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Published on: May 20, 2016
Prevention of lung cancer progression by bexarotene in mouse models
1Department of Surgery and the Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.
Abstract:
Bexarotene (Targretin), is a synthetic high-affinity RXR receptor agonist with limited affinity for RAR receptors. Bexarotene has shown efficacy in a phase I/II trial of non-small-cell lung cancers. However, the chemopreventive efficacy of bexarotene has not been determined in mouse lung cancer models. In this study, we have investigated the ability of bexarotene to inhibit lung tumor progression in the mutant A/J mouse models with genetic alterations in p53 or K-ras, two of the most commonly altered genes in human lung tumorigenesis. Mice were administered vinyl carbamate (VC), a carcinogen, by a single intraperitoneal injection (i.p.) at 6 weeks of age. Bexarotene was given by gavage starting at 16 weeks after VC and was continued for 12 weeks. Although all mice developed lung tumors, only 7% of lung tumors were adenocarcinomas in wild-type mice, whereas 22 and 26% of lung tumors were adenocarcinomas in p53 transgenic or K-ras heterozygous deficient mice. Bexarotene inhibited both tumor multiplicity and tumor volume in mice of all three genotypes. Furthermore, bexarotene reduced the progression of adenoma to adenocarcinoma by approximately 50% in both p53(wt/wt)K-ras(ko/wt) and p53(wt/wt)K-ras(wt/wt) mice. Thus, bexarotene appears to be an effective preventive agent against lung tumor growth and progression.
Insights
Bexarotene effectively inhibited lung tumor growth and progression in mouse models. This retinoid X receptor agonist shows promise as a chemopreventive agent for lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- Bexarotene (Targretin) is a synthetic RXR receptor agonist with demonstrated efficacy in non-small-cell lung cancer trials.
- The chemopreventive potential of bexarotene in lung cancer models remained undetermined.
- Human lung tumorigenesis frequently involves alterations in p53 and K-ras genes.
Purpose of the Study:
- To investigate the efficacy of bexarotene in preventing lung tumor progression.
- To evaluate bexarotene's effects in genetically modified mouse models (p53 or K-ras alterations).
Main Methods:
- A/J mice with p53 or K-ras genetic alterations were used.
- Mice received a single intraperitoneal injection of vinyl carbamate (VC) at 6 weeks of age.
- Bexarotene treatment (gavage) commenced 16 weeks post-VC and continued for 12 weeks.
Main Results:
- Bexarotene significantly inhibited lung tumor multiplicity and volume across all genotypes.
- The drug reduced the progression from adenoma to adenocarcinoma by approximately 50% in specific mouse groups.
- Tumor progression was observed in all mice, but bexarotene mitigated adenocarcinoma development.
Conclusions:
- Bexarotene demonstrates significant preventive effects against lung tumor growth and progression.
- This study supports bexarotene's potential as a chemopreventive agent for lung cancer.
- Targeting RXR receptors with bexarotene may be a viable strategy for lung cancer prevention.
