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  • Review Article
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Ovarian cancer: strategies for overcoming resistance to chemotherapy

Nature Reviews Cancer volume 3, pages 502–516 (2003)Cite this article

Key Points

  • The standard care for ovarian cancer is a combination of surgery and chemotherapy.

  • Carboplatin and paclitaxel form the cornerstone of chemotherapy in ovarian cancer.

  • In patients with tumour-cell dissemination beyond the ovaries, most relapse and ultimately die due to the development of drug resistance.

  • Drug resistance can arise due to pharmacokinetic, tumour micro-environmental and cancer-cell-specific abnormalities.

  • A number of resistance mechanisms have been defined in vitro. However, the importance of these in patients remains unclear.

  • Novel experimental approaches for analysis of clinical samples, such as comparative genomic hybridization, expression profiling and tissue microarrays, are likely to improve our understanding of drug resistance in patients.

  • Pharmacokinetic approaches to overcoming drug resistance, such as intraperitoneal chemotherapy and high-dose chemotherapy, are under evaluation.

  • A number of novel cytotoxic agents and drugs that target cell survival, drug resistance and apoptotic pathways are now entering clinical trials, and are aimed at overcoming drug resistance.

Abstract

Ovarian cancer is responsible for 4% of deaths from cancer in women. Treatment comprises a combination of surgery and chemotherapy, but patients typically experience disease relapse within 2 years of the initial treatment. Further treatment can extend survival, although relapse eventually occurs again. A better understanding of the mechanisms that underlie this drug resistance should allow treatment to be optimized, so that substantial improvements in the outlook for women with this disease can be achieved.

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Figure 1: Drug-resistance mechanisms.
Figure 2: Models of treatment failure in ovarian cancer.
Figure 3: Signalling pathways involved in taxane and platinum-therapy-induced apoptosis and cell-cycle arrest.
Figure 4: Strategies for identifying mechanisms of drug resistance.

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References

  1. Mutch, D. G. Surgical management of ovarian cancer. Semin. Oncol. 29, 3–8 (2002).

    Article  PubMed  Google Scholar 

  2. Aabo, K. et al. Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group. Br. J. Cancer 78, 1479–1487 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Einzig, A. I., Wiernik, P. H., Sasloff, J., Runowicz, C. D. & Goldberg, G. L. Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J. Clin. Oncol. 10, 1748–1753 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. McGuire, W. P. et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N. Engl. J. Med. 334, 1–6 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Piccart, M. J. et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J. Natl Cancer Inst. 92, 699–708 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Ozols, R. F. et al. Randomized Phase III study of cisplatin (cis)/paclitaxel (PAC) versus carboplatin (CARBO)/PAC in optimal stage III epithelial ovarian cancer (OC): a Gynecologic Oncology Group Trial (GOG 158). Proc. Am. Soc. Clin. Oncol. 18, A1373 (1999).

    Google Scholar 

  7. du Bois, A., Neijt, J. P. & Thigpen, J. T. First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer — a new standard of care? Ann. Oncol. 10, S35–S41 (1999).

    Article  Google Scholar 

  8. Neijt, J. P. et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J. Clin. Oncol. 18, 3084–3092 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. ICON Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 360, 505–515 (2002).

  10. Muggia, F. M. et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J. Clin. Oncol. 18, 106–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Sandercock, J., Parmar, M. K., Torri, V. & Qian, W. First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence. Br. J. Cancer 87, 815–824 (2002). Systematic review and meta-analysis of trials of first-line chemotherapy in ovarian cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Greenlee, R. T., Hill-Harmon, M. B., Murray, T. & Thun, M. Cancer statistics, 2001. CA Cancer J. Clin. 51, 15–36 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Gore, M. E., Fryatt, I., Wiltshaw, E. & Dawson, T. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol. Oncol. 36, 207–211 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Harries, M. & Kaye, S. B. Recent advances in the treatment of epithelial ovarian cancer. Expert Opin. Investig. Drugs 10, 1715–1724 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Kartalou, M. & Essigmann, J. M. Recognition of cisplatin adducts by cellular proteins. Mutat. Res. 478, 1–21 (2001). Review of pathways and proteins involved in the recognition of cisplatin-mediated DNA damage.

    Article  CAS  PubMed  Google Scholar 

  16. Dijt, F. J., Fichtinger-Schepman, A. M., Berends, F. & Reedijk, J. Formation and repair of cisplatin-induced adducts to DNA in cultured normal and repair-deficient human fibroblasts. Cancer Res. 48, 6058–6062 (1988).

