Optimisation of replication-selective oncolytic adenoviral mutants in combination with chemotherapeutics.
Replication-selective oncolytic adenoviruses are promising anti-tumour therapeutic agents that have been proven safe in hundreds of patients. While clinical efficacy was limited with the viral mutants alone, outcomes were improved in combination with chemotherapeutics. To further increase efficacy of viral-based therapies it is necessary to explore the cellular mechanisms responsible for enhanced tumour elimination in combination with cytotoxic drugs and to develop mutants with higher potency. To this end we generated a set of novel adenoviral mutants with deletions of the anti-apoptotic E1B19K-gene and the pRb-binding E1ACR2-region. Mutants with the E1B19K deletion significantly increased tumour cell killing in combination with cytotoxic drugs including gemcitabine, 5-fluorouracil (5-FU), docetaxel and mitoxantrone through enhancement of drug-induced apoptosis but did not sensitise normal cells to drugs. The double-deleted AdDeltaDelta (DeltaE1ACR2 and DeltaE1B19K) mutant had high cell killing activity in prostate and pancreatic carcinoma models. Replication was similar to the parental Ad5 and DeltaCR2 viruses in all tumour cells and was attenuated in normal cells. In combination with chemotherapeutics AdDeltaDelta synergistically enhanced cell death in all tested cancer cell lines and in prostate and pancreatic xenografts in vivo. These data suggest that the AdDeltaDelta mutant is a candidate for targeting of solid tumours specifically in combination with cytotoxic factors. Our findings imply that less toxic doses than currently practised in the clinic could efficiently target adenocarcinomas when combined with the AdDeltaDelta mutant.
Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. g.hallden@qmul.ac.uk
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D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077143:Docetaxel; D005472:Fluorouracil / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D008942:Mitoxantrone / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D043823:Taxoids / Q000627:therapeutic use; D014779:Virus Replication / Q000235:genetics; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D008942:Mitoxantrone; D005472:Fluorouracil; D000093542:Gemcitabine