Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel.
CV787, a PSA+ prostate cell-specific adenovirus variant, is currently in Phase I/II clinical trials for the treatment of prostate cancer. We have previously demonstrated that a single administration of CV787 at 1 x 10(11) particle/animal could eliminate established tumors within 6 weeks in nude mouse xenografts (Yu et al., Cancer Res., 59: 4200-4203, 1999). We now demonstrate that CV787-mediated replication-dependent cytotoxicity is synergistic with the chemotherapeutic agents paclitaxel (Taxol) or docetaxel (Taxotere) both in vitro and in vivo. In vitro, cells were pretreated with CV787 24 h before taxane, pretreated with taxane 24 h before CV787, or treated with both agents simultaneously. Cell viability was determined at various time points by 3-[4,5-dimethylthiazole-2-4]-2,5-diphenyl-2H-tetrazolium bromide assay, and virus yield was examined by plaque assay. Addition of taxane to CV787 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP, regardless of the timing of administration. There was no reduction in virus replication or specificity of CV787-based cytopathogenicity for prostate cancer cells (approximately 10,000 to 1) with the taxanes. p53 expression was significantly elevated in the cells treated with CV787 and taxane. In vivo, using the PSA+ LNCaP xenograft model of prostate cancer, a single i.v. dose of 1 x 10(8) particles CV787 and docetaxel in combination eliminates large preexistent distant tumors. Toxicity studies do not show a synergistic increase of toxicity of CV787 and taxane. These experiments demonstrate a synergistic antitumor efficacy for CV787 when combined with taxane and demonstrate an in vivo single-dose curative therapeutic index for CV787 of over 1000:1.
Yu
D C
DC
Calydon, Incorporated, Sunnyvale, California 94089, USA.
Chen
Y
Y
Dilley
J
J
Li
Y
Y
Embry
M
M
Zhang
H
H
Nguyen
N
N
Amin
P
P
Oh
J
J
Henderson
D R
DR
D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival; D004279:DNA, Viral / Q000008:administration & dosage; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D043823:Taxoids; D013997:Time Factors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D004279:DNA, Viral; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; D017239:Paclitaxel