Antitumor Effects of Doxorubicin Against a Virally-Induced Rat Osteosarcoma with Minimal Immunosuppression

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Abstract
Intratibial inoculation of a Moloney strain of Murine Sarcoma Virus (MSV-M) in neonatal Wistar-Lewis rats produced osteosarcoma in 96% of animals and resulted in a median survival of 20 days. Intraperitoneal (i.p.) administration of doxorubicin (adriamycin) (1–2 mg/kg/d, on day 10–12) resulted in reduced tumor growth and prolonged median survival to 95+ and 64 days, respectively. Higher dose doxorubicin (3–4 mg/kg/d, on day 10–12) caused early lethal toxicity. Autopsy data revealed a characteristic sarcomatous tumor producing osteoid. Gross pulmonary nodules appeared in 30% of both treated and untreated animals. Microscopic evaluation of lung tissue revealed anaplastic tumors without osteoid in as many as 90% of rats. Hepatosplenomegaly was usually present but microscopic sections of the spleen did not reveal tumor. Long bone metastases were increased in frequency in those animals receiving doxorubicin. Cell mediated immunity (CMI) to osteosarcoma cells by peripheral blood lymphocytes of tumor-bearing animals was detectable between days 21–48. This was bimodal with an early peak at day 21 (CMI=56%) and a late peak at day 39 (CMI=48%). CMI in rats given 1 mg/kg/d × 3d of doxorubicin was similar, with peak cytotoxicity (CMI=61%) on day 26. Two mg/kg/d × 3d of doxorubicin did not significantly suppress either the early response (CMI=50% on day 22) or the second peak (CMI=38% and 50% on day 40 and 46, respectively). Thus, doxorubicin was effective in decreasing the growth of an MSV-M induced osteosarcoma and prolonging survival in the rat while usually failing to suppress CMI against rat osteosarcoma cells.