[Toxicity studies of VP 16-213 (IV)--Intravenous one-month subacute toxicity in rats].

VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to Crj : CD (Sprague-Dawley) rats of both sexes at dose levels of 0.15, 0.50, 1.5 and 4.5 mg/kg/day for one month with the object of examining its subacute toxicity and the reversibility of toxic effects. For the purpose of comparison, vincristine (abbr. to VCR) was administered in the same manner at dose levels of 0.04 and 0.08 mg/kg/day. The summarized results obtained are as follows: VP 0.50 mg/kg and higher suppressed body weight increase and food intake dose-responsively. VP 4.5 mg/kg brought depilation and anemia, and some of male animals receiving this dose died showing systemic debility, emaciation and ataxia. VP 0.50 mg/kg and higher decreased white blood cell count accompanied with lowered lymphocyte fraction, and 1.5 and 4.5 mg/kg predominantly decreased red blood cell count. VP 1.5 and 4.5 mg/kg lowered total serum protein content and serum alkaline phosphatase activity, and elevated A/G ratio. VP 0.50 mg/kg and higher predominantly decreased testicular weight, and 1.5 and 4.5 mg/kg predominantly brought thymic atrophy, hypoplasia of bone marrow and testicular atrophy with suppression of spermatogenesis and tubular atrophy. VP 4.5 mg/kg induced atrophy of germinal centers and hemosiderosis in spleen, and epididymal atrophy with decrease of sperms in number and appearance of giant cells. Above-described changes excluding the findings on testis and epididymis were generally reversible. Most of the findings for a reference drug, VCR, were similar to those for VP, and their severities brought by VP 1.5 and 4.5 mg/kg were comparable to those by VCR 0.04 and 0.08 mg/kg, respectively. Based on these results, the non-effect dose level of VP under the present experimental condition was estimated to be 0.15 mg/kg/day against rats of both sexes.