Activity of the Adenoviral E1A Deletion Mutant dl922-947 in Ovarian Cancer: Comparison with E1A Wild-type Viruses, Bioluminescence Monitoring, and Intraperitoneal Delivery in Icodextrin

Abstract

The adenoviral mutant dl922-947 has potent activity in a variety of tumors. We investigated the efficacy of dl922-947 in ovarian carcinoma; compared its activity to wild-type adenovirus, dl309, and dl1520; and investigated the use of icodextrin to enhance activity in vivo. We also assessed the utility of luciferase bioluminescence imaging to quantify the response of human ovarian carcinoma xenografts to dl922-947. Ovarian carcinoma cell lines were transfected in vitro with dl922-947, adenovirus 5 wild-type (Ad5 WT), dl309, and dl1520 and monitored for S-phase induction, viral protein expression, replication, and overall survival. In vivo, the efficacy of dl922-947 when delivered in PBS or icodextrin to female nude mice bearing IGROV1 xenografts was determined. In vitro, dl922-947 induced lysis with greater efficacy than Ad5 WT, dl309, or dl1520 in all ovarian carcinoma cell lines tested, which was associated with earlier expression of viral proteins and S-phase induction. The lytic effect in immortalized ovarian surface epithelial cells confirmed that cellular retinoblastoma pathway status is a strong determinant of dl922-947 activity. In vivo, i.p. delivery of dl922-947 (5  10 9 particles daily  5) increased median survival from 20 to 96 days (P < 0.0001) and delivery in icodextrin-enhanced survival further. However, delayed hepatic toxicity was evident in some dl922-947-treated mice, which was not dependent upon viral replication within tumor cells or the liver. dl922-947 has potency in ovarian carcinoma and i.p. delivery in icodextrin may enhance this activity. Immunocompetent models of ovarian carcinoma are required for further evaluation of hepatotoxicity. (Cancer Res 2006; 66(2): 989-98)

Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions

“…Of note, these differences that became evident after only 7 days of culture are expected to amplify upon extended virus propagation. Consistent with findings by others, 8,26,34,35 ONYX-015 was attenuated compared with Ad5, whereas AdD24 was similarly effective as Ad5. In our experiments, the latter was not influenced by the presence or absence of the E3 region, whereas insertion of an RGD motif or a p53 expression cassette yielded a small potency enhancement.…”

An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine

“…22,[28][29][30]44 In contrast, the prototype oncolytic adenovirus dl1520 was significantly less potent than Ad5 in the majority of cell lines, but surprisingly not in Hs766T that express p53. However, the major determinants for efficient replication of the dl1520 mutant appear to be altered nuclear mRNA export in cancer cells.…”

The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models

“…21,23,26 However, both higher levels of replication in normal cells and liver toxicity were reported for the E1ACR2-deleted dl922-947 mutant compared with ONYX-015. 21,27 The first clinical evaluation of an E1ACR2-deleted mutant, adenovirus serotype 5 (Ad5)-D24RGD was recently completed in a phase I trial for recurrent malignant gliomas (http://www.clinicaltrialsfeeds.org/ clinical-trials/show/NCT00805376).…”