Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies

Abstract

9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD® rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate-aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day.

Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention

“…5 9cUAB30 exhibited no increase in serum TG in its preclinical evaluation in rats and dogs or in human trials. 19, 20 We previously reported that serum TG increased by 566% over controls when rats were fed 200 mg/kg diet of (±)- 1 for 7 days. 8 Each enantiomer of 1 was evaluated in a similar manner and compared to (±)- 1 .…”

Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

“…In addition, other formulations such as fenretinide have also demonstrated difficulties in attaining adequate plasma levels and were limited due to formulations that were difficult to administer to young children [28]. The absence of known toxicities with UAB30 [7] prompted study of this agent for neuroblastoma.…”

“…UAB30 is a synthetic analog of 9- cis -RA that selectively activates retinoid X receptors [6]. Toxicity studies in rodents and dogs showed no treatment related toxicities [7]. A pilot clinical trial study in humans has demonstrated a favorable toxicity profile with primarily hepatic metabolism and no significant increase in serum triglycerides [8].…”

UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts

“…After injection, the mice were randomized to receive vehicle-treated, RA-treated (53 mg/kg/day), or UAB30-treated chow (100 mg/kg/day) (n = 10 mice per group). These dosages were based upon previous in vivo experiments [19, 20, 28]. The flank tumors were measured twice weekly using calipers.…”

“…These doses were based upon previous data in the literature [19, 20, 28]. The animals were monitored twice daily for neurologic symptoms and followed for overall survival.…”