BR96-Doxorubicin Conjugate (BMS-182248) Versus Doxorubicin: A Comparative Toxicity Assessment in Rats

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Abstract
The toxicity of BMS-182248, an immunoglobulin (cBR96)-cytotoxic drug (doxorubicin) conjugate, was investigated in Sprague-Dawley rats at single intravenous doses of 508, 1,200, and 2,550 mg/m2 (conjugated doxorubicin doses of 14.7, 34.8, and 74 mg/m 2, respectively) and compared to that obtained from administration of free doxorubicin at single doses of 33.6 and 72 mg/m2 (approximately equivalent to that contained in the 1,200- and 2,550-mg/m2 doses of BMS-182248, respectively). Necropsies were conducted on day 8, upon death/moribund sacrifice, or after an approximate 3-mo observation period following completion of treatment. Death/moribundity of all rats that received 72 mg/m2 and of 9 of 20 rats given 33.6 mg/m2 free doxorubicin were attributed primarily to delayed cardiotoxicity and glomerulonephropathy. With BMS-182248, death from glomerulonephropathy and cardiotoxicity occurred in only 4 of 20 rats given 2,550 mg/m2 (74 mg/m2 doxorubicin equivalent). No deaths or cardiotoxicity occurred in rats given 508 or 1,200 mg/m2 BMS-182248. Additional effects noted with either drug included testicular atrophy, axonal degeneration of sciatic nerve and nerve tracts of brain and spinal cord, teeth (incisor) abnormalities, thymic atrophy, bone marrow hypocellularity, splenic lymphoid and red-pulp depletion, and increased extramedullary hematopoiesis in the spleen and liver. Also noted were altered chief cells in the stomach, vacuolation of adrenal gland and corpora lutea in the ovary, uterine and seminal vesicle atrophy, ulceration and myocyte regeneration/degeneration in the tongue, increased osteoclasts and osteoblasts in bone, and lymphoid hyperplasia of mandibular lymph node. In general, these effects were more severe in doxorubicin-treated rats. All changes observed with BMS-182248 were considered primarily due to the effects of doxorubicin and were substantially less severe (most notably cardiotoxicity) compared to those produced by an equivalent amount of doxorubicin.