title: Assessment of chronic toxicity and carcinogenicity in an accelerated cancer bioassay in rats of Nifurtimox, an antitrypanosomiasis drug.
abstract: The chronic toxicity and carcinogenicity of Nifurtimox (NFX), a 5-nitrofuran derivative used in the treatment of American trypanosomiasis, were studied in male and female Wistar rats in an accelerated cancer bioassay (ACB). The ACB is a mechanistic initiation/promotion chronic toxicity and carcinogenicity bioassay designed to assess potential carcinogenic activity of a test substance in critical organs and tissues of rodents in which human carcinogens are active. The organs studied were liver, lungs, urinary bladder (UB), mammary gland (MG), bone marrow, spleen, kidneys, colon, stomach and any grossly observed lesions. NFX is a genotoxin which has been reported previously to exert a variable degree of carcinogenic activity in rat liver, kidney, UB and MG. The present study was undertaken to assess whether NFX has initiating activity in these four named target sites. In the initiation phase, groups of 20 Wistar rats were given NFX daily in the diet at 0.2% for the first 12 weeks of the study to assess initiating activity, followed by promoters (PROs) for four organs for an additional 24 weeks. NFX was compared to the following known initiators (INs) for each of these four tissues: diethylnitrosamine (DEN) for liver and kidney, N-butyl-N(4-hydroxybutyl)nitrosamine (BBN) for UB and 7,12-dimethylbenz(a)anthracene (DMBA) for MG. PROs included phenobarbital (PB) for liver and kidney, nitrilotriacetic acid (NTA) for UB, and diethylstilbestrol (DES) for MG. NFX was also administered continuously without PROs for 40 weeks. At the end of dosing (40 weeks) and at the end of recovery (52 weeks), animals were sacrificed and subjected to complete gross and histopathological examinations, along with evaluations of body weight gain over time and terminal body weights. Mortality was highest with DEN+PB (group 6) (40%), followed by BBN+NTA (group 7) (15%) and NFX+DES (group 5) and DMBA+DES (group 8) (10% each). The same groups also showed significant reductions in body weight gain over time and terminal body weights at sacrifice. In these groups, the expected preneoplastic, neoplastic and metastatic neoplastic lesions were produced, demonstrating the sensitivity of the model. In groups given NFX+PROs (groups 3-5), either no neoplasms occurred (group 4) or only single neoplasms (groups 3 and 5). In contrast, the PROs all elicited tumors in groups given INs (groups 6-8). Also, NFX given alone for 40 weeks did not produce any chronic toxicity, preneoplastic or neoplastic lesions. Thus, in this study, NFX did not demonstrate chronic toxicity or carcinogenicity. Moreover, in four target sites, i.e., liver, kidney, UB and MG, it exhibited no neoplastic initiating activity manifested by PROs for these four target sites.
authors.affiliation: Department of Pathology, New York Medical College, Basic Science Building, Valhalla, NY 10595, USA. mjiatropoulos@aol.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Iatropoulos
authors.forename: C X
authors.initials: CX
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: von Keutz
authors.forename: G M
authors.initials: GM
authors.lastname: Williams
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000145:classification / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D003043:Cocarcinogenesis; D004359:Drug Therapy, Combination; D005260:Female; D008136:Longevity / Q000187:drug effects; D008297:Male; D009374:Neoplasms, Experimental / Q000209:etiology*; D009547:Nifurtimox / Q000145:classification / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D036401:Toxicity Tests, Chronic; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000977:Antiparasitic Agents; D009547:Nifurtimox