Abstract
The use of oncolytic herpes simplex virus type 1 is a promising stategy for cancer treatment. We constructed herpes simplex virus type 1 vector G47Delta by deleting the alpha47 gene and the promoter region of US11 from G207. We now report studies demonstrating the potential of G47Delta as a therapeutic modality for prostate cancer in combination with androgen ablation. The cytopathic activities of G47Delta at low multiplicities of infection was tested in human prostate cancer cell lines LNCaP, PC-3, and DU145 in vitro. Two androgen-dependent mouse s.c. tumor models, murine TRAMP and human HONDA, were used to investigate the in vivo efficacy of G47Delta in combination with androgen ablation. G47Delta at low multiplicities of infection showed more rapid tumor cell killing than G207 in LNCaP and DU145 in vitro and showed a 22-fold higher virus yield in a single-step growth experiment. In vivo, G47Delta treatment resulted in reduced tumor growth of established s.c. TRAMP and HONDA tumors and inhibited the growth of recurrent HONDA tumors that once regressed by androgen ablation therapy. In both TRAMP and HONDA tumor xenografts, the combination therapy of G47Delta with androgen ablation led to significantly enhanced inhibition of the tumor growth and prolonged survival. These results suggest that oncolytic virus therapy with G47Delta can be usefully combined with androgen ablation therapy for the treatment of prostate cancer.
Highlights
The use of oncolytic herpes simplex virus type 1 is a promising stategy for cancer treatment
We show that (a) G47D shows enhanced antitumor activity in prostate cancer cells in vitro and in vivo; (b) combination therapy of G47D and androgen ablation has cooperative effects, resulting in greater inhibition of tumor growth than either therapy alone; and (c) G47D is effective for those prostate cancers that once responded to androgen ablation but eventually became refractory and recurred
DU145 cells were resistant to killing by both G207 and G47D at an multiplicity of infection (MOI) of 0.01 but were killed significantly more rapidly with G47D than G207 at an MOI of 0.1 (P < 0.05 on days 1-4)
Summary
The use of oncolytic herpes simplex virus type 1 is a promising stategy for cancer treatment. The use of oncolytic conditionally replicating herpes simplex virus type 1 (HSV-1) vectors is an attractive strategy for prostate cancer therapy [1]. From G207, we constructed a multimutated, replicationcompetent HSV-1 vector, G47D, by creating a further deletion within the nonessential a47 gene [6] This additional deletion has been shown to provide enhanced viral replication and to partially restore MHC class I expression in infected human cells. We show that (a) G47D shows enhanced antitumor activity in prostate cancer cells in vitro and in vivo; (b) combination therapy of G47D and androgen ablation has cooperative effects, resulting in greater inhibition of tumor growth than either therapy alone; and (c) G47D is effective for those prostate cancers that once responded to androgen ablation but eventually became refractory and recurred
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