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

被引:32
作者
Passer, B. J. [1 ]
Castelo-Branco, P.
Buhrman, J. S.
Varghese, S.
Rabkin, S. D.
Martuza, R. L.
机构
[1] Massachusetts Gen Hosp, Dept Neurosurg, Brain Tumor Res Ctr, Boston, MA 02114 USA
关键词
prostate cancer; oncolytic HSV's; taxanes; PROTEIN-SYNTHESIS; FLAVOPIRIDOL; REPLICATION; COMBINATION; PACLITAXEL; THERAPY; ACTIVATION; EXPRESSION; INHIBITOR; APOPTOSIS;
D O I
10.1038/cgt.2009.10
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 G47 Delta 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, G47 Delta 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 G47 Delta, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47 Delta, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47 Delta may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo. Cancer Gene Therapy (2009) 16, 551-560; doi:10.1038/cgt.2009.10; published online 6 February 2009
引用
收藏
页码:551 / 560
页数:10
相关论文
共 31 条
[1]   Effect of chemotherapy-induced DNA repair on oncolytic herpes simplex viral replication [J].
Aghi, M ;
Rabkin, S ;
Martuza, RL .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (01) :38-50
[2]  
Cassady KA, 1998, J VIROL, V72, P7005
[3]   Cell death by mitotic catastrophe: a molecular definition [J].
Castedo, M ;
Perfettini, JL ;
Roumie, T ;
Andreau, K ;
Medema, R ;
Kroemer, G .
ONCOGENE, 2004, 23 (16) :2825-2837
[4]  
Chen JG, 2003, CANCER RES, V63, P7891
[5]  
Chen JG, 2002, CANCER RES, V62, P1935
[6]  
CHOU J, 1995, P NATL ACAD SCI USA, V98, P6396
[7]   QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].
CHOU, TC ;
TALALAY, P .
ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55
[8]   Herpes simplex virus type 1 infection imposes a G1/S block in asynchronously growing cells and prevents G1 entry in quiescent cells [J].
Ehmann, GL ;
McLean, TI ;
Bachenheimer, SL .
VIROLOGY, 2000, 267 (02) :335-349
[9]   5-fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer [J].
Eisenberg, DP ;
Adusumilli, PS ;
Hendershott, KJ ;
Yu, ZK ;
Mullerad, M ;
Chan, MK ;
Chou, TC ;
Fong, Y .
JOURNAL OF GASTROINTESTINAL SURGERY, 2005, 9 (08) :1068-1077
[10]   Oncolytic herpes simplex virus vector G47Δ in combination with androgen ablation for the treatment of human prostate adenocarcinoma [J].
Fukuhara, H ;
Martuza, RL ;
Rabkin, SD ;
Ito, Y ;
Todo, T .
CLINICAL CANCER RESEARCH, 2005, 11 (21) :7886-7890