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/m2, 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.

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PubMedDate not supplied

Etoposide- and BMY-40481-induced sensory neuropathy in mice.

The effects of high toxic doses of the anticancer drugs, etoposide and its phosphate derivative, BMY-40481, on the nervous system of female CD-1 mice were examined by light microscopy (LM) and transmission electron microscopy. Mice were euthanatized 4 wk following a single iv injection of either 0, 50, 100, or 150 mg/kg of BMY-40481 or 44 or 88 mg/kg of etoposide. Mice treated with 100 or 150 mg/kg of BMY-40481 or 88 mg/kg of etoposide had clinical symptomology of progressive ataxia, impaired righting reflex, and splaying and paresis of fore- and hindlimbs at day 8. Similar, dose-related LM changes were observed with both drugs at all doses and consisted of degeneration of dorsal root ganglion cells and axonal degeneration of their distal and proximal processes in peripheral nerves, dorsal spinal roots, and dorsal funiculi of spinal cord. Axonal degeneration was characterized by LM as shrinkage, swelling, and fragmentation of axon cylinders accompanied by secondary demyelination. Degenerative changes in ganglion cell bodies included eccentric nuclei, cytoplasmic vacuolation, central chromatolysis, and peripheral clumping of Nissl's bodies. Ultrastructurally, ganglion cell bodies had focally extensive dilation of the rough endoplasmic reticulum, mitochondrial swelling, increased numbers of phagolysosomes and prominent aggregations of microfilaments (globular filamentous bodies). Ultrastructural axonal changes occurred primarily in large, myelinated fibers and consisted of axonal swelling or loss, thinning of myelin sheaths, and a decrease in the number of organelles. This is the first report of etoposide-related sensory neuropathy in laboratory rats, a model that my be useful for the study of etoposide-related peripheral neuropathy in humans.

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