, Ninewells Hospital and Medical School, Dundee, Scotland

    Alan Evans

  3. Labor für Chemosensitivitatestungen Universitats - Frauenklinik, University of Cologne Medical Center, Cologne, Germany

    Christian Kurbacher

  4. Department of Pathology, Institute of Ophthalmology, University College London, Bath Street, ECIV 9EL, London, England

    Ian Cree

Authors
  1. Russel Petty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Iain Duncan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Kurbacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ian Cree
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian Cree.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Petty, R., Evans, A., Duncan, I. et al. Drug resistance in ovarian cancer — the role of p53. Pathol. Oncol. Res. 4, 97–102 (1998). https://doi.org/10.1007/BF02904701

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02904701

Keywords

Search

Navigation