Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis.
Therapeutic approaches which are effective in tumour cells resistant to conventional chemotherapy would be of value. An E1B 55 kDa-deleted adenovirus (ONYX-015) induces lysis in cells with mutant p53, although the specificity of these observations for different cell types is unclear. We have used a matched set of drug-resistant human ovarian tumour cell lines to examine the potential of ONYX-015 for preferential replication and lysis of drug-resistant ovarian tumour cells with documented alterations in p53 function. Marked preferential replication of ONYX-015 is observed after infection of mutant p53 transfectant and cisplatin-resistant derivatives, compared to the wild-type p53 expressing parental A2780 line. Infection causes increased cytopathic effects in vitro and inhibition of tumour growth in vivo of the drug-resistant derivatives, but not the parental line. In apparent contrast, increased apoptosis and reduced clonogenic survival is induced by ONYX-015 infection of the chemosensitive parental cell line. ONYX-015 induces increased pro-apoptotic BAX and reduced anti-apoptotic BCLX(L) in parental cells, but not in the resistant derivative A2780/cp70. We propose that induction of apoptosis is one factor which prevents ONYX-015 spread and cytolysis after infection of chemosensitive cells, while it is the failure to engage apoptosis in drug-resistant cells that allows preferential viral replication, spread and cytolysis.
Ganly
I
I
CRC Department Medical Oncology, CRC Beatson Laboratories, Glasgow, UK.
Kim
Y T
YT
Hann
B
B
Balmain
A
A
Brown
R
R
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D000970:Antineoplastic Agents; D002945:Cisplatin