title: Combining adenoviral oncolysis with temozolomide improves cell killing of melanoma cells.
abstract: Oncolytic adenoviruses are emerging agents for treatment of cancer by tumor-restricted virus replication, cell lysis and virus spread. Clinical studies with first generation oncolytic adenoviruses have revealed that an increased potency is warranted in order to achieve therapeutic efficacy. One approach towards this end is to combine adenoviral oncolysis with chemotherapy. Here, a fundamental requirement is that chemotherapy does not interfere with adenovirus replication in cancer cells. We have previously developed a melanoma-targeted oncolytic adenovirus, Ad5/3.2xTyr, which features tyrosinase promoter regulated replication and enhanced cell entry into melanoma cells. In this study, we investigated a combination treatment of melanoma cells with Ad5/3.2xTyr and temozolomide (TMZ), which produces the same active metabolite as Dacarbazine/DTIC, the standard chemotherapy for advanced melanoma. We report that TMZ does not inhibit adenovirus replication in melanoma cells. Additive or synergistic cell killing of melanoma cells, dependent on the cell line used, was observed. Enhanced cell binding was not responsible for synergism of adenoviral oncolysis and TMZ treatment. We rather observed that higher numbers of virus genomes are produced in TMZ-treated cells, which also showed a cell cycle arrest in the G2 phase. Our results have important implications for the clinical implementation of adenoviral oncolysis for treatment of malignant melanoma. It suggests that such studies are feasible in the presence of TMZ or DTIC chemotherapy and recommends the investigation of a viro-chemo combination therapy.
authors.affiliation: Virotherapy Lab, Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Quirin
authors.forename: Astrid
authors.initials: A
authors.lastname: Mainka
authors.forename: Andrea
authors.initials: A
authors.lastname: Hesse
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
mesh_terms: D000256:Adenoviridae; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016195:G2 Phase / Q000187:drug effects; D005784:Gene Amplification; D016679:Genome, Viral; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D000077204:Temozolomide; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide