Pharmacology of Cyclophosphamide and Other Alkylators

环磷酰胺和其他烷基化剂的药理学

• 批准号: 7169818
• 负责人: OLIVER MICHAEL COLVIN
• 金额: $ 28.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-09-30 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169818
• 关键词: Active Sites; Alkylating Agents; Alkylation; Area; Autoimmune Diseases; Biochemical; Bone Marrow; Bone Marrow Transplantation; Candidate Disease Gene; Cell Line; Chemistry; Clinical; Clinical Pharmacology; Clinical Trials; Cyclophosphamide; Cytochrome P450; DNA; DNA Modification Process; DNA Repair; Data; Dose; Drug Kinetics; End Point; Enzymes; Exhibits; Gene Silencing; Genes; Genetic Polymorphism; Genotype; Hepatic; Human; Ifosfamide; Immunosuppressive Agents; Ink; Isoenzymes; Lead; Liver; Liver Microsomes; Metabolism; Numbers; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phenotype; Prodrugs; Production; Property; Reaction; Relative (related person); Resistance; Sampling; Site-Directed Mutagenesis; Small Interfering RNA; System; Techniques; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Protocols; Variant; analog; antitumor agent; clinically relevant; crosslink; design; gene repair; genetic variant; molecular modeling; neurotoxic; oxidation; repair enzyme; repaired; research study; success; tumor

DESCRIPTION (provided by applicant): This is an application for a competing continuation of a long standing RO1 to study the chemistry and biochemical and clinical pharmacology of the antitumor agent cyclophosphamide (CP) and its close analog, ifosfamide (IF). CP was first introduced into clinical usage in the 1950's and remains one of the most widely used alkylating agents. It has a number of properties which contribute to its continued utility, including the fact that it exhibits relative sparing of the bone marrow and gi tract, as compared to other related agents. CP is remarkably immunosuppressive and is utilized in the treatment of a number of autoimmune diseases and is a major component of most bone marrow transplantation regimens. IF has similar pharmacologic properties and is preferentially used in the treatment of certain tumors. CP and IF are prodrugs which must be activated by hepatic P450. Competing with the activation reaction are secondary oxidations that lead to the production of neurotoxic metabolites. These undesirable oxidations are more prevalent with IF, making this drug a prime target for modification. In this renewal, we propose to continue and expand our studies of CP/IF alkylation, crosslinking and activation by determining those factors that are important in protecting against toxicities and critical to enhancing therapeutic effects. In Specific Aim 1, we will use various techniques including siRNA technology to determine the contributions of specific DNA-repair mechanisms to CP/IF resistance and toxicity. Identified mechanisms and genes could be targeted for inhibition with a result of relevant therapies for overcoming resistance. In Specific Aim 2 we will use human liver samples to evaluate the degree of human variation in the metabolism of CP and IF. We will also identify the SNPs in candidate genes including drug metabolizing genes or genes regulating these enzymes that are responsible for human variation in the phenotype. An understanding of the genotype(s) involved would allow for the identification of patients, before treatment, in whom the normal dose of CP or IF would be inadequate or toxic.

描述（由申请人提供）：这是一项长期 RO1 的竞争性延续申请，旨在研究抗肿瘤剂环磷酰胺 (CP) 及其密切类似物异环磷酰胺 (IF) 的化学、生化和临床药理学。 CP 于 20 世纪 50 年代首次引入临床应用，至今仍是使用最广泛的烷化剂之一。它具有许多有助于其持续使用的特性，包括与其他相关药物相比，它对骨髓和胃肠道的影响相对较小。 CP 具有显着的免疫抑制作用，可用于治疗多种自身免疫性疾病，并且是大多数骨髓移植方案的主要组成部分。 IF 具有相似的药理学特性，优先用于治疗某些肿瘤。 CP和IF是前药，必须被肝P450激活。与活化反应竞争的是二次氧化，导致神经毒性代谢物的产生。这些不良氧化在 IF 中更为普遍，使该药物成为修饰的主要目标。在本次更新中，我们建议通过确定那些对于防止毒性重要且对于增强治疗效果至关重要的因素，继续并扩大我们对 CP/IF 烷基化、交联和活化的研究。在具体目标 1 中，我们将使用包括 siRNA 技术在内的各种技术来确定特定 DNA 修复机制对 CP/IF 抗性和毒性的贡献。已确定的机制和基因可以作为抑制的目标，从而通过相关疗法来克服耐药性。在具体目标 2 中，我们将使用人类肝脏样本来评估人类 CP 和 IF 代谢的变异程度。我们还将鉴定候选基因中的 S​​NP，包括药物代谢基因或调节这些酶的基因，这些酶负责人类表型的变异。了解所涉及的基因型将有助于在治疗前识别出正常剂量的 CP 或 IF 不足或有毒的患者。