Increased sensitivity of a metastatic model of prostate cancer to a novel tetravalent platinum analog
Increased sensitivity of a metastatic model of prostate cancer to a novel tetravalent platinum analog
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DOI：
10.1002/pros.20114
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发表时间：
2005-01-01
期刊：
影响因子：
2.8
通讯作者：
Siddik, ZH
中科院分区：
文献类型：
--
作者：
Mujoo, K;Watanabe, M;Siddik, ZH
背景资料。[(1R，2R-diaminocyclohexane)-(trans-diacetato)-(dichloro)platinum(])(IV)是一种新的顺铂类似物，我们评估了它在人类前列腺癌中的潜在活性。方法：用铂类药物进行细胞毒性、生化药理学、细胞周期和蛋白质印迹分析，以评估p53基因和雄激素依赖状态对细胞反应的作用。结果：CDDP和DACH-Ac-PT对突变型p53和雄激素非依赖性DU-145或PC-3肿瘤细胞具有同等的抗肿瘤活性。在野生型P53细胞中，CDDP对雄激素依赖的LNCaP的抑制能力是同基因雄激素非依赖性LNCaP-LN3细胞的三倍。然而，在这两个野生型p53肿瘤模型中，类似物是等价的。在野生型p53细胞中，DACH-Ac-Pt比CDDP具有更强的效力，这不是因为细胞对药物摄取的增加或加合物水平的增加，而是与对DNA损伤的较低耐受性有关。该类似物还能更有效地激活LNCaP和LNCaP-LN3细胞中的P53-p21(WAF1)/(CIP1)信号转导通路，使细胞周期停滞于G(1)期。相比之下，CDDP只在LNCaP细胞中有效地激活了这一途径。此外，与CDDP相比，DACH-Ac-PT在两种肿瘤模型中均能更有效地诱导Bax，增加Bax/Bcl2比值。结论：DACH-Ac-PT对野生型p53 LNCaP及其LN3变异体具有高效的抗肿瘤活性，且这种活性是雄激素非依赖性的。CDDP和DACH-Ac-Pt对LNCaP-LN3细胞p21(WAF1)/(CIP1)的不同诱导和Bax/Bcl2比值的升高似乎与这两种药物对该模型的相对活性有关。(C)2004年Wiley-Liss，Inc.
BACKGROUND. DACH-Ac-Pt [(1R,2R-diaminocyclohexane)-(trans-diacetato)-(dichloro)platinum(])(IV) is a novel cisplatin (CDDP) analog, and we have evaluated its potential activity in human prostate cancers.METHODS. Cytotoxic, biochemical pharmacologic, cell cycle, and Western blot evaluations were conducted with platinum agents to assess the role of p53 genotype and androgen-dependence status on cellular response.RESULTS. CDDP and DACH-Ac-Pt were equiactive against mutant p53 and androgen-independent DU-145 or PC-3 tumor cells. In wild-type p53 cells, CDDP was threefold more potent against androgen-dependent LNCaP than isogenic androgen-independent LNCaP-LN3 cells. However, the analog was equipotent in these two wild-type p53 tumor models. The greater potency of DACH-Ac-Pt than CDDP in wild-type p53 cells was not due to increased cellular drug uptake or increased adduct levels, but correlated with a lower tolerance to DNA damage. The analog also activated the p53-p21(WAF1)/(CIP1) signal transduction pathway more efficiently in LNCaP and LNCaP-LN3 cells, and this induced G(1)-phase cell-cycle arrest. CDDP, in contrast, activated this pathway efficiently in LNCaP cells only. In addition, and compared to CDDP, DACH-Ac-Pt was more effective in inducing Bax and increasing the Bax/Bcl-2 ratios in both the tumor models.CONCLUSIONS. DACH-Ac-Pt is highly effective against wild-type p53 LNCaP and its LN3 variant, and this activity is androgen-independent. The differential induction of p21(WAF1)/(CIP1) and increase in Bax/Bcl-2 ratios with CDDP and DACH-Ac-Pt in LNCaP-LN3 cells appear to be linked to the relative activity of the two agents against this model. (C) 2004Wiley-Liss, Inc.