Efficacy of a replication-selective adenovirus against ovarian carcinomatosis is dependent on tumor burden, viral replication and p53 status.

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.

journal_name

Gene Ther

journal_title

Gene therapy

authors

Heise C,Ganly I,Kim YT,Sampson-Johannes A,Brown R,Kirn D

doi

10.1038/sj.gt.3301319

keywords:

subject

Has Abstract

pub_date

2000-11-01 00:00:00

pages

1925-9

issue

22

eissn

0969-7128

issn

1476-5462

journal_volume

7

pub_type

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