Prevention of mouse lung tumors by targretin

Abstract

Targretin has indicated chemotherapeutic activity against nonsmall-cell lung cancer and chemoprevention in rat mammary gland. Therefore, targretin was evaluated for the prevention of 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNK) and vinyl carbamate-induced lung tumors in female strain A mice. Three experiments were performed: (i) a dose-response study with vinyl carbamate-induced tumors; (ii) a limited treatment study also with vinyl carbamate and (iii) prevention of NNK-induced tumors. In the dose-response study, 0, 10, 30, 100 and 300 mg/kg targretin were administered after vinyl carbamate. Dose levels of 30 mg/kg and greater significantly decreased tumor multiplicity by >19%. However, the efficacy of 30 and 300 mg/kg was not significantly different demonstrating a shallow dose-response relationship. In the limited treatment study, 200 mg/kg targretin was administered to the mice from 4-13, 4-19, 4-25 and 23-25 weeks after vinyl carbamate. Administering targretin from weeks 4-19 and 4-25 decreased the multiplicity of tumors from 35.3 6 1.43 to 29.1 6 1.51 and 25.0 6 0.93, respectively, and along with administering it from weeks 23-25 decreased tumor size. In the third study, when targretin (100 and 300 mg/kg) was administered for 3 weeks after NNK followed by a 20 weeks holding period, tumor multiplicity was reduced from 10.6 6 1.13 to 6.38 6 0.75 and 4.60 6 0.70, respectively. Hence, targretin demonstrated both preventive and therapeutic activity with respect to mouse lung tumors supporting its further development as a preventive and therapeutic agent for lung cancer. ' 2005 Wiley-Liss, Inc.

Aerosolized Bexarotene Inhibits Lung Tumorigenesis without Increasing Plasma Triglyceride and Cholesterol Levels in Mice

“…Bexarotene has shown to be effective chemopreventive agent in many rodent models including those for lung cancer (6,22,23). Pereira and colleagues showed that oral gavage of 30 to 300 mg/kg bexarotene reduced the multiplicity of vinyl carbamate-induced mouse lung tumors by 22% to 33%, furthermore, oral gavage of 100 and 300 mg/kg bexarotene decreased NNK [4-methylnitrosamino-1-(3-pyridyl)-1-butanone]-induced tumor multiplicity by 40% to 50% (22).…”

“…Pereira and colleagues showed that oral gavage of 30 to 300 mg/kg bexarotene reduced the multiplicity of vinyl carbamate-induced mouse lung tumors by 22% to 33%, furthermore, oral gavage of 100 and 300 mg/kg bexarotene decreased NNK [4-methylnitrosamino-1-(3-pyridyl)-1-butanone]-induced tumor multiplicity by 40% to 50% (22). Its effectiveness by oral delivery was further demonstrated by our group where oral gavage of 180 mg/kg bexarotene significantly decreased small cell lung carcinoma incidence in a lungspecific Rb1 and p53 knockout model (23).…”

Retinoids and rexinoids in cancer prevention: from laboratory to clinic

“…Rexinoids were effective in A/J mouse models of lung carcinogenesis induced by K-ras or p53 dominant negative mutations, in monotherapy or in combination with triterpenoids [124, 125]. In both cases cancer preventive activities were associated with reduced cell proliferation and decreased expression of tumor growth-related biomarkers, i.e.…”

Effects on Gene Expression in Rat Liver after Administration of RXR Agonists: UAB30, 4-Methyl-UAB30, and Targretin (Bexarotene)

“…There has been significant interest in this class of compounds in cancer because an RXR agonist [Targretin (TRG)] is approved clinically for the treatment of cutaneous T-cell lymphoma (Lansigan and Foss 2010) and has demonstrated clinical efficacy in non-small-cell lung cancer (Dragnev et al, 2011;Kim et al, 2011). In addition, this class of compounds has shown efficacy in a variety of mammary and lung cancer models in rodents (Pereira et al, 2006;Wang et al, 2006bWang et al, , 2009Liby, et al, 2007;Zhang et al, 2011), and more recently in humans (Dragnev et al, 2011;Kim et al, 2011). However, the elevation of triglycerides levels by 9-cis-RA, TRG, and various retinoids has been known for many years and is a major concern in the use of these agents, particularly in a cancer-prevention setting (Grubbs et al, 2006;Kolesar et al, 2010).…”