视黄酸X受体选择性配体LGD1069对他莫昔芬治疗失败后乳腺癌的影响。

Effect of the retinoid X receptor-selective ligand LGD1069 on mammary carcinoma after tamoxifen failure.

作者信息

Bischoff E D, Heyman R A, Lamph W W

机构信息

Department of Retinoid Research, Ligand Pharmaceuticals Inc., San Diego, CA 92121, USA.

出版信息

J Natl Cancer Inst. 1999 Dec 15;91(24):2118. doi: 10.1093/jnci/91.24.2118.

DOI:10.1093/jnci/91.24.2118

PMID:10601384

Abstract

BACKGROUND

We have previously shown that a retinoid X receptor (RXR)-selective ligand (a rexinoid), called LGD1069, is highly efficacious in both the chemoprevention and the chemotherapy for N-nitrosomethylurea-induced rat mammary carcinomas. To evaluate a possible role for rexinoids in breast cancer therapy further, we have designed and characterized a novel carcinogen-induced model to mimic the clinical situation in which the tumors of patients stop responding to tamoxifen therapy and develop resistance to this drug.

METHODS

Rats with experimentally induced mammary tumors were treated with tamoxifen to select a population with primary tumors that failed to respond completely to the drug. Once the failure of tamoxifen therapy had been established, LGD1069 was added to the treatment regimen, and the tumors in these animals were compared with tumors in a group of animals that remained on tamoxifen alone.

RESULTS

LGD1069 in combination with tamoxifen for up to 20 weeks yielded an overall objective response rate of 94% (95% confidence interval [CI] = 86%-100%) (includes complete and partial responses) in primary tumors compared with a rate of 33% (95% CI = 11%-56%) in primary tumors treated with tamoxifen alone, a statistically significant difference (two-sided P<.0001). In addition, the LGD1069 and tamoxifen combination was associated with a statistically significant decrease in total tumor burden (two-sided P =.03). In a second study, tumors that failed to respond to tamoxifen therapy exhibited a 51% (95% CI = 34%-71%) objective response rate when treated with LGD1069 alone for 6 weeks after tamoxifen therapy was withdrawn.

CONCLUSION

We have demonstrated that the RXR-selective ligand LGD1069 in combination with tamoxifen is a highly efficacious therapeutic agent for tumors that fail to respond completely to tamoxifen. This finding suggests that rexinoid therapy offers a novel approach to the treatment of breast tumors that may have developed resistance to antihormonal therapies such as tamoxifen.

摘要

背景

我们之前已经表明，一种称为LGD1069的视黄酸X受体（RXR）选择性配体（一种类视黄醇）在N-亚硝基甲基脲诱导的大鼠乳腺癌的化学预防和化疗中都具有很高的疗效。为了进一步评估类视黄醇在乳腺癌治疗中的可能作用，我们设计并表征了一种新的致癌物诱导模型，以模拟患者肿瘤对他莫昔芬治疗不再有反应并对该药物产生耐药性的临床情况。

方法

用他莫昔芬治疗实验性诱导乳腺肿瘤的大鼠，以选择一组原发性肿瘤对该药物未完全反应的群体。一旦确定他莫昔芬治疗失败，将LGD1069添加到治疗方案中，并将这些动物中的肿瘤与仅继续使用他莫昔芬的一组动物中的肿瘤进行比较。

结果

LGD1069与他莫昔芬联合使用长达20周，原发性肿瘤的总体客观缓解率为94%（95%置信区间[CI]=86%-100%）（包括完全缓解和部分缓解），而单独使用他莫昔芬治疗的原发性肿瘤的缓解率为33%（95%CI=11%-56%），差异有统计学意义（双侧P<.0001）。此外，LGD1069与他莫昔芬联合使用与总肿瘤负荷的统计学显著降低相关（双侧P=.03）。在第二项研究中，对他莫昔芬治疗无反应的肿瘤在停用他莫昔芬治疗后单独使用LGD1069治疗6周时，客观缓解率为51%（95%CI=34%-71%）。