Oncolytic herpes simplex virus-1 lacking ICP34.5 induces p53-independent death and is efficacious against chemotherapy-resistant ovarian cancer

Replication-restricted herpes simplex virus-1 (HSV-1) strains lacking ICP34 .5 are emerging as powerful anticancer agents against several solid tumors including epithelial ovarian cancer (EOC), Although chemotherapy-resistant tumors would be likely candidates for treatment with HSV-1 mutants lacking ICP34.5, the efficacy of these mutants on such tumors is unknown. In the pr esent study, we investigated whether chemotherapy resistance affects the re sponse of ovarian cancer cells to HSV-R3616, an ICP34.5-deficient, replicat ion-restricted HSV-I. Primary EOC cultures obtained from patients who varie d in their responses to platinum/paclitaxel induction chemotherapy displaye d similar sensitivity to HSV-R3616. Similarly, chemotherapy-sensitive ovari an cancer cells A2780 and PA-1, possessing wild-type p53, and their respect ive chemotherapy-resistant clones A2780/200CP, lacking p53 function, and PA -1/E6, permanently expressing the HPV E6 gene, were equally sensitive to HS V oncolysis. Because wild-type HSV can ldh cells by apoptosis and nonapopto tic mechanisms, we investigated the involvement of apoptosis and the role o f the p53 tumor suppressor gene in oncolysis induced by HSV-R3616. Infectio n of ovarian cancer cell lines by HSV-R3616 was followed by cell death via apoptosis or nonapoptotic mechanisms as noted by morphology, cell cycle ana lysis, and in situ TUNEL assay. p53 protein levels remained unchanged, and Bar protein levels decreased in cells possessing intact p53 and that mainly underwent HSV-induced apoptosis, Loss of p53 function did not affect the f requency or rate of apoptosis or the sensitivity of EOC cells to the oncoly tic effect of HSV-R3616, These results suggest that recombinant HSV-I lacki ng ICP34.5 is capable of killing ovarian cancer cells that lack p53 functio n, resist apoptosis, and/or are chemotherapy resistant. These data support the hypothesis that HSV-based oncolytic therapy may be efficacious in chemo therapy-resistant tumors, including tumors that are deficient in p53.