    CAS  PubMed  Google Scholar 

  17. Perez, R. P. Cellular and molecular determinants of cisplatin resistance. Eur. J. Cancer 34, 1535–1542 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Nehme, A. et al. Differential induction of c-Jun NH2-terminal kinase and c-Abl kinase in DNA mismatch repair-proficient and deficient cells exposed to cisplatin. Cancer Res. 57, 3253–3257 (1997).

    CAS  PubMed  Google Scholar 

  19. Niedner, H., Christen, R., Lin, X., Kondo, A. & Howell, S. B. Identification of genes that mediate sensitivity to cisplatin. Mol. Pharmacol. 60, 1153–1160 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Vasey, P. A. & on behalf of the Scottish Gynecologic Cancer Trials Group. Preliminary results of the SCOTROC trial: a phase III comparison of paclitaxel-carboplatin and docetaxel-carboplatin as first-line chemotherapy for stage Ic–IV epithelial ovarian cancer. Proc. Am. Soc. Clin. Oncol. 21, A804 (2001).

    Google Scholar 

  21. Dumontet, C. & Sikic, B. I. Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J. Clin. Oncol . 17, 1061–1070 (1999). Review of the molecular biology of taxanes in cancer.

    Article  PubMed  Google Scholar 

  22. Wang, L. G., Liu, X. M., Kreis, W. & Budman, D. R. The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother. Pharmacol. 44, 355–361 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Blagosklonny, M. V. et al. Taxol induction of p21WAF1 and p53 requires c-raf-1. Cancer Res. 55, 4623–4626 (1995).

    CAS  PubMed  Google Scholar 

  24. Haldar, S., Basu, A. & Croce, C. M. Bcl2 is the guardian of microtubule integrity. Cancer Res. 57, 229–233 (1997).

    CAS  PubMed  Google Scholar 

  25. Puthalakath, H., Huang, D. C., O'Reilly, L. A., King, S. M. & Strasser, A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell. 3, 287–296 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Wahl, A. F. et al. Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nature Med. 2, 72–79 (1996). First report of enhanced chemosensitivity due to loss of p53 in cancer.

    Article  CAS  PubMed  Google Scholar 

  27. Iyer, L. & Ratain, M. J. Pharmacogenetics and cancer chemotherapy. Eur. J. Cancer 34, 1493–1499 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Ratain, M. J. Cancer: Principles and Practice of Oncology (eds. DeVita, V. T. J., Hellman, S. & Rosenberg, S. A.) 335–344 (Lippincott Williams & Wilkins, Philadelphia, 2001).

    Google Scholar 

  29. Tomida, A. & Tsuruo, T. Drug resistance mediated by cellular stress response to the microenvironment of solid tumors. Anticancer Drug Des. 14, 169–177 (1999).

    CAS  PubMed  Google Scholar 

  30. Teicher, B. A. Hypoxia and drug resistance. Cancer Metastasis Rev. 13, 139–168 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Green, S. K., Frankel, A. & Kerbel, R. S. Adhesion-dependent multicellular drug resistance. Anticancer Drug Des. 14, 153–168 (1999).

    CAS  PubMed  Google Scholar 

  32. Teicher, B. A. et al. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247, 1457–1461 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Kobayashi, H. et al. Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc. Natl Acad. Sci. USA 90, 3294–3298 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. St Croix, B. et al. Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents. Nature Med. 2, 1204–1210 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976). First publication describing the somatic mutation hypothesis of oncogenesis.

    Article  CAS  PubMed  Google Scholar 

  36. Shah, M. A. & Schwartz, G. K. Cell cycle-mediated drug resistance: an emerging concept in cancer therapy. Clin. Cancer Res. 7, 2168–2181 (2001).

    CAS  PubMed  Google Scholar 

  37. Borst, P., Evers, R., Kool, M. & Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl Cancer Inst. 92, 1295–1302 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Izquierdo, M. A. et al. Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma. J. Natl Cancer Inst. 87, 1230–1237 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Rubin, S. C. et al. Expression of P-glycoprotein in epithelial ovarian cancer: evaluation as a marker of multidrug resistance. Am. J. Obstet. Gynecol. 163, 69–73 (1990).

    Article  CAS  PubMed  Google Scholar 

  40. Arts, H. J. et al. Drug resistance-associated markers P-glycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma. Clin. Cancer Res. 5, 2798–2805 (1999).

