The alkylating agent penclomedine induces degeneration of purkinje cells in the rat cerebellum

• Published in: Investigational new drugs 2003-08, Vol.21 (3), p.269-279
• Main Authors: O'REILLY, Seamus, O'HEARN, Elizabeth, STRUCK, Robert F, ROWINSKY, Eric K, MOLLIVER, Mark E
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - metabolism; Antineoplastic Agents - toxicity; Ataxia; Biological and medical sciences; Cancer; Chemotherapy; Dose-Response Relationship, Drug; Drug dosages; Drug toxicity and drugs side effects treatment; Injections, Intraperitoneal; Male; Medical sciences; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Neuropathology; Neurotoxicity; Pharmacology. Drug treatments; Picolines - blood; Picolines - metabolism; Picolines - toxicity; Plasma; Purkinje Cells - drug effects; Purkinje Cells - pathology; Rats; Rats, Sprague-Dawley; Rodents; Toxicity; Toxicity: nervous system and muscle; Vehicles
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1023/A:1025456224751

Penclomedine (PEN), a multichlorinated alpha-picoline derivative which is metabolized to highly reactive alkylating species, was selected for clinical development due to its prominent activity against a wide range of human tumor xenografts when administered either parentally or orally. Its principal dose-limiting toxicity in preclinical and clinical studies has been neurocerebellar toxicity, which has been related to the magnitude of peak plasma PEN concentrations, but not to plasma concentrations of its putative principal alkylating metabolite, 4,o-demethylpenclomedine (DMPEN). These observation, as well as PEN's toxicologic, pharmacologic, and tissue distribution profiles, have suggested that the parent compound is primarily responsible for cerebellar toxicity. The studies described in this report were undertaken to characterize the neuropathology of PEN neurotoxicity, with a long-term goal of developing strategies to maximize its therapeutic index. Male Sprague-Dawley rats were treated with therapeutically relevant doses of PEN, orally and intraperitoneally (i.p.), on various administration schedules, and DMPEN administered i.p. The animals were monitored for neurotoxicity, and brain sections were examined for neuropathology, particularly Purkinje cell loss and neuronal injury. Brain sections were stained using standard histochemical techniques and immunostained with OX-42 to detect microglial cells that are activated following neuronal damage, and calbindin D(28K), a calcium-binding protein expressed by cerebellar Purkinje cells. Dose-related neurocerebellar toxicity associated with parasagittal bands of Purkinje cell degeneration and microglial activation in the cerebellar vermis were evident in rats treated with PEN 100-400 mg/kg i.p. as a single dose. Neuronal injury was not observed in other regions of the brain. Furthermore, neither clinical nor histopathological evidence of cerebellar toxicity was apparent in rats treated with similar total doses of PEN administered i.p. on a dailyx5-day dosing schedule. Similar histological findings, in an identical neuroanatomical distribution, were observed in rats treated with PEN orally; however, the magnitude of the neuronal toxicity was much less than in animals treated with equivalent doses of PEN administered i.p. Although acute lethality occurred in some rats treated with equimolar doses of DMPEN as a single i.p. treatment, surviving animals exhibited neither signs nor histopathological evidence of neur