Suramin-induced neuropathy in an animal model.
Suramin is being used either alone, or in combination with other chemotherapeutic agents, in the treatment of hormone-refractory or metastatic prostate cancer. Use of this potentially valuable chemotherapy is limited by a dose-dependent polyneuropathy. It has been difficult in human studies to characterize peripheral suramin toxicity separately from cancer-related neuropathy. To characterize suramin-induced neuropathy in a rat model, adult rats were given either a single dose of 500 mg/kg (high dose) or 50 mg/kg (low dose) weekly suramin for 2 months. Electrophysiology and peroneal/sural nerve morphometry were performed. In high dose animals, neuropathy developed within 2 weeks, most severe in the digital sensory responses (DSR) (p<0.05) and tail and hind limb compound muscle action potential (p<0.001). Histologically, there was evidence of axonal degeneration and axon atrophy. With low dose suramin, the DSR (p<0.05) and tail distal sensory and motor responses (p<0.01) were most severely affected at 2 months. Axonal degeneration was seen in teased fibers from most animals. With TEM, there were abundant characteristic lysosomal inclusion bodies in DRG and Schwann cells. Electrophysiological and histological evidence of peripheral demyelination was rare, being observed in only one animal. Suramin induced a length, dose and time-dependent axonal sensorimotor polyneuropathy associated with axonal degeneration, atrophy, and accumulation of glycolipid lysosomal inclusions.
Russell
J W
JW
University of Michigan, Department of Neurology, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, MI 48109-0588, USA. jruss@umich.edu
Gill
J S
JS
Sorenson
E J
EJ
Schultz
D A
DA
Windebank
A J
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001369:Axons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D002479:Inclusion Bodies / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027161:Satellite Cells, Perineuronal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D013498:Suramin / Q000633:toxicity*; D015996:Survival Rate
D000970:Antineoplastic Agents; D013498:Suramin