    CAS  PubMed  Google Scholar 

  41. Godwin, A. K. et al. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc. Natl Acad. Sci. USA 89, 3070–3074 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Britten, R. A., Green, J. A. & Warenius, H. M. Cellular glutathione (GSH) and glutathione S-transferase (GST) activity in human ovarian tumor biopsies following exposure to alkylating agents. Int. J. Radiat. Oncol. Biol. Phys. 24, 527–531 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Ferrandina, G. et al. Glutathione S-transferase activity in epithelial ovarian cancer: association with response to chemotherapy and disease outcome. Ann. Oncol. 8, 343–350 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Kavallaris, M. et al. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J. Clin. Invest. 100, 1282–1293 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Giannakakou, P. et al. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J. Biol. Chem. 272, 17118–17125 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Sale, S. et al. Conservation of the class I beta-tubulin gene in human populations and lack of mutations in lung cancers and paclitaxel-resistant ovarian cancers. Mol. Cancer Ther. 1, 215–225 (2002).

    CAS  PubMed  Google Scholar 

  47. Koberle, B., Masters, J. R., Hartley, J. A. & Wood, R. D. Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Curr. Biol. 9, 273–276 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Dabholkar, M. et al. ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J. Natl Cancer Inst. 84, 1512–1517 (1992).

    Article  CAS  PubMed  Google Scholar 

  49. Dabholkar, M., Vionnet, J., Bostick-Bruton, F., Yu, J. J. & Reed, E. Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J. Clin. Invest. 94, 703–708 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Plumb, J. A., Strathdee, G., Sludden, J., Kaye, S. B. & Brown, R. Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 60, 6039–6044 (2000).

    CAS  PubMed  Google Scholar 

  51. Brown, R. et al. hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. Oncogene 15, 45–52 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Samimi, G. et al. Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy. Clin. Cancer Res. 6, 1415–1421 (2000).

    CAS  PubMed  Google Scholar 

  53. Gifford, G. et al. Increased microsatellite instability in plasma DNA of ovarian cancer patients at relapse in the SCOTROC1 trial. Proc. Am. Assoc. Cancer Res. 44, A1937 (Toronto, 2003).

    Google Scholar 

  54. Taniguchi, T. et al. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nature Med. 9, 568–574 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Hengartner, M. O. The biochemistry of apoptosis. Nature 407, 770–776 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Perego, P. et al. Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer Res. 56, 556–562 (1996).

    CAS  PubMed  Google Scholar 

  57. Thames, H. D., Petersen, C., Petersen, S., Nieder, C. & Baumann, M. Immunohistochemically detected p53 mutations in epithelial tumors and results of treatment with chemotherapy and radiotherapy. A treatment-specific overview of the clinical data. Strahlenther. Onkol. 178, 411–421 (2002). Systematic review and meta-analysis that demonstrates the inconsistent impact of TP53 mutation on prognosis in ovarian cancer in studies so far.

    Article  PubMed  Google Scholar 

  58. Calvert, A. H. et al. Carboplatin and paclitaxel, alone and in combination: dose escalation, measurement of renal function, and role of the p53 tumor suppressor gene. Semin. Oncol. 26, 90–94 (1999).

    CAS  PubMed  Google Scholar 

  59. Silvestrini, R. et al. The clinical predictivity of biomarkers of stage III-IV epithelial ovarian cancer in a prospective randomized treatment protocol. Cancer 82, 159–167 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Smith-Sorensen, B. et al. Therapy effect of either paclitaxel or cyclophosphamide combination treatment in patients with epithelial ovarian cancer and relation to TP53 gene status. Br. J. Cancer 78, 375–381 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sheridan, E., Silcocks, P., Smith, J., Hancock, B. W. & Goyns, M. H. p53 mutation in a series of epithelial ovarian cancers from the UK, and its prognostic significance. Eur. J. Cancer 30A, 1701–1704 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Sui, L. et al. Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors. Int. J. Oncol. 21, 315–320 (2002).

    CAS  PubMed  Google Scholar 

  63. Mano, Y. et al. Bcl-2 as a predictor of chemosensitivity and prognosis in primary epithelial ovarian cancer. Eur. J. Cancer 35, 1214–1219 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Marx, D. et al. Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer. Anticancer. Res. 17, 2233–2240 (1997).

    CAS  PubMed  Google Scholar 

  65. Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Agus, D. B., Bunn, P. A. Jr, Franklin, W., Garcia, M. & Ozols, R. F. HER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, and ovarian cancer. Semin. Oncol. 27, 53–63; discussion 92–100 (2000).

    CAS  PubMed  Google Scholar 

  67. Marth, C. et al. Cisplatin resistance is associated with reduced interferon-gamma-sensitivity and increased HER-2 expression in cultured ovarian carcinoma cells. Br. J. Cancer 76, 1328–1332 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pegram, M. D. et al. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15, 537–547 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Hengstler, J. G. et al. Contribution of c-erbB-2 and topoisomerase II alpha to chemoresistance in ovarian cancer. Cancer Res. 59, 3206–3214 (1999).

    CAS  PubMed  Google Scholar 

  70. Page, C. et al. Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res. 20, 407–416 (2000).

    CAS  PubMed  Google Scholar 

  71. Mitsuuchi, Y. et al. The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel. Cancer Res. 60, 5390–5394 (2000).

    CAS  PubMed  Google Scholar 

  72. Bellacosa, A. et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 64, 280–285 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Frankel, A. & Mills, G. B. Peptide and lipid growth factors decrease cis-diamminedichloroplatinum-induced cell death in human ovarian cancer cells. Clin. Cancer Res. 2, 1307–1313 (1996).

    CAS  PubMed  Google Scholar 

  74. Furui, T. et al. Overexpression of edg-2/vzg-1 induces apoptosis and anoikis in ovarian cancer cells in a lysophosphatidic acid-independent manner. Clin. Cancer Res. 5, 4308–4318 (1999).

    CAS  PubMed  Google Scholar 

  75. Evan, G. I. & Vousden, K. H. Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342–348 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Pan, B. et al. Reversal of cisplatin resistance in human ovarian cancer cell lines by a c-jun antisense oligodeoxynucleotide (ISIS 10582): evidence for the role of transcription factor overexpression in determining resistant phenotype. Biochem. Pharmacol. 63, 1699–1707 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Scanlon, K. J. et al. Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein. Proc. Natl Acad. Sci. USA 88, 10591–10595 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cabral, F. Factors determining cellular mechanisms of resistance to antimitotic drugs. Drug Resist. Update 4, 3–8 (2001).

    Article  CAS  Google Scholar 

  79. Hamilton, T. C., Young, R. C. & Ozols, R. F. Experimental model systems of ovarian cancer: applications to the design and evaluation of new treatment approaches. Semin. Oncol. 11, 285–298 (1984).

    CAS  PubMed  Google Scholar 

  80. Hamilton, T. C. et al. Characterization of a xenograft model of human ovarian carcinoma which produces ascites and intraabdominal carcinomatosis in mice. Cancer Res. 44, 5286–5290 (1984).

    CAS  PubMed  Google Scholar 

  81. Ozols, R. F. et al. Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor-bearing nude mice by buthionine sulfoximine depletion of glutathione. Biochem. Pharmacol. 36, 147–153 (1987).

    Article  CAS  PubMed  Google Scholar 

  82. Andrews, P. A., Jones, J. A., Varki, N. M. & Howell, S. B. Rapid emergence of acquired cis-diamminedichloroplatinum(II) resistance in an in vivo model of human ovarian carcinoma. Cancer Commun. 2, 93–100 (1990).

    Article  CAS  PubMed  Google Scholar 

  83. Roby, K. F. et al. Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis 21, 585–591 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Orsulic, S. et al. Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell 1, 53–62 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Connolly, D. C. et al. Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer. Cancer Res. 63, 1389–1397 (2003). First description of a transgenic mouse model that spontaneously develops ovarian cancer.

    CAS  PubMed  Google Scholar 

  86. Hahn, W. C. & Weinberg, R. A. Modelling the molecular circuitry of cancer. Nature Rev. Cancer 2, 331–341 (2002).

    Article  CAS  Google Scholar 

  87. Simon, R. & Altman, D. G. Statistical aspects of prognostic factor studies in oncology. Br. J. Cancer 69, 979–985 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Murphy, D., McGown, A. T., Crowther, D., Mander, A. & Fox, B. W. Metallothionein levels in ovarian tumours before and after chemotherapy. Br. J. Cancer 63, 711–714 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Marth, C., Kisic, J., Kaern, J., Trope, C. & Fodstad, O. Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis. Cancer 94, 707–712 (2002).

    Article  PubMed  Google Scholar 

  90. Gray, J. W. & Collins, C. Genome changes and gene expression in human solid tumors. Carcinogenesis 21, 443–452 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Huang, K. C. et al. Relationship of XIST expression and responses of ovarian cancer to chemotherapy. Mol. Cancer Ther. 1, 769–776 (2002). First paper to use expression profiling to study drug resistance in ovarian cancer.

    CAS  PubMed  Google Scholar 

  92. Shridhar, V. et al. Genetic analysis of early- versus late-stage ovarian tumors. Cancer Res. 61, 5895–5904 (2001).

    CAS  PubMed  Google Scholar 

  93. Bingham, C. et al. Identification of gene expression differences in drug resistant and sensitive ovarian tumours using suppression subtractive hybridization. Proc. Am. Assoc. Cancer Res. 42, A660 (2001).

    Google Scholar 

  94. van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Ozols, R. F. Future directions in the treatment of ovarian cancer. Semin. Oncol . 29, 32–42 (2002).

