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Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells

Cancer Gene Therapy volume 16, pages 551–560 (2009)Cite this article

Abstract

Genetically engineered oncolytic herpes simplex virus-1 (HSV-1) vectors selectively replicate in tumor cells causing direct killing whereas sparing normal cells. One clinical limitation of using oncolytic HSV vectors is their attenuated growth. We hypothesized that the appropriately chosen chemotherapeutic agent combined with an oncolytic HSV could be an effective means to promote augmented prostate cancer cell killing both in vitro and in vivo. Here we have identified that G47Δ synergizes with the microtubule-stabilizing taxane agents docetaxel and paclitaxel to enhance the in vitro killing of prostate cancer cells. In vivo efficacy studies show that when combined with docetaxel, G47Δ could be reduced at least 10-fold. Immunoblot analysis revealed that docetaxel-induced accumulation of the phospho-specific mitotic markers op18/stathmin or histone-H3 was markedly reduced by G47Δ, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47Δ, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47Δ may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo.

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Acknowledgements

We thank Dr Martin Gullberg (Umeå University, Sweden) and Dr Patricia Schaffer (Harvard Medical School, Boston, MA) for very helpful advice and insightful discussions, and Melissa Marinelli for technical support with the mice studies. Fluorescent microscopy was performed in the Microscopy Core of the Program in Membrane Biology, which receives additional support from an Inflammatory Bowel Disease Center Grant DK43351 and a Boston Area Diabetes and Endocrinology Research Center Award DK57521.This study was in part supported by a grant to RLM (RO1 CA102139).

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  1. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    B J Passer, P Castelo-Branco, J S Buhrman, S Varghese, S D Rabkin & R L Martuza

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  1. B J Passer
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  2. P Castelo-Branco
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Correspondence to B J Passer.

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Passer, B., Castelo-Branco, P., Buhrman, J. et al. Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells. Cancer Gene Ther 16, 551–560 (2009). https://doi.org/10.1038/cgt.2009.10

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