title: 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.
abstract: 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.
authors: J.K. Haseman Consulting, 1054 Tacketts Pond Drive, Raleigh, NC 27614-7886, United States. Electronic address: hasemanjk@aol.com.
authors: Joseph K
authors: JK
authors: Haseman
authors: International Federation for Family Health, 1127 River Forest Road, Pittsboro, NC 27312, United States. Electronic address: growe.roger@gmail.com.
authors: Roger G
authors: RG
authors: Growe
authors: Errol Zeiger Consulting, 800 Indian Springs Road, Chapel Hill, NC 27514, United States. Electronic address: zeiger@nc.rr.com.
authors: Errol
authors: E
authors: Zeiger
authors: Toxpath, Inc., 3028 Ethan Lane, Raleigh, NC 27613, United States. Electronic address: toxpathmcc@bellsouth.net.
authors: Ernest E
authors: EE
authors: McConnell
authors: M.I. Luster Associates, 39 Quail Road, Morgantown, WV 26508, United States. Electronic address: miklus22@comcast.net.
authors: Michael I
authors: MI
authors: Luster
authors: State University of New York at Buffalo, School of Medicine, 31 Hampton Hill Drive, Buffalo, NY 14221, USA. Electronic address: jlip@buffalo.edu.
authors: Jack
authors: J
authors: Lippes
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000473:pathology; D002626:Chemistry, Pharmaceutical; D002908:Chronic Disease; D003271:Contraceptive Agents, Female / Q000737:chemistry / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004715:Endometriosis / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008747:Methylcellulose / Q000737:chemistry; D051379:Mice; D011796:Quinacrine / Q000737:chemistry / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013045:Species Specificity; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000473:pathology; D014599:Uterus / Q000187:drug effects* / Q000473:pathology
chemical_list: D003271:Contraceptive Agents, Female; D004337:Drug Carriers; D008747:Methylcellulose; D011796:Quinacrine
keywords: Biological relevance; Carcinogenicity bioassay (CaBio); Chronic inflammation; Contraception; Maximum tolerated dose (MTD); Mode of action; Quinacrine