    Article  PubMed  CAS  Google Scholar 

  96. Levin, L. & Hryniuk, W. M. Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J. Clin. Oncol. 5, 756–767 (1987).

    Article  CAS  PubMed  Google Scholar 

  97. Gore, M. et al. Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group. J. Clin. Oncol. 16, 2426–2434 (1998).

    Article  CAS  PubMed  Google Scholar 

  98. Kaye, S. B. et al. Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group. J. Clin. Oncol. 14, 2113–2119 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Cure, H. et al. Phase III randomized trial of high dose chemotherapy and PBSC support as consolidation in patients with responsive low burden advanced ovarian cancer: preliminary results of a GINECO/FNLCC/SFGM–TC study. Proc. Am. Soc. Clin. Oncol. 20, A815 (2001).

    Google Scholar 

  100. Amstrong, D. K. et al. Randomized phase III study of intravenous(IV) paclitaxel and cisplatin versus IV paclitaxel, intraperitoneal(IP) cisplatin and IP paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group trial (GOG 172). Proc. Am. Soc. Clin. Oncol. 21, A803 (2002).

    Google Scholar 

  101. Alberts, D. S. et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N. Engl. J. Med. 335, 1950–1955 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Markham, M. et al. Randomised phase III study of intravenous cisplatin/paclitaxel versus moderately high dose intravenous carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in optimal residual ovarian cancer: an intergroup trial (GOG, SWOG, ECOG). Proc. Am. Soc. Clin. Oncol. 17, A1392 (1998).

    Google Scholar 

  103. Los, G. et al. Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res. 49, 3380–3384 (1989).

    CAS  PubMed  Google Scholar 

  104. Nicholson, S. et al. Radioimmunotherapy after chemotherapy compared to chemotherapy alone in the treatment of advanced ovarian cancer: a matched analysis. Oncol. Rep. 5, 223–226 (1998).

    CAS  PubMed  Google Scholar 

  105. Calvert, H. et al. Randomized phase II trial of two intravenous schedules of the liposomal topoisomerase I inhibitor, NX211, in women with relapsed epithelial ovarian cancer: an NCIC CTG study. Proc. Am. Soc. Clin. Oncol. 21, A830 (2002).

    Google Scholar 

  106. Muggia, F. M. et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J. Clin. Oncol. 15, 987–993 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Sabbatini, P. et al. A Phase I/II of PG-paclitaxel (CT–2103) in patients with recurrent ovarian, fallopian tube, or peritoneal cancer. Proc. Am. Soc. Clin. Oncol. 21, A871 (2002).

    Google Scholar 

  108. Bradley, M. O. et al. Tumor targeting by conjugation of DHA to paclitaxel. J. Control Release 74, 233–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Hasenburg, A. et al. Adenovirus mediated thymidine kinase gene therapy for ovarain cancer: first indications of efficacy. Proc. Am. Soc. Clin. Oncol. 20, A832 (2001).

    Google Scholar 

  110. Gore, M. E. et al. A phase II trial of ZD0473 in platinum-pretreated ovarian cancer. Eur. J. Cancer 38, 2416–2420 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Manzotti, C. et al. BBR 3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin. Clin. Cancer Res. 6, 2626–2634 (2000).

    CAS  PubMed  Google Scholar 

  112. Calvert, H. et al. Phase II clinical study of BBR3464, a novel bifunctional platinum analogue, in patients with ovarian cancer. Eur. J. Cancer 37, A965 (2001).

    Article  Google Scholar 

  113. Piccart, M. J. et al. Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J. Clin. Oncol. 18, 1193–1202 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Dieras, V. et al. Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin +/− taxane-pretreated ovarian cancer patients. Ann. Oncol. 13, 258–266 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Lee, F. Y. et al. BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin. Cancer Res. 7, 1429–1437 (2001).

    CAS  PubMed  Google Scholar 

  116. Kaye, S. et al. Preliminary results from a Phase II trial of EPO906 in patients with advanced refractory ovarian cancer. Eur. J. Cancer 38, A127 (2002).

    Article  Google Scholar 

  117. Scotto, K. W. ET-743: more than an innovative mechanism of action. Anticancer Drugs 13, S3–S6 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Colombo, N. et al. Phase II and pharmacokinetics study of 3-hr infusion of ET-743 in ovarian cancer patients failing platinum–taxanes Proc. Am. Soc. Clin. Oncol. 21, A880 (2002).

    Google Scholar 

  119. Kavanagh, J. J. et al. Phase 2 study of TLK286 (GSTpi–1 activated glutathione analog) in patients with platinum and paclitaxel refractory/resistant advanced epithelial ovarian cancer. Eur. J. Cancer 38, A100 (2002).

