Combined therapy with chemotherapeutic agents and herpes simplex virus type IICP34.5 mutant (HSV-1716) in human non-small cell lung cancer

A replication-selective herpes simplex virus type 1 ICP34.5 mutant (HSV-171 6) has shown efficacy both in vitro and in vivo against human non-small cel l lung cancer (NSCLC) cell lines but complete eradication of tumor has not been accomplished with a single viral treatment in our murine xenograft mod els. Therefore, strategies to enhance the efficacy of this treatment were i nvestigated. We determined the oncolytic activity of,HSV-1716 in NCI-H460 c ells in combination with each of four chemotherapeutic agents: mitomycin C (MMC), cis-platinum II (cis-DDP), methotrexate (MTX), or doxorubicin (ADR), Isobologram analysis was performed to evaluate the interaction between the viral and chemotherapeutic agents. The oncolytic effect of HSV-1716 in com bination with MMC was synergistic in two of five NSCLC cell lines. In the o ther three cell lines, the combined effect appeared additive. No antagonism was-observed, The in vivo effect of this combination was then examined in a murine xenograft model. NCI-H460 flank tumors were directly injected with HSV-1716 (4 x 10(6) PFU) followed by intravenous MMC administration: (0.17 mg/kg) 24 hr later. After 3 weeks, the mean tumor weight in the combined t reatment group was significantly less than either individual treatment in a n additive manner. The synergistic dose of MMC neither augmented nor inhibi ted viral replication in vitro and HSV-1716 infection did not upregulate DT -diaphorase, which is the primary enzyme responsible for MMC activation. In summary, the combination of HSV-1716 with common chemotherapeutic agents m ay augment the effect of HSV-based therapy in the treatment of NSCLC.