Retinoids, RAMBAs, and Histone Deacetylase Inhibitors

描述（由申请人提供）：全反式维甲酸（ATRA）是维生素A（视黄醇）的衍生物，是正常人前列腺上皮细胞适当细胞增殖和分化所必需的。人前列腺癌细胞中ATRA的含量比正常细胞低得多。我们推测前列腺肿瘤细胞中ATRA的代谢异常和基因表达失调与肿瘤细胞的异常生长特性有关。ATRA治疗急性早幼粒细胞白血病（APL）的有效性进一步支持了在前列腺癌治疗中使用维甲酸的基本原理。我们假设，如果全反式维甲酸与维甲酸代谢阻断剂（RAMBAs）联合使用，加上低剂量的选择性组蛋白脱乙酰酶抑制剂（HDACIs），如阿司他丁A（TSA）或辛二酰苯胺异羟肟酸（SAHA），可以提高全反式维甲酸的疗效。HDACI将通过使前列腺癌细胞对ATRA分化活性敏感来起作用。视黄酸受体（RAR）/ADAC复合物的发现为结合RA和HADCI提供了理论基础。本提案的目的是使用体外细胞培养以及小鼠异种移植模型来确定ATRA、各种RAMBA加HDACI在抑制人前列腺细胞系LNCaP、LAPC-4、PC-3和DU-145的生长和诱导其分化方面的有效性。该项目的第二个目标是在分子水平上了解联合治疗导致人前列腺肿瘤细胞生长抑制的机制。这些研究可能为人类前列腺癌的新临床治疗提供更清晰的理论基础。如果这种方法似乎是成功的，我们将考虑在随后的RO 1提案中开发新型HDAC抑制剂的需要，以我们在药物设计，发现和开发方面的专业知识为优势。该项目的长期目标是开发具有可能对雄激素依赖性和雄激素非依赖性前列腺癌提供有效抗肿瘤活性的特征的化合物。以下提出的具体目标应使我们能够获得大量数据，可以支持我们的假设。

DESCRIPTION (provided by applicant): All-trans retinoic acid (ATRA), a derivative of vitamin A (retinol), is required for the appropriate cellular proliferation and differentiation of normal human prostate epithelial cells. Human prostate cancer cells contain much lower levels of ATRA than normal cells. We hypothesize that aberrant metabolism of ATRA and dysregulation of gene expression in prostate tumor cells are related to the abnormal growth properties of the tumor cells. A rationale for using retinoic acid in prostate cancer therapy is further supported by the effectiveness of ATRA in the treatment of acute promyelocytic leukemia (APL). We hypothesize that the efficacy of ATRA can be enhanced if it is administered in combination with retinoic acid metabolism blocking agents (RAMBAs) plus low doses of selective histone deacetylase inhibitors (HDACIs) such as trichostatin A(TSA) or suberoylanilide hydroxamic acid (SAHA). HDACIs will act by sensitizing prostate cancer cells towards ATRA differentiation activity. The discovery of the retinoic acid receptor (RAR)/ADAC complex provides a rationale for combining RAs and HADCIs. The goals of this proposal are to use in vitro cell culture and also mouse xenograft models to ascertain the effectiveness of ATRA, various RAMBAs plus HDACIs in inhibiting the growth and inducing the differentiation of the human prostate cell lines, LNCaP, LAPC-4, PC-3 and DU-145. A second goal of the project is to understand at the molecular level the mechanisms by which the combination treatments result in human prostate tumor cell growth inhibition. These studies may provide a much clearer rationale for new clinical treatments for prostate cancer in humans. If this approach appears successful, we will consider the need for developing novel HDAC inhibitors in the subsequent RO1 proposal on the strengths of our expertise in drug design, discovery and development. The long-term goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen-dependent and androgen independent prostatic cancer. The following specific aims that are proposed should enable us obtain substantial data that may support our hypothesis.