    Google Scholar 

  120. Bavetsias, V. et al. Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents. J. Med. Chem. 43, 1910–1926 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Ottone, F. et al. Relationship between folate-binding protein expression and cisplatin sensitivity in ovarian carcinoma cell lines. Br. J. Cancer 76, 77–82 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Toffoli, G. et al. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int. J. Cancer 79, 121–126 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Joly, F. et al. A phase 3 study of PSC 833 in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithlial ovarian cancer or primary cancer of the peritoneum. Proc. Am. Soc. Clin. Oncol. 21, A806 (2002).

    Google Scholar 

  124. Seiden, M. V. et al. A phase II study of the MDR inhibitor biricodar (INCEL, VX-710) and paclitaxel in women with advanced ovarian cancer refractory to paclitaxel therapy. Gynecol. Oncol. 86, 302–310 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Lewandowicz, G. M. et al. Cellular glutathione content, in vitro chemoresponse, and the effect of BSO modulation in samples derived from patients with advanced ovarian cancer. Gynecol. Oncol. 85, 298–304 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. O'Dwyer, P. J. et al. Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer. J. Clin. Oncol. 14, 249–256 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. O'Dwyer, P. J. et al. Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. Cancer Res. 51, 6059–6065 (1991).

    CAS  PubMed  Google Scholar 

  128. Lai, G. M., Ozols, R. F., Young, R. C. & Hamilton, T. C. Effect of glutathione on DNA repair in cisplatin-resistant human ovarian cancer cell lines. J. Natl Cancer Inst. 81, 535–539 (1989).

    Article  CAS  PubMed  Google Scholar 

  129. Sessa, C. et al. Phase I and clinical pharmacological evaluation of aphidicolin glycinate. J. Natl Cancer Inst. 83, 1160–1164 (1991).

    Article  CAS  PubMed  Google Scholar 

  130. Appleton, K. et al. Pharmacodynamic responses to 2'-deoxy-5-azacytidine in mice and humans. Proc. Am. Assoc. Can. Res. 44, A4023 (2003).

    Google Scholar 

  131. Wolf, J. et al. A phase I trial of ADp53 for ovarian cancer patients: correlation with p53 and anti–adenovirus Ab status. Proc. Am. Soc. Clin. Oncol. 19, A1510 (2000).

    Google Scholar 

  132. Buller, R. E. et al. Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500. Cancer Gene Ther. 9, 567–572 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Buller, R. E. et al. A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther. 9, 553–566 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Foster, B. A., Coffey, H. A., Morin, M. J. & Rastinejad, F. Pharmacological rescue of mutant p53 conformation and function. Science 286, 2507–2510 (1999).

    Article  CAS  PubMed  Google Scholar 

  135. Luu, Y., Bush, J., Cheung, K. J. Jr & Li, G. The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway. Exp. Cell Res. 276, 214–222 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Vasey, P. A. et al. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J. Clin. Oncol. 20, 1562–1569 (2002).

    CAS  PubMed  Google Scholar 

  137. Brader, K. R. et al. Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism. Clin. Cancer Res. 3, 2017–2024 (1997).

    CAS  PubMed  Google Scholar 

  138. Hortobagyi, G. N. et al. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J. Clin. Oncol. 19, 3422–3433 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Mendelsohn, J. & Baselga, J. The EGF receptor family as targets for cancer therapy. Oncogene 19, 6550–6565 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. Baselga, J. et al. Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J. Natl Cancer Inst. 85, 1327–1333 (1993).

    Article  CAS  PubMed  Google Scholar 

  141. Ciardiello, F. et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin. Cancer Res. 6, 2053–2063 (2000).

    CAS  PubMed  Google Scholar 

  142. Finkler, N. et al. Phase 2 evaluation of OSI-774, a potent oral antagonist of the EGFR–TK in patients with advanced ovarian carcinoma. Proc. Am. Soc. Clin. Oncol. 20, A831 (2001).

    Google Scholar 

  143. Giaccone, G. et al. A phase III clinical trial of ZD1839 ('Iressa') in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer (INTACT 1). ESMO Congress Abstract 4 (Nice, France, 2002).

  144. Johnson, D. et al. ZD1839 ('Iressa') in combination with paclitaxel and carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: results from a phase III clinical trial (INTACT 2). ESMO Congress Abstract 468 (Nice, France, 2002).

  145. Kris, M. G. et al. A phase II trial of ZD1839 ('Iressa') in advanced non-small-cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc. Am. Soc. Clin. Oncol. 21, A1166 (2002).

