CHEMOPROT OF HEMATOPOIETIC CELLS BY MDR GENE TRANSFER

治愈晚期癌症的一种方法是使用更多的 强化化疗。避免严重或危及生命的骨髓 伴随着这种治疗的毒性，相关的干细胞支持 目前正在对大剂量化疗方案进行评估 很多肿瘤。然而，即使在这种情况下，患者的干细胞 再生正常造血的细胞和骨髓能力是 往往最终会受到严格的限制。这项提议的目标是 建立耐化疗的骨髓细胞群 可以导致使用更高剂量的化疗而不是更少的 毒性。正常骨髓细胞表达低水平的人类 多药耐药(MDR)基因，因此对 需要多药耐药基因作用的药物类别的杀戮 跨膜蛋白，P-糖蛋白，用于从细胞输出； 这些药物包括蒽环类、长春花碱、鬼臼 和紫杉烷，都是治疗癌症的常用药物。我们已经展示了 我们有一种安全的逆转录病毒载体可以转移和表达 人多药耐药基因在CD34+细胞中的表达，并对紫杉醇耐药 这些细胞。然而，在一期临床试验中，我们只看到 患者低水平的多药耐药转导。我们现在建议找到更多 基因转导人造血干细胞的有效方法 人多药耐药基因在体内建立耐药骨髓。 这些研究可能导致允许更高剂量的 化疗将用于晚期癌症患者 血液毒性、长期缓解或这些疾病的潜在治愈 病人。

One approach to the cure of advanced cancer is by the use of more intensive chemotherapy. To avoid severe or life-threatening bone marrow toxicity accompanying this treatment, stem cell support in association with high-dose chemotherapy regimens is currently being evaluated for many tumors. However, even in this circumstance, the patient's stem cells and marrow capacity for regenerating normal hematopoiesis are often eventually severely limited. The goal of this proposal is to establish a chemotherapy-resistant population of bone marrow cells which can result in the use of higher doses of chemotherapy with less toxicity. Normal bone marrow cells express low levels of the human multiple drug resistance (MDR) gene, and thus, are susceptible to killing by classes of drugs that require the action of the MDR gene transmembrane protein, p-glycoprotein, for their export from cells; these drugs include the anthracyclines, vinca alkaloids, podophyllins and taxanes, all commonly used to treat cancer. We have already shown that we have a safe retroviral vector that can transfer and express the human MDR gene in CD34+ cells, and provide paclitaxel resistance to these cells. However, in a Phase 1 clinical trial, we have seen only low level MDR transduction in patients. We now propose to find more effective methods to transduce human hematopoietic stem cells (HSC) with the human MDR gene to establish a drug-resistant bone marrow in vivo. These studies could lead to conditions for permitting higher doses of chemotherapy to be administered to advanced cancer patients with less hematologic toxicity, longer remissions or potential cure of these patients.