3-(1-deoxyribofuranosyl)benzamide and Disease-Models--Animal

Benzamide riboside (BR), a synthetic C-nucleoside, acts as a strong growth inhibitor of cancer cells in vitro and in vivo. BR, like TR and related nucleoside prodrugs, act by anabolism to NAD analogs. These analogs selectively inhibit IMPDH, leading to depletion of cellular GTP, growth cessation, and cell differentiation. To date only preclinical studies have been carried out. However, in tiazofurin (TR), a related drug, phase I/II clinical trials have been conducted in patients with acute leukemia and shown to be a very promising agent with a response rate of 85% in 26 patients in one of the trials. Tiazofurin is now undergoing phase III clinical trials as a result. Dose limiting toxicity of tiazofurin was headache, somnolence and nausea with no myelosuppression noted. By contrast, BR showed skeletal muscle toxicity, hepatotoxicity and myelosuppression in preclinical data. Skeletal muscle toxicity was noted in the paraspinal muscles and may represent dose-limiting toxicity. Since BR does exhibit myelosuppression, the most common chemotherapy-related side effect in humans, careful judgment is warranted should BR be included in multidrug regimens, although BR's potent cytotoxicity to tumor cells in preclinical models still makes it a promising drug.

Topics: Animals; Antineoplastic Agents; Cell Survival; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; IMP Dehydrogenase; Leukemia L1210; Mice; Mice, Nude; Nucleosides; Ribavirin; Tumor Cells, Cultured

Benzamide riboside (BR) causes apoptosis in multiple tumor cell lines by its inhibition of guanylate biosynthesis. The purpose of this study was to determine the feasibility of the use of BR as a therapeutic agent for hepatic artery infusional cancer therapy in a rabbit VX2 papilloma tumor model.. VX2 tumor was implanted into the left lobe of the liver of each of 14 New Zealand White rabbits and allowed to grow for 19 days +/- 3. The proper hepatic artery was selected with a 3-F catheter via right femoral cutdown. The animals were treated with one infusion of 0.9% saline solution (n = 2), 1 mg/kg BR (n = 4), 5 mg/kg BR (n = 4), or 10 mg/kg BR (n = 4). One animal treated with 5 mg/kg BR did not develop tumor. Livers were explanted after 24 hours and sectioned through the tumor. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed on the slides and they were imaged at a magnification of 40 to detect apoptotic cells. Four random fields were obtained from each slide and the percentage of apoptotic cells was calculated by dividing the number of TUNEL-positive cells by the total number of cells. Sections of liver not involved with tumor were seen in five animals: two that received 1 mg/kg BR, one that received 5 mg/kg, and two that received 10 mg/kg.. The mean tumor apoptosis rates were 1.3% with saline solution treatment, 44.8% with 1 mg/kg BR, 52.7% with 5 mg/kg BR, and 70.7% with 10 mg/kg BR. The mean tumor apoptosis in treated animals was significantly greater than in control animals (P = .003) and mean tumor apoptosis was significantly greater with 10 mg/kg BR than with 1 mg/kg BR (P = .03). There were no apoptotic cells in normal liver treated with 1 mg/kg BR or 10 mg/kg BR. The animal that received 5 mg/kg BR exhibited 10.5% apoptotic cells in the field examined (eight of 76 cells). In the animal treated with 5 mg/kg BR but in which tumor did not grow, only one of 76 cells (0.65%) was apoptotic in the area of the injection scar.. BR induces apoptosis in VX2 tumor in the rabbit model with minimal apoptosis in normal liver.

Topics: Animals; Antineoplastic Agents; Apoptosis; Disease Models, Animal; Dose-Response Relationship, Drug; Feasibility Studies; Female; Hepatic Artery; In Situ Nick-End Labeling; Liver Neoplasms, Experimental; Nucleosides; Papilloma; Rabbits; Tumor Burden