    Google Scholar 

  146. Fukuoka, M. et al. Final results from a phase II trial of ZD1839 ('Iressa') for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc. Am. Soc. Clin. Oncol. Vol. 21, A1188 (2002).

    Google Scholar 

  147. Johnston, S. R. Farnesyl transferase inhibitors: a novel targeted therapy for cancer. Lancet Oncol. 2, 18–26 (2001).

    Article  CAS  PubMed  Google Scholar 

  148. Moore, M. et al. Phase I study of the Raf-1 kinase inhibitor BAY43-9006 in patients with advanced refractory solid tumours. Proc. Am. Soc. Clin. Oncol. 21, A1816 (2002).

    Google Scholar 

  149. Hidalgo, M. & Rowinsky, E. K. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19, 6680–6686 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. Adams, J. Proteasome inhibition: a novel approach to cancer therapy. Trends Mol. Med. 8, S49–S54 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. Windbichler, G. H. et al. Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br. J. Cancer 82, 1138–1144 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Med. 5, 157–163 (1999).

    Article  CAS  PubMed  Google Scholar 

  153. Milross, C. G., Peters, L. J., Hunter, N. R., Mason, K. A. & Milas, L. Sequence-dependent antitumor activity of paclitaxel (taxol) and cisplatin in vivo. Int. J. Cancer 62, 599–604 (1995).

    Article  CAS  PubMed  Google Scholar 

  154. Judson, P. L., Watson, J. M., Gehrig, P. A., Fowler, W. C. Jr & Haskill, J. S. Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: possible explanation for failure of combination therapy. Cancer Res. 59, 2425–2432 (1999).

    CAS  PubMed  Google Scholar 

  155. Hansen, S. W. Gemcitabine, platinum, and paclitaxel regimens in patients with advanced ovarian carcinoma. Semin. Oncol. 29, 17–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Kaye, S. B. Future directions for the management of ovarian cancer. Eur. J. Cancer 37 (Suppl. 9), S19–S23 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Bonadonna, G., Zambetti, M. & Valagussa, P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results. JAMA 273, 542–547 (1995).

    Article  CAS  PubMed  Google Scholar 

  158. Vermorken, J. B. et al. Multicenter randomised phase II study of oxaliplatin or topotecan in platinum-pretreated epithelial ovarian cancer patients. Proc. Am. Soc. Clin. Oncol. 20, A847 (2001).

    Google Scholar 

  159. Agarwal, M. et al. A phase I clinical trial of BMS 247550 (NSC71028), an epothilone B derivative, in patients with refractory neoplasms. Proc. Am. Soc. Clin. Oncol. 21, A410 (2002).

    Google Scholar 

  160. Muller, C. Y. et al. Phase I intraperitoneal adenoviral p53 gene transfer in ovarian cancer. Proc. Am. Soc. Clin. Oncol. 20, A1025 (2001).

    Google Scholar 

  161. Baselga, J. et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J. Clin. Oncol. 18, 904–914 (2000).

    Article  CAS  PubMed  Google Scholar 

  162. Tabernero, J. et al. A phase I pharmacokinetic and serial tumour and skin pharmacodynamic study of weekly, every 2 weeks or every 3 weeks 1-hour infusion of EMD 72000, a humanised monoclonal anti–epidermal growth factor receptor antibody, in patients with advanced tumours known to overexpress the EGFR. Eur. J. Cancer 38, A216 (2002).

    Article  Google Scholar 

  163. Baselga, J. et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J. Clin. Oncol. 20, 4292–4302 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Ranson, M. et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J. Clin. Oncol. 20, 2240–2250 (2002).

    Article  CAS  PubMed  Google Scholar 

  165. Herbst, R. S. et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J. Clin. Oncol. 20, 3815–3825 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Schellens, J. et al. Phase I and pharmacologic study with the novel farnesyltransferase inhibitor R115777. Proc. Am. Soc. Clin. Oncol. 19, A715 (2000).

    Google Scholar 

  167. Aghajanian, C. et al. Phase I trial of the proteosome inhibitor PS–341 in advanced malignancy. Proc. Am. Soc. Clin. Oncol. 19, A736 (2000).

    Google Scholar 

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Acknowledgements

The authors are grateful to CRUK, the Kidani Trust and the Sir John Egan Trust for their support.

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Authors and Affiliations

  1. Section of Medicine, Institute for Cancer Research, Sutton, SM2 5NG, Surrey, UK

    Roshan Agarwal & Stan B. Kaye

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  1. Roshan Agarwal
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Supplementary information

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DATABASES

Cancer.gov

ovarian cancer

LocusLink

BAD

BAK

BAX

BCL-2

BCL-XL

BIM

BMF

c-ABL

CD95

ERBB2

EGFR

GST

HIF1

JNK

KIP1

MLH-1

MAPK

PI3K

p53

PKC

TRAIL

Glossary

PROGRESSION-FREE SURVIVAL

The time interval from the start of treatment to disease progression. It is a measure of the clinical benefit from therapy.

