Selenium protection of bone marrow during chemotherapy

描述（由申请人提供）：硒-L-甲硫氨酸形式的非遗传毒性硒正在临床试验中作为常规化疗的辅助治疗。在小鼠中，使用硒与化疗药物组合获得了异种移植肿瘤的戏剧性治愈，治愈与骨髓和其他组织的剂量限制性毒性保护有关。剂量限制性毒性是人类患者治愈率的主要障碍。硒保护骨髓，同时保持抗肿瘤疗效。事实上，硒可以使最大耐受剂量（MTD）增加一倍甚至两倍。很明显，分子决定因素将癌细胞与正常细胞区分开来。一个重要的分子决定簇p53在硒处理的细胞中的关键半胱氨酸巯基残基上被修饰。除了在细胞凋亡中的作用外，p53还可以保护细胞免受DNA损伤。硒被发现激活p53的保护功能，而不是凋亡。假设p53是硒参与骨髓保护的分子靶点。该假设将通过三个具体目标进行检验：目标1将检验硒通过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的假设，该机制在缺乏p53的小鼠中缺乏，和/或其下游效应基因参与DNA修复和细胞周期检查点。目的2将检验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，而不是易错机制的假设。预计硒可减少诱变。目标3将检验以下假设：其他组织可能在化疗毒性中发挥作用，即如果硒保护骨髓，则对其他组织的损伤可能具有剂量限制性。这些研究将为硒与癌症化疗药物联合使用提供骨髓保护的分子机制，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.