Overcoming Multidrug Resistance in Cancer: Clinical Studies of P-Glycoprotein Inhibitors
Overcoming Multidrug Resistance in Cancer: Clinical Studies of P-Glycoprotein Inhibitors
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DOI：
10.1007/978-1-60761-416-6_15
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发表时间：
2010-01-01
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影响因子：
--
通讯作者：
Coley, Helen M.
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作者：
Coley, Helen M.
化疗仍然是许多癌症治疗和管理的主要手段。然而，这种治疗方式充满了与毒性相关的困难，并且化疗耐药性的出现也是一个相当大的问题。癌症科学家和肿瘤学家已经合作了一段时间来寻找了解抗癌药物耐药性的方法，并开发出克服这种耐药性的药理学策略。最大的焦点是通过抑制ATP结合盒（ABC）药物转运蛋白来逆转多药耐药（MDR）表型。ABC转运蛋白的抑制剂-称为MDR调节剂-在过去有很多，并且在药物发现计划中占据了工业和学术界。该领域充满了困难和失望，但尽管如此，我们目前正在考虑第四代MDR调节剂的开发，第三代调节剂的临床试验中有很多数据有待确定。第一代MDR调节剂化合物是非常多样化和广谱的药理学试剂，其在当时推动了围绕癌症MDR表型研究的兴奋。第二代药物在机制研究中得到了非常严格的评估，并成为许多大型制药公司的肿瘤学投资组合的基础。鉴于这一输入，进行了一些临床试验，其结果有些令人失望。即使有少量的活性组合证据，试验数据也被认为足够有希望保证第三代调节剂的开发。已经鉴定出许多关键分子具有强效、持久的MDR逆转特性，并且与联合给药的细胞毒性剂的药代动力学相互作用最小。许多这些试验的结果都是人们热切期待的，癌症研究界有许多人仍然致力于抗癌药物发现的这一领域。
Chemotherapy remains the mainstay in the treatment and management of many cancers. However, this treatment modality is fraught with difficulties associated with toxicity and also the emergence of chemotherapy resistance is a considerable problem. Cancer scientists and oncologists have worked together for some time to find ways Of understanding anticancer drug resistance and also to develop pharmacological strategies to overcome that resistance. The greatest focus has been on the reversal of the multidrug resistance (MDR) phenotype by inhibition of the ATP-binding cassette (ABC) drug transporters. Inhibitors of ABC transporters - termed MDR modulators - have in the past been numerous and have Occupied industry and academia in drug discovery programs. The field has been fraught with difficulties and disappointments but, nonetheless, we are Currently considering the fourth generation of MDR modulator development with much data pending from the clinical trials with the third-generation modulators. First-generation MDR modulator compounds were very diverse and broad spectrum pharmacological agents which fuelled the excitement surrounding the research into the MDR phenotype in cancer at the time. Second-generation agents were very heavily evaluated in mechanistic Studies and formed the basis for a number of oncology, portfolios of big pharmaceutical companies. Given this input, a number of clinical trials were carried Out, the results of which were somewhat disappointing. Even with the modest evidence of active combinations, trial data were considered promising enough to warrant development of the third - generation of modulators. A number of key molecules have been identified with potent, long lasting MDR reversal properties, and minimal pharmacokinetic interaction with the co-administered cytotoxic agent. The results from a number of these trials are eagerly awaited and there are many in the cancer research community who remain committed to this area of anticancer drug discovery.