DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).
Cancer chemoprevention is the use of pharmacologic agents to inhibit the development of cancer. The adrenal steroid dehydroepiandrosterone (DHEA) has demonstrated chemopreventive efficacy in animal models of tumorigenesis. However, due to DHEA's undesirable hormonal actions, the fluorinated analog fluasterone (fl-DHEA), which also has chemopreventive characteristics, was synthesized as a potential alternate agent. It is not known whether fl-DHEA has hormonal actions. The endocrinologic effects of DHEA and fl-DHEA in adult male and female Fischer 344 rats were examined following 28 days of daily oral treatment. Initial doses tested were 30 and 300 mg/kg/day for each drug (n ¼ 12/sex/group), which are equivalent to 104 and 1,042 mmoles/kg/day DHEA, and 103 and 1,034 mmoles/kg/day fl-DHEA. However, due to weight loss at the high dose, doses were lowered to 150 mg/kg/day for each drug (521 and 517 mmoles/kg/day DHEA and fl-DHEA, respectively). Administration of DHEA resulted in dose-dependent increases in plasma DHEA and DHEA-S 1 h after dosing in week 4. DHEA produced an estrogenic effect in female rats expressed as decreased plasma FSH and LH, inhibition of ovulation, prolonged estrus, and increased uterine estrogen receptors. DHEA also increased plasma levels of androstenedione in males and females. Administration of fl-DHEA increased the estrus cycle length due to a prolonged diestrus II phase and decreased the weights of the uterus, prostate, seminal vesicles, and testes. In addition, fl-DHEA decreased plasma FSH, LH, and tissue estradiol, and increased plasma dihydrotestosterone levels in both sexes. These results indicate that fl-DHEA is hormonally active and additional studies are warranted to further describe its endocrinologic effects. Drug Dev.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.