Abstract
Intraperitoneal (i.p.) recurrence of cisplatin-refractory and p53 mutant ovarian cancer is a major clinical problem, despite surgery and chemotherapy. dl1520 (ONYX-015) is an E1B–55 kDa gene-deleted adenovirus engineered selectively to replicate in and destroy cancer cells lacking functional p53. However, a correlation between efficacy and p53 function has not been definitively studied in vivo to date, and efficacy following i.p. administration had not been previously described. We therefore carried out experiments to address these issues in three nude mouse–human ovarian carcinomatosis xenograft models. Intraperitoneal treatment with dl1520 led to complete tumor eradication and/or significantly improved survival in two p53(−) nude mouse–human ovarian tumor xenograft models. OVCAR3 i.p. xenografts underwent complete regressions in 11 of 12 mice (versus one of seven controls; P = 0.001), while mice bearing cisplatin-resistant A2780 tumors had significantly improved survival versus controls (P = 0.05). In contrast, the A2780 p53(+) ovarian cancer xenograft was resistant to dl1520. The efficacy of i.p. dl1520 in the p53(−) models correlated strongly with tumor burden present at the time of treatment initiation, and no efficacy was seen with non-replicating/UV-inactivated dl1520. Selectively replicating viruses such as dl1520 hold promise as i.p. therapies for p53-deficient and chemotherapy-resistant ovarian carcinomas. A phase I clinical trial of i.p. dl1520 (ONYX-015) is underway in patients with cisplatin-resistant ovarian carcinoma.
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References
Young RC Jr et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials New Engl J Med 1990 322: 1021–1027
McGuire WP et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer New Engl J Med 1996 334: 1–6
Alberts DS et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer New Engl J Med 1996 335: 1950–1955
Kaye SB . Ovarian cancer, from the laboratory to the clinic: challenges for the future Ann Oncol 1996 7: 9–13
Zheng J et al. Genetic disparity between morphologically benign cysts contiguous to ovarian carcinomas and solitary cystadenomas J Natl Cancer Inst 1995 87: 1146–1153
Righetti SC et al. A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma Cancer Res 1996 56: 689–693
Perego P et al. Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems Cancer Res 1996 56: 556–562
Eliopoulos AG et al. The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2 Oncogene 1995 11: 1217–1228
Yaginuma Y, Westphal H . Abnormal structure and function of the p53 gene in human ovarian carcinoma cell lines Cancer Res 1992 52: 4196–4199
Chang F, Syrjanen S, Syrjanen K . Implications of the p53 tumor-suppressor gene in clinical oncology J Clin Oncol 1995 13: 1009–1022
Anthoney DA et al. Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells Cancer Res 1996 56: 1374–1381
Behrens BC et al. Characterization of a cis-diammine dichloroplatinum resistant human ovarian cell line and its use in evaluation of platinum analogues Cancer Res 1987 47: 414–418
Braun et al. Increased accumulation of p53 in cisplatin-resistant ovarian cells Int J Cancer 1993 55: 678–684
Bischoff JR et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells Science 1996 274: 373–376
Rogulski KR et al. In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy Cancer Res 2000 60: 1193–1196
Heise C et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents Nature Med 1997 3: 639–645
Hall AR, Dix BR, O'Carroll SJ, Braithwaite AW . p53-dependent cell death/apoptosis is required for a productive adenovirus infection Nature Med 1998 4: 1068–1072
Harada J, Berk A . p53-independent and -dependent requirements for E1B-55kD in adenovirus type 5 replication J Virol 1999 73: 5333–5344
Goodrum FD, Ornelles DA . p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection J Virol 1998 72: 9479–9490
Scheffner M et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 Cell 1990 63: 1129–1136
Leach FS et al. p53 Mutation and MDM2 amplification in human soft tissue sarcomas Cancer Res 1993 53: 2231–2234
Ganly I et al. A phase I study of ONYX-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer Clin Cancer Res 2000 6: 798–806
Kirn D et al. A phase II trial of intratumoral injection with an E1B-deleted adenovirus, ONYX-015, in patients with recurrent, refractory head and neck cancer Proc Am Soc Clin Oncol 1998 17: 391 (Abstr.)
Khuri F et al. A controlled trial of intratumoral ONYX-015, a selectively replicating adenovirus, in combination with cisplatin and 5-FU in patients with recurrent head and neck cancer Nature Med 2000 6: 879–885
Barker DD, Berk AJ . Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection Virology 1987 156: 107–121
Heise C et al. Intravenous administration of ONYX-015, a selectively replicating adenovirus, induces antitumoral efficacy Cancer Res 1999 59: 2623–2628
Heise C, Williams A, Olesch J, Kirn DH . Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection: intratumoral spread and distribution effects Cancer Gene Ther 1999 6: 499–504
Mujoo K, Maneval D, Anderson S, Gutterman J . Adenoviral-mediated p53 tumor suppressor gene therapy of human ovarian carcinoma Oncogene 1996 12: 1617–1623
Munshi A, Ramesh R, Marrogi A, Freeman S . Evaluation of adenovirus p53-mediated ‘bystander effect’ in vivo Cancer Gene Ther 1997 4: S13 (Abstr.)
Freeman SM et al. The role of cytokines in mediating the bystander effect using HSV-TK xenogeneic cells Cancer Lett 1995 92: 167–174
Mineta T et al. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas Nature Med 1995 1: 938–943
Coukos G et al. Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer Clin Cancer Res 1999 5: 1523–1537
Acknowledgements
We would like to thank Ynez Dugen and Olga Diri for technical assistance with this manuscript; Suzette Weber for animal study work; Prof Stan Kaye and Patrick Trown for many insightful discussions.
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Heise, C., Ganly, I., Kim, Y. et al. Efficacy of a replication-selective adenovirus against ovarian carcinomatosis is dependent on tumor burden, viral replication and p53 status. Gene Ther 7, 1925–1929 (2000). https://doi.org/10.1038/sj.gt.3301319
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DOI: https://doi.org/10.1038/sj.gt.3301319
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