Spectrum of cellular responses to pyriplatin, a monofunctional cationic antineoplastic platinum(II) compound, in human cancer cells.
Spectrum of cellular responses to pyriplatin, a monofunctional cationic antineoplastic platinum(II) compound, in human cancer cells.
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DOI：
10.1158/1535-7163.mct-11-0250
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发表时间：
2011-09
影响因子：
5.7
通讯作者：
Lippard SJ
中科院分区：
文献类型：
--
作者：
Lovejoy KS;Serova M;Bieche I;Emami S;D'Incalci M;Broggini M;Erba E;Gespach C;Cvitkovic E;Faivre S;Raymond E;Lippard SJ
吡铂（顺式二氨（吡啶）氯铂（II）或cDPCP）是一种基于铂的候选抗肿瘤药物，是一种在小鼠中具有抗癌特性的阳离子化合物，是有机阳离子转运蛋白hOCT 1和hOCT 2的底物，可促进奥沙利铂的摄取。与形成DNA交联的顺铂和奥沙利铂不同，卡铂以单功能方式结合DNA。在一组上皮癌细胞系中评价了吡铂以及吡铂与已知抗癌药物（紫杉醇、吉西他滨、SN 38、顺铂或5-氟尿嘧啶）的组合的抗增殖作用，并与顺铂和奥沙利铂进行了直接比较。还研究了吡铂对基因表达和铂-DNA加合物形成的影响。24小时后，吡铂对人细胞系表现出细胞毒性作用（IC 50：171 - 443 μM），72小时后，对HOP-62非小细胞肺癌细胞的细胞毒性最大（IC 50：24 μM）。与顺铂和奥沙利铂相似，吡铂可使细胞周期阻滞于G2/M期。凋亡性细胞死亡得到膜联蛋白-V分析和磷酸化H2 AX和Chk 2检测的支持。顺铂治疗引起CDKN 1/p21表达增加，ERCC 1 mRNA表达减少。在铂每核苷酸的基础上，卡铂加合物导致的细胞毒性低于顺铂和奥沙利铂-DNA加合物。涉及药物转运和DNA损伤修复的几个基因（包括MSH 2和GSTP 1）的mRNA水平与我们的细胞系中的卡铂细胞活性相关。在吡铂与紫杉醇的组合中观察到协同作用。由于其活性谱与顺铂或奥沙利铂不同，因此可将其视为开发其他候选药物的先导化合物，这些候选药物的细胞毒性特征与目前使用的药物不同。
Pyriplatin (cis-diammine(pyridine)chloroplatinum(II) or cDPCP), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for the organic cation transporters, hOCT1 and hOCT2, which facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, as well as combintions of pyriplatin with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin or 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum-DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 h (IC50: 171 – 443 μM), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 h (IC50: 24 μM). Pyriplatin caused a G2/M block of cell cycle similar to that induced by cisplatin and oxaliplatin. Apoptotic cell death was supported by Annexin-V analysis and detection of phosphorylated H2AX and Chk2. Treatment with pyriplatin caused an increase in CDKN1/p21 and decrease in ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin adducts resulted in less cytotoxicity than cisplatin- and oxaliplatin-DNA adducts. The mRNA levels of several genes implicated in drug transport and repair of DNA damage, including MSH2 and GSTP1, correlate with pyriplatin cellular activity in our panel of cell lines. Synergy was observed in combinations of pyriplatin with paclitaxel. Because it has a different spectrum of activitythan that of cisplatin or oxaliplatin, pyriplatin may be regarded as a lead compound for the development of other drug candidates with cytotoxicity profiles that differ from those of the drugs currently in use.