Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture.
Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture.
复制标题
氧氮磷细胞抑制剂：过去-现在-未来。
DOI：
10.1159/000205929
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发表时间：
1989
期刊：
影响因子：
11.2
通讯作者：
Norbert Brock
中科院分区：
文献类型：
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作者：
Norbert Brock
氧氮磷杂环类细胞抑制剂环磷酰胺、异环磷酰胺和曲环磷酰胺的开发基于将转运形式/活性形式原理应用于高反应性氮芥基团的想法。对现有结果和知识的批判性分析和概要将包括对这一概念所依据的假设已被实验和临床结果证实的程度的检查：1.化学合成成功地将反应性氮芥转化为非活性运输形式（潜伏）。2.在靶器官（癌细胞）中，转运形式被酶促激活为活性形式的要求已经通过一系列代谢反应实现。3.通过氧氮磷杂环丁烷细胞抑制剂已经实现了显著增加烷化剂的治疗指数的目的。更大的癌毒性选择性与其活化的初级代谢产物的细胞毒性特异性密切相关。4.当美司钠作为局部尿保护剂引入时，氧氮磷杂环类的癌毒性选择性进一步增加。美司钠消除了氧氮磷类药物治疗限制性尿毒性副作用的风险。在美司钠保护下，这些细胞抑制剂可以以更高的剂量给予，安全性增加，并且其治疗效果可以增强。5.伯氧氮磷杂环类化合物的稳定化，通过连接2-巯基乙磺酸（马磷酰胺），在临床前研究和治疗中开辟了新的可能性，例如，用于克隆生成干细胞测定、用于自体骨髓移植中的体外净化、用于肿瘤的局部灌注，以及在小剂量下用于免疫调节，在适当的情况下，与“生物反应调节剂”结合。"
The development of the oxazaphosphorine cytostatics cyclophosphamide, ifosfamide, and trofosfamide was based on the idea of applying the transport form/active form principle to the highly reactive nitrogen mustard group. A critical analysis and synopsis of the available results and knowledge will include examination of the extent to which the hypotheses on which this concept is based have been confirmed by experimental and clinical findings: 1. Chemical synthesis succeeded in converting the reactive nitrogen mustard into an inactive transport form (latentiation). 2. The requirement that the transport form be enzymatically activated to the active form in the target organ (the cancer cell) has been achieved by a sequence of metabolic reactions. 3. The aim of considerably increasing the therapeutic index of alkylating agents has been achieved by the oxazaphosphorine cytostatics. The greater cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. 4. The cancerotoxic selectivity of oxazaphosphorines was further increased when mesna was introduced as a regional uroprotector. Mesna eliminates the risk of therapy-limiting urotoxic side effects of oxazaphosphorines. With mesna protection, these cytostatics can be given in higher doses with increased safety, and their therapeutic efficacy can be enhanced. 5. Stabilization of the primary oxazaphosphorines, e.g., by attaching 2-mercaptoethanesulfonic acid (mafosfamide), opens up new possibilities in preclinical investigations and in therapy, e.g., for the clonogenic stem cell assay, for in vitro purging in autologous bone marrow transplantation, for regional perfusion of tumors, and, in small doses, for immunomodulation, where appropriate, in conjunction with "biological response modifiers."