Ovarian cancer: strategies for overcoming resistance to chemotherapy


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.

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

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

  2. 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).

  3. 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).

  4. 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).

  5. 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).

  6. 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).

  7. 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).

  8. 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).

  9. 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. 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).

  11. 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.

  12. 12

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

  13. 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).

  14. 14

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

  15. 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.

  16. 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).

  17. 17

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

  18. 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).

  19. 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).

  20. 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).

  21. 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.

  22. 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).

  23. 23

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

  24. 24

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

  25. 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).

  26. 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.

  27. 27

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

  28. 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).

  29. 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).

  30. 30

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

  31. 31

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

  32. 32

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

  33. 33

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

  34. 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).

  35. 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.

  36. 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).

  37. 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).

  38. 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).

  39. 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).

  40. 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).

  41. 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).

  42. 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).

  43. 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).

  44. 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).

  45. 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).

  46. 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).

  47. 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).

  48. 48

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

  49. 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).

  50. 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).

  51. 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).

  52. 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).

  53. 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).

  54. 54

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

  55. 55

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

  56. 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).

  57. 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.

  58. 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).

  59. 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).

  60. 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).

  61. 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).

  62. 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).

  63. 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).

  64. 64

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

  65. 65

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

  66. 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).

  67. 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).

  68. 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).

  69. 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).

  70. 70

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

  71. 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).

  72. 72

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

  73. 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).

  74. 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).

  75. 75

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

  76. 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).

  77. 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).

  78. 78

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

  79. 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).

  80. 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).

  81. 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).

  82. 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).

  83. 83

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

  84. 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).

  85. 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.

  86. 86

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

  87. 87

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

  88. 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).

  89. 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).

  90. 90

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

  91. 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.

  92. 92

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

  93. 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).

  94. 94

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

  95. 95

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

  96. 96

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

  97. 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).

  98. 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).

  99. 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).

  100. 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).

  101. 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).

  102. 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).

  103. 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).

  104. 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).

  105. 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).

  106. 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).

  107. 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).

  108. 108

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

  109. 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).

  110. 110

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

  111. 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).

  112. 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).

  113. 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).

  114. 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).

  115. 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).

  116. 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).

  117. 117

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

  118. 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).

  119. 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).

  120. 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).

  121. 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).

  122. 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).

  123. 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).

  124. 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).

  125. 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).

  126. 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).

  127. 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).

  128. 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).

  129. 129

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

  130. 130

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

  131. 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).

  132. 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).

  133. 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).

  134. 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).

  135. 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).

  136. 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).

  137. 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).

  138. 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).

  139. 139

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

  140. 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).

  141. 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).

  142. 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).

  143. 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. 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. 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).

  146. 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).

  147. 147

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

  148. 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).

  149. 149

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

  150. 150

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

  151. 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).

  152. 152

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

  153. 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).

  154. 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).

  155. 155

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

  156. 156

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

  157. 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).

  158. 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).

  159. 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).

  160. 160

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

  161. 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).

  162. 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).

  163. 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).

  164. 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).

  165. 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).

  166. 166

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

  167. 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).

Download references


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

Author information

Supplementary information

Online Table 1Studies in ovarian cancer of molecular markers of drug resistance or prognosis (PDF 33 kb)

Related links

Related links



ovarian cancer

























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


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.


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


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


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


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


DNA repair in response to incorrect pairing of bases.


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.


(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.


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.


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


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


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


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.


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


(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.


Accumulation of fluid in the peritoneal cavity.


Drainage of ascitic fluid via a percutaneously inserted abdominal catheter.


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


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.


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.


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


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.


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.


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.


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


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

Rights and permissions

Reprints and Permissions

About this article

Further reading