BR96 DOXORUBICIN CONJUGATE (BMS-182248) VERSUS DOXORUBICIN - A COMPARATIVE TOXICITY ASSESSMENT IN RATS

The toxicity of BMS-182248, an immunoglobulin (cBR96)-cytotoxic drug ( doxorubicin) conjugate, was investigated in Sprague-Dawley rats at sin gle intravenous doses of 508, 1,200, and 2,550 mg/m(2) (conjugated dox orubicin doses of 14.7, 34.8, and 74 mg/m(2), respectively) and compar ed to that obtained from administration of free doxorubicin at single doses of 33.6 and 72 mg/m(2) (approximately equivalent to that contain ed in the 1,200- and 2,550-mg/m(2) 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/m(2) and of 9 of 20 rats given 33.6 mg/m(2) free doxorubicin were attributed pr imarily to delayed cardiotoxicity and glomerulonephropathy. With BMS-1 82248, death from glomerulonephropathy and cardiotoxicity occurred in only 4 of 20 rats given 2,550 mg/m(2) (74 mg/m(2) doxorubicin equivale nt). No deaths or cardiotoxicity occurred in rats given 508 or 1,200 m g/m(2) BMS-182248. Additional effects noted with either drug included testicular atrophy, axonal degeneration of sciatic nerve and nerve tra cts of brain and spinal cord, teeth (incisor) abnormalities, thymic at rophy, bone marrow hypocellularity, splenic lymphoid and red-pulp depl etion, and increased extramedullary hematopoiesis in the spleen and li ver. Also noted were altered chief cells in the stomach, vacuolation o f adrenal gland and corpora lutea in the ovary, uterine and seminal ve sicle atrophy, ulceration and myocyte regeneration/degeneration in the tongue, increased osteoclasts and osteoblasts in bone, and lymphoid h yperplasia of mandibular lymph node. In general, these effects were mo re severe in doxorubicin-treated rats. All changes observed with EMS-1 82248 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.