CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity

Radiation is an effective means of treating localized prostate cancer. Howe ver, up to 40% of men with certain risk factors will develop biochemical fa ilure 5 years after radiotherapy. CV706, a prostate cell-specific adenoviru s variant, is currently in clinical trials for the treatment of recurrent o rgan-confined prostate cancer. We demonstrated previously that a single adm inistration of CV706 at 5 x 10(8) particles/mm(3) of tumor eliminated estab lished tumors within 6 weeks in nude mouse xenografts (Rodriguez et al,, Ca ncer Res. 57: 2559-2563, 1997), We now demonstrate that CV706-mediated cyto toxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human p rostate cancer cell line LNCaP and a significant increase of virus burst si ze, with no reduction in specificity of CV706-based cytopathogenicity for p rostate cancer cells. In vivo, prostate-specific antigen (+) LNCaP xenograf ts of human prostate cancer were treated with CV706 (1 x 10(7) particles/mm 3 of tumor), 10 Gy of single fraction local tumor radiation, or both. Tumor volumes of the group treated with CV706 or radiation was 97 % or 120 % of baseline 6 weeks after treatment. However, when the same dose of CV706 was followed 24 h later with the same dose of radiation, the tumor volume dropp ed to 4 % of baseline at this time point and produced antitumor activity th at was 6.7-fold greater than a predicted additive effect of CV706 and radia tion. Histological analyses of tumors revealed that, compared with CV706 or radiation alone, combination treatment with two agents increased necrosis by 180 % and 690 %, apoptosis by 330 % and 880 %, and decreased blood vesse l number by 1290 % and 600 %, respectively. Importantly, no increase in tox icity was observed after combined treatment when compared with CV706 or rad iation alone. These data demonstrate that CV706 enhances the in vivo radior esponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.