A critical examination of the mode of action of quinacrine in the reproductive tract in a 2-year rat cancer bioassay and its implications for human clinical use

• Published in: Regulatory toxicology and pharmacology 2015-04, Vol.71 (3), p.371-378
• Main Authors: Haseman, Joseph K., Growe, Roger G., Zeiger, Errol, McConnell, Ernest E., Luster, Michael I., Lippes, Jack
• Format: Article
• Language: English
• Subjects: Animals; Biological relevance; Carcinogenicity bioassay (CaBio); Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - pathology; Chemistry, Pharmaceutical; Chronic Disease; Chronic inflammation; Contraception; Contraceptive Agents, Female - chemistry; Contraceptive Agents, Female - toxicity; Dose-Response Relationship, Drug; Drug Carriers; Endometriosis - chemically induced; Endometriosis - pathology; Female; Humans; Male; Maximum Tolerated Dose; Maximum tolerated dose (MTD); Methylcellulose - chemistry; Mice; Mode of action; Quinacrine; Quinacrine - chemistry; Quinacrine - toxicity; Rats, Sprague-Dawley; Risk Assessment; Species Specificity; Uterine Neoplasms - chemically induced; Uterine Neoplasms - pathology; Uterus - drug effects; Uterus - pathology
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2015.02.006

•Intrauterine quinacrine produced reproductive tract tumors in a two-year rat CaBio.•Organ toxicity demonstrates that the three highest dose groups exceeded the MTD.•Reproductive tract tumors were highly correlated with chronic inflammation.•In rats with no chronic inflammation, quinacrine was not carcinogenic.•The tumors in this CaBio are not relevant to the proposed human use of quinacrine. A rat carcinogenicity bioassay (CaBio) of quinacrine was reanalyzed to investigate its mode of tumor induction. Quinacrine’s effects in the rat uterus when administered as a slurry in methylcellulose were contrasted with the human clinical experience which uses a solid form of the drug, to determine the relevance of the tumors produced in the rat to safe clinical use of quinacrine for permanent contraception (QS). A review was performed of the study report, dose feasibility studies, and clinical evaluations of women who had undergone the QS procedure. The top three doses of quinacrine in the CaBio exceeded the maximum tolerated dose, and produced chronic damage, including inflammation, resulting in reproductive tract tumors. Chronic inflammation was significantly correlated with the tumors; there was no evidence of treatment-related tumors in animals without chronic inflammation or other reproductive system toxicity. Because such permanent uterine damage and chronic toxicity have not been observed in humans under therapeutic conditions, we conclude that this mode of action for tumor production will not occur at clinically relevant doses in women who choose quinacrine for permanent contraception.