Wang Y, Zhang Z, Yao R, Jia D, Wang D, Lubet R A, You M
Department of Surgery and the Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.
Oncogene. 2006 Mar 2;25(9):1320-9. doi: 10.1038/sj.onc.1209180.
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.
贝沙罗汀（他扎罗汀）是一种合成的高亲和力RXR受体激动剂，对RAR受体的亲和力有限。贝沙罗汀在非小细胞肺癌的I/II期试验中已显示出疗效。然而，贝沙罗汀在小鼠肺癌模型中的化学预防效果尚未确定。在本研究中，我们研究了贝沙罗汀在p53或K-ras基因发生遗传改变的突变A/J小鼠模型中抑制肺肿瘤进展的能力，p53和K-ras是人类肺癌发生中最常发生改变的两个基因。在6周龄时，通过单次腹腔注射（i.p.）给小鼠施用致癌物氨基甲酸乙烯酯（VC）。从VC注射后16周开始通过灌胃给予贝沙罗汀，并持续12周。尽管所有小鼠都发生了肺肿瘤，但在野生型小鼠中只有7%的肺肿瘤是腺癌，而在p53转基因或K-ras杂合缺陷小鼠中，分别有22%和26%的肺肿瘤是腺癌。贝沙罗汀抑制了所有三种基因型小鼠的肿瘤数量和肿瘤体积。此外，在p53（wt/wt）K-ras（ko/wt）和p53（wt/wt）K-ras（wt/wt）小鼠中，贝沙罗汀使腺瘤向腺癌的进展减少了约50%。因此，贝沙罗汀似乎是一种有效的预防肺肿瘤生长和进展的药物。
