Selenium protection of bone marrow during chemotherapy

描述(申请人提供)：硒-L-蛋氨酸形式的非遗传毒性硒正在进行临床试验，作为常规化疗的辅助。在小鼠身上，使用硒和化疗药物联合治疗异种移植瘤获得了戏剧性的治愈，这些治疗与保护骨髓和其他组织免受剂量限制毒性有关。剂量限制性毒性是人类患者治愈率的主要障碍。在保持抗肿瘤疗效的同时，硒对骨髓具有保护作用。事实上，硒可以使最大耐受量(MTD)增加一倍甚至三倍。很明显，分子决定因素将癌细胞与正常细胞区分开来。在硒处理的细胞中，一个重要的分子决定子P53被修饰在关键的半胱氨酸巯基残基上。除了在细胞凋亡中的作用外，已知P53还可以保护细胞免受DNA损伤。研究发现，硒能激活P53的保护作用，但不能激活细胞凋亡。假设P53是硒参与骨髓保护的分子靶点。这一假说将通过三个特定的目标进行检验：目标1将检验这一假说，即硒通过DNA修复/细胞周期检查点机制保护P53野生型骨髓免受化疗诱导的骨髓抑制，这是缺乏P53的小鼠所缺乏的机制，和/或其下游参与DNA修复和细胞周期检查点的效应基因。目的2将验证这样的假设，即硒保护野生型小鼠骨髓的机制是通过真正的DNA修复/细胞周期检查点机制，而不是容易出错的机制。据预测，硒可以减少诱变性。目的3将检验这样一个假设，即额外的组织可能在化疗毒性中发挥作用，即如果硒保护骨髓，对其他组织的损害可能成为剂量限制。这些研究将提供硒与癌症化疗药物联合使用保护骨髓的分子机制，并将促进进一步的临床研究。

DESCRIPTION (provided by applicant): Non-genotoxic selenium in the form of seleno-L-methionine is in clinical trials as an adjunct to conventional chemotherapy. In mice, dramatic cures of xenograft tumors were obtained using selenium in combination with chemotherapy drugs, cures associated with protection from dose-limiting toxicity of bone marrow and other tissues. Dose-limiting toxicity is a major impediment to cure rates of human patients. Selenium protected bone marrow while maintaining antitumor efficacy. Indeed, selenium allowed a doubling or even tripling of the maximum tolerated dose (MTD). It is clear that molecular determinants distinguish cancer cells from normal cells. One important molecular determinant, p53, is modified on key cysteine sulfhydryl residues in selenium-treated cells. Separate from its role in apoptosis, p53 is known to protect cells from DNA damage. Selenium was found to activate the protective functions of p53 and not apoptosis. The hypothesis is that p53 is a molecular target of selenium involved in bone marrow protection. The hypothesis will be tested by three specific aims: Aim 1 will test the hypothesis that selenium protects p53-wildtype bone marrow from chemotherapy-induced myelosuppression by a DNA repair/cell cycle checkpoint mechanism, a mechanism lacking in mice lacking p53, and/or its downstream effector genes involved in DNA repair and cell cycle checkpoints. Aim 2 will test the hypothesis that the mechanism whereby selenium protects wildtype mouse bone marrow is by a bona fide DNA repair/cell cycle checkpoint mechanism, and not an error-prone mechanism. Selenium is predicted to decrease mutagenesis. Aim 3 will test the hypothesis that additional tissues may play a role in chemotherapeutic toxicity, i.e. if selenium protects the bone marrow, damage to other tissues may become dose-limiting. These studies will provide a molecular mechanism for bone marrow protection by selenium in combination with cancer chemotherapeutics, and will foster further clinical studies.