TOXICITY OF THE NOVEL ANIMAL-DERIVED ANTICANCER AGENT, VRCTC-310 - ACUTE AND SUBCHRONIC STUDIES IN BEAGLE DOGS

Acute and subchronic toxicities of VRCTC-310, a combination product of crotoxin (CT) and cardiotoxin (CD), which has shown antitumor activit y in vivo, have been studied in Beagle dogs, Single i.m. doses of 0.25 , 0.5 and 1.0 mg/kg resulted in dose-dependent local muscular toxicity consisting of myofiber atrophy, interstitial edema and macro-phage in filtration. Also, AST, ALT and LDH levels increased on day 2, returnin g to normal values on days 6-8. Local lesions were absent after recove ry on day 45. At 2.0 mg/kg, signs of neurotoxicity (ataxia) appeared, in addition to vomitus, salivation, hematuria and myotoxicity in tongu e and diaphragm on day 8. Local lesions healed with fibrosis at the si te of injection on day 45. Administration of fixed (0.025 and 0.05 mg/ kg) or escalating (0.025-0.1 mg/kg) daily doses for 30 days also produ ced local muscular damage, which was absent at day 75. The increases i n AST, ALT and LDH serum activities on days 2-4 were independent of do sing schedule and sharply decreased on day 8, despite continuation of treatment. An escalating dose schedule of 0.025-2.0 mg/kg showed local muscle damage at the site of injection on day 31, however, there were no lesions of myotoxicity in the tongue or diaphragm and no clinical signs of neurotoxicity were observed, Animals tolerated the subchronic treatment better than the acute. The resolution of serum enzymes to n ormal values during treatment may be attributed to a decrease of sensi tivity to VRCTC-310-mediated myotoxic effects.