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首页> 外文学位 >Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer.
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Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer.

机译：研究磷铂的分子靶标：一类在卵巢癌治疗中的新型非DNA结合铂抗癌药。

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摘要

Platinum drugs have been the cornerstone in treating human ovarian cancer, as a result of major advances in the field of synthetic and analytical chemistry. Drugs such as cisplatin and carboplatin that are routinely used for chemotherapy, form intra- and inter-strand platinum-DNA cross links, ultimately leading to cancer cell death. But unfortunately in many cases this platinum-DNA association is also responsible for treatment resistance, leading to patient death. It has been extensively documented that inhibition of DNA repair pathways and a greater understanding of cellular reactions upon platinum drug treatment, are crucial in diminishing toxicity and improving the effectiveness of such drugs. Pyrodach-2, belonging to a class of novel platinum compounds called phosphaplatins, demonstrated enhanced cytotoxicity against ovarian cancer cells and no DNA-binding in a recently published study (Bose et. al., 2009). These observations inspired the following study, which aims at determining the anti-cancer properties of two other pyrophosphate complexes, namely pyrodach-4 and RRD4.;Platinum compounds have been known to channel their effects through multiple pathways. In the first part of this study, the signaling mechanism(s) of pyrodach-4, which induced ovarian cancer cell death upon treatment, were investigated. Cell-death and apoptosis associated genes along with their products make good targets, which can be exploited in the development of drugs to treat human diseases. Using various assays such as gene expression microarray and qRT-PCR, levels of various such genes were analyzed. Interestingly pyrodach-4 utilized genes belonging to both the extrinsic and intrinsic apoptotic cell death machinery, namely Bax, Fas, PTEN and PUMA to induce maximal cisplatin-sensitive and -resistant ovarian cancer cell death at 24 hours post treatment. Further, anti-apoptotic genes such as Bcl-2 decreased in treated cells. In contrast, protein expression results for Fas and Bax proteins did not exactly mimic the results from the gene expression analyses, suggesting that post-transcriptional modifications might be at play. Additionally, findings from investigating RRD4 cytotoxicity, suggested that both the cisplatin-sensitive and resistant cell lines were sensitive to 24 hour treatment with RRD4. Combined results from the gene expression, protein expression and ELISA analyses proved that RRD4-treated cells may be differentially regulated than those treated with pyrodach-4, hinting a faster uptake process, and a distinct mechanism of action of RRD4, in comparison to pyrodach-4.;Effects of platinum drugs on tumor vasculature have become the subject of increased study. In part two of this study, treatment of HUVECs with pyrodach-4 and RRD4 caused intense cell death, adding anti-angiogenesis to the repertoire of phosphaplatin anti-cancer functions. Finally, in accordance with the anti-cancer activities seen in vitro, pyrodach-4 toxicity and efficacy studies were performed, as the third part of the study. Results from the toxicity and efficacy studies demonstrated that phosphaplatins were well tolerated and performed much better in comparison to cisplatin- and carboplatin-treated mice. Collectively, data presented in this study reveal the probable pathways triggered upon pyrodach-4 and RRD4 treatments, making phosphaplatins a class of novel targeted compounds, which can be used to treat human ovarian cancer.
机译：由于合成和分析化学领域的重大进展，铂类药物一直是治疗人类卵巢癌的基石。常规用于化学疗法的药物如顺铂和卡铂形成链内和链间铂-DNA交联，最终导致癌细胞死亡。但是不幸的是，在许多情况下，这种铂-DNA结合也导致了治疗耐药性，导致患者死亡。大量文献证明，抑制铂蛋白治疗后的DNA修复途径和对细胞反应的更多了解，对于降低毒性和提高此类药物的有效性至关重要。在最近发表的一项研究中，Pyrodach-2属于一类新颖的铂化合物，称为磷铂，对卵巢癌细胞具有增强的细胞毒性，并且没有DNA结合（Bose等，2009）。这些发现激发了以下研究的目的，该研究旨在确定另外两种焦磷酸盐复合物，即pyrodach-4和RRD4的抗癌特性。已知铂化合物可通过多种途径传递其作用。在这项研究的第一部分中，研究了吡达达4的信号传导机制，该信号在治疗后可诱导卵巢癌细胞死亡。与细胞死亡和细胞凋亡相关的基因及其产物成为良好的靶标，可在治疗人类疾病的药物开发中加以利用。使用各种测定法，例如基因表达微阵列和qRT-PCR，分析了各种此类基因的水平。有趣的是，pyrodach-4利用了属于外在和内在凋亡细胞死亡机制的基因，即Bax，Fas，PTEN和PUMA，在治疗后24小时诱导了最大的顺铂敏感性和耐药性卵巢癌细胞死亡。此外，在处理过的细胞中抗凋亡基因例如Bcl-2减少。相反，Fas和Bax蛋白的蛋白表达结果并不能完全模仿基因表达分析的结果，表明转录后修饰可能正在发挥作用。另外，从对RRD4细胞毒性的研究中发现，顺铂敏感细胞和耐药细胞系均对24小时RRD4治疗敏感。基因表达，蛋白质表达和ELISA分析的综合结果证明，与用pyrodach-4处理的细胞相比，RRD4处理的细胞可能比用pyrodach-4处理的细胞受到不同的调节，这提示RRD4的吸收过程更快，并且具有独特的作用机理。 4 .;铂类药物对肿瘤血管的作用已成为越来越多的研究课题。在这项研究的第二部分中，用pyrodach-4和RRD4处理HUVEC会引起强烈的细胞死亡，并增加了抗血管生成作用，从而增加了磷铂的抗癌功能。最后，根据体外观察到的抗癌活性，进行了pyrodach-4毒性和功效研究，作为研究的第三部分。毒性和功效研究的结果表明，与顺铂和卡铂治疗的小鼠相比，磷铂具有良好的耐受性，并且表现更好。总的来说，这项研究中提供的数据揭示了pyrodach-4和RRD4处理触发的可能途径，使磷铂成为一类新型的靶向化合​​物，可用于治疗人类卵巢癌。

著录项

  • 作者

    Majmudar, Pooja M.;

  • 作者单位

    Ohio University.;

  • 授予单位 Ohio University.;
  • 学科 Biology Molecular.;Health Sciences Pharmacy.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 200 p.
  • 总页数 200
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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