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. However, up to 40% of men with certain risk factors will develop biochemical failure 5 years after radiotherapy. CV706, a prostate cell-specific adenovirus variant, is currently in clinical trials for the treatment of recurrent organ-confined prostate cancer. We demonstrated previously that a single administration of CV706 at 5 x 10(8) particles/mm3 of tumor eliminated established tumors within 6 weeks in nude mouse xenografts (Rodriguez et al., Cancer Res. 57: 2559-2563, 1997). We now demonstrate that CV706-mediated cytotoxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP and a significant increase of virus burst size, with no reduction in specificity of CV706-based cytopathogenicity for prostate cancer cells. In vivo, prostate-specific antigen (+) LNCaP xenografts of human prostate cancer were treated with CV706 (1 x 10(7) particles/mm3 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 dropped to 4% of baseline at this time point and produced antitumor activity that was 6.7-fold greater than a predicted additive effect of CV706 and radiation. 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 vessel number by 1290% and 600%, respectively. Importantly, no increase in toxicity was observed after combined treatment when compared with CV706 or radiation alone. These data demonstrate that CV706 enhances the in vivo radioresponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.

Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type II diabetes.

Extracts of the creosote bush (Larrea tridentata, family Zygophyllaceae) have long been used as a folk remedy for Type II (non-insulin-dependent) diabetes by native Americans in southwestern North America. In this study we have evaluated the metabolic effects of masoprocol, a pure compound isolated from the creosote bush, in a rat model of Type II diabetes. Animals were fed a 20% fat (by weight) diet for 2 weeks prior to intravenous injection with streptozotocin (STZ, 0.19 mmol/kg). Diabetic animals (glucose 16-33 mmol/l) were treated with vehicle, metformin (0.83 mmol/kg body weight) or masoprocol (0.83 mmol/kg body weight) twice a day for 4 days. Masoprocol treatment lowered glucose concentrations an average of 35% compared with vehicle (14.2+/-1.1 vs 21.7+/-1.0 mmol/l, p < 0.001), a reduction similar to metformin treatment (12.8+/-0.9 mmol/l), without any change in insulin concentration. Masoprocol treatment also lowered triglyceride concentrations 80% compared with vehicle (1.0+/-0.1 vs 4.8+/-0.3 mmol/l, p < 0.001), a reduction far greater than following metformin treatment (3.6+/-0.3 mmol/l). Non-esterified fatty acid and glycerol concentration were decreased by approximately 65% by masoprocol compared with vehicle, a reduction approximately twice as great as seen with metformin (p < 0.001). The effect of masoprocol on in vivo insulin-mediated glucose disposal was evaluated by infusing fat-fed/STZ rats with glucose (0.22 mmol kg x min(-1)) and insulin (30 pmol x kg x min(-1)) for 5 h. In response to the infusion, steady-state plasma glucose concentrations were reduced 30% in masoprocol-treated animals compared with vehicle controls (p < 0.05) with no change noted in rats treated with metformin. The effect of masoprocol treatment was also tested in primary adipocytes isolated from normal animals. Adipocytes treated with masoprocol (30 micromol/l) had higher basal and insulin-stimulated glucose clearance than did adipocytes treated with vehicle (p <0.05). These data show that masoprocol decreases both plasma glucose and triglyceride concentrations in fat-fed/STZ rats, presumably as a result of its ability to both increase glucose disposal and decrease lipolysis.