Mechanistic Studies on New Platinum Clinical Agents

新型铂类临床药物的作用机制研究

基本信息

  • 批准号:
    6545213
  • 负责人:
  • 金额:
    $ 31.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-09-30 至 2007-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This application proposes to study the unique aspects of the DNA adducts formed by the polynuclear platinum compounds that have emerged from our laboratory and the biological consequences of formation of these novel structures. These compounds, where two or three platinum coordination units are linked in a linear fashion, comprise an important new class of anticancer drugs. The first clinical compound, currently denominated BBR3464, is a trinuclear, bifunctional DNA binding agent with an overall 4+ charge. BBR3464 is now in Phase II clinical trials in cancer patients. The Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin, (cis-DDP cis-[PtCl(2)(NH(3))(2)]) including responses in melanoma, pancreatic and lung cancer. Objective responses in Phase II have been verified in relapsed ovarian cancer and non-small cell lung cancer. Pre-clinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. A second drug, a polyamine-bridged dinuclear compound, will enter Phase I clinical trials in early 2002, and thus allows comparison between di- and trinuclear compounds within the general class. The high positive charge, the presence of at least two Pt coordination units binding to DNA and the consequences of such DNA binding are remarkable structural and mechanistic departures from the cisplatin paradigm, and indeed all other DNA-modifying anticancer agents. It is the long-term goal of this project to understand how a unique pattern of DNA adduct formation may result in different cellular signaling or "downstream" effects such as protein recognition and whether such events may be dictated to lead to a genuinely new pattern of antitumor activity. It is a further long-term goal of this project to place the cytotoxic effects of these compounds into the context of molecular pathways leading to cell death. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The proposed research explores a variety of structure-function relationships within the diverse polynuclear platinum class. The specific aims build on the understanding gained to date. The hypothesis that formation of long-range interstrand crosslinks, and their conformational flexibility, may lead to delocalization of the lesion and represent formidable challenges to repair will be examined. The importance of pre-association of the charged drug on the DNA backbone in determining the nature and direction of long-range intra and interstrand crosslinks will be elucidated. New, high-affinity DNA-binding agents will be studied to determine the effect of electrostatic and hydrogen-bonding interactions on DNA structure and function, in the absence of covalent binding. Finally, the unique structure of polynuclear platinum compounds will be exploited to study consequences of binding to single-stranded DNA.
描述(由申请人提供):本申请旨在研究由我们实验室中出现的多核铂化合物形成的DNA加合物的独特方面,以及这些新结构形成的生物学后果。这些化合物由两个或三个铂配位单元以线性方式连接,构成了一类重要的新型抗癌药物。第一个临床化合物,目前命名为BBR3464,是一种带有4+电荷的三核双功能DNA结合剂。BBR3464目前正在癌症患者的II期临床试验中。I期试验显示,在通常无法用顺铂治疗的癌症中,(顺- ddp顺-[PtCl(2)(NH(3))(2)])出现了明确的反应模式,包括黑色素瘤、胰腺癌和肺癌的反应。在复发的卵巢癌和非小细胞肺癌中,II期的客观反应已经得到证实。临床前研究表明,BBR3464治疗对p53突变肿瘤有活性,对p53的诱导作用最小。第二种药物是一种多胺桥接的双核化合物,将于2002年初进入I期临床试验,从而可以在一般类别中比较二核和三核化合物。高正电荷,至少两个铂配位单元与DNA结合的存在,以及这种DNA结合的后果,在结构和机制上与顺铂范式不同,实际上与所有其他DNA修饰抗癌药物不同。

项目成果

期刊论文数量(0)
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NICHOLAS P FARRELL其他文献

NICHOLAS P FARRELL的其他文献

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{{ truncateString('NICHOLAS P FARRELL', 18)}}的其他基金

Metals in Medicine Gordon Research Conference
医学中的金属戈登研究会议
  • 批准号:
    6535514
  • 财政年份:
    2002
  • 资助金额:
    $ 31.73万
  • 项目类别:
Metals in Medicine Gordon Research Conference
医学中的金属戈登研究会议
  • 批准号:
    6777591
  • 财政年份:
    2002
  • 资助金额:
    $ 31.73万
  • 项目类别:
Metals in Medicine Gordon Research Conference
医学中的金属戈登研究会议
  • 批准号:
    6615767
  • 财政年份:
    2002
  • 资助金额:
    $ 31.73万
  • 项目类别:
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
新型铂类临床药物的机理研究
  • 批准号:
    2686173
  • 财政年份:
    1998
  • 资助金额:
    $ 31.73万
  • 项目类别:
Mechanistic Studies on New Platinum Clinical Agents
新型铂类临床药物的作用机制研究
  • 批准号:
    8235958
  • 财政年份:
    1998
  • 资助金额:
    $ 31.73万
  • 项目类别:
Mechanistic Studies on New Platinum Clinical Agents
新型铂类临床药物的作用机制研究
  • 批准号:
    6931019
  • 财政年份:
    1998
  • 资助金额:
    $ 31.73万
  • 项目类别:
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
新型铂类临床药物的机理研究
  • 批准号:
    6377194
  • 财政年份:
    1998
  • 资助金额:
    $ 31.73万
  • 项目类别:
Mechanistic Studies on New Platinum Clinical Agents
新型铂类临床药物的作用机制研究
  • 批准号:
    7476038
  • 财政年份:
    1998
  • 资助金额:
    $ 31.73万
  • 项目类别:
Mechanistic Studies on New Platinum Clinical Agents
新型铂类临床药物的作用机制研究
  • 批准号:
    8035451
  • 财政年份:
    1998
  • 资助金额:
    $ 31.73万
  • 项目类别:
Mechanistic Studies on New Platinum Clinical Agents
新型铂类临床药物的作用机制研究
  • 批准号:
    6780926
  • 财政年份:
    1998
  • 资助金额:
    $ 31.73万
  • 项目类别:

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