OVERALL SURVIVAL

The time interval from the start of treatment to death is a more objective measure of clinical benefit than progression-free survival. However, it is also affected by treatments that might be given after the failure of the treatment under evaluation.

META-ANALYSIS

A statistical technique that is used for combining the results of several randomized clinical trials.

RESPONSE RATE

The percentage of patients in whom treatment results in a significant reduction in tumour size.

COMPLETE RESPONSE

Clinical and radiological resolution of all evidence of a tumour following treatment.

NUCLEOTIDE EXCISION REPAIR

DNA repair in response to damaged bases or the spatial configuration of DNA. The abnormal sequence is excised and replaced by newly synthesized DNA.

MISMATCH REPAIR

DNA repair in response to incorrect pairing of bases.

INTRINSIC APOPTOTIC PATHWAY

Activation of programmed cell death by intracellular signals that are mediated by BAX and BCL2, resulting in the release of cytochrome c and APAF1 from the mitochondrial membrane, with subsequent activation of caspase-9 and downstream effector caspases such as caspase-3.

MAPK PATHWAY

(Mitogen-activated protein kinase pathway). Signal-transduction pathway that is crucial for the integration of mitogenic signals. Activation of this pathway is involved in many cellular processes, including cell-cycle progression.

PROGRESSIVE DISEASE

At least a 20% increase in the sum of the maximum diameter of target tumour lesions, or the appearance of one or more new lesions.

THERAPEUTIC INDEX

Measures the clinical benefit of a treatment relative to its toxicity.

PHARMACOKINETICS

Processes that are involved in the distribution and metabolism of a drug in an organism.

FIRST-PASS METABOLISM

Initial inactivation of a drug following administration, usually by the liver.

PI3K PATHWAY

The phosphatidylinositol 3- kinase (PI3K) family of enzymes are activated in response to a wide variety of stimuli and catalyse the phophorylation of inositol lipids at the D-3 position of the inositol ring. These phosphoinositides act as second messengers; a primary target is the serine/threonine kinase AKT, which phosphorylates several cellular targets, including proteins involved in cell survival, proliferation and migration.

MICROSATELLITE INSTABILITY

Alterations of the length of simple repetitive genomic sequences due to mutations in MMR genes MSH2 or MLH1.

IAP

(Inhibitor of apoptosis proteins). A class of proteins that inhibit caspases and thereby block activation of the effector caspase cascade that is responsible for cell death.

ASCITES

Accumulation of fluid in the peritoneal cavity.

PARACENTESIS

Drainage of ascitic fluid via a percutaneously inserted abdominal catheter.

COMPARATIVE GENOMIC HYBRIDIZATION

(CGH). A method for simultaneously measuring gains or losses in cellular DNA at all chromosomal loci relative to normal genomic DNA

SUBTRACTIVE HYBRIDIZATION

A technique that is used for identifying differentially expressed transcripts between two sources. cDNA from one source is hybridized to mRNA from another source to remove comparably expressed transcripts, and the resulting differentially expressed cDNAs are separated by chromotography.

mRNA EXPRESSION PROFILING

A method for measuring the global pattern of mRNA levels within a cell by hybridization to a preformed array that contains cDNA or oligonucleotides representative of known genes or expressed sequence tags.

LIPOSOMAL DRUGS

Drugs that are encapsulated in a lipid bilayer to alter their pharmacokinetic properties.

ADEPT

A method for the selective delivery of a drug to tumour cells. This is achieved by attaching an enzyme to a tumour-cell-specific antibody, which, in turn, can catalyse the conversion of a systemically administered non-toxic pro-drug to its active form at the tumour-cell surface.

GDEPT

A method for the selective delivery of a drug to tumour cells. This is achieved by using gene-therapy approaches to express a foreign enzyme specifically in tumour cells. The enzyme, in turn, can then catalyse the conversion of a systemically administered non-toxic pro-drug to its active form in the tumour cell.

PARTIAL RESPONSE

At least a 30% reduction in the sum of the maximum diameter of target tumour lesions, with no new lesions or increase in the size of an existing lesion.

STABLE DISEASE

Change in size of tumours not sufficient to be classified as partial response or progressive disease.

RT-PCR

(Reverse transcriptase polymerase chain reaction). Allows the amplification and quantitation of specific mRNA species.

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Agarwal, R., Kaye, S. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 3, 502–516 (2003). https://doi.org/10.1038/nrc1123

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