CHEMOPROT OF HEMATOPOIETIC CELLS BY MDR GENE TRANSFER

治疗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 伴随这种治疗的毒性， 目前正在评估高剂量化疗方案， 许多肿瘤。 然而，即使在这种情况下， 细胞和骨髓再生正常造血的能力， 最终往往会受到严重限制。 本提案的目的是 建立耐化疗的骨髓细胞群， 可能导致使用更高剂量的化疗， 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，易受 需要MDR基因作用的药物类别的杀伤 跨膜蛋白，p-糖蛋白，用于它们从细胞输出; 这些药物包括蒽环类、长春花生物碱类、鬼臼类 和紫杉烷类，这些都是治疗癌症的常用药物 我们已经表明 我们有一个安全的逆转录病毒载体， 人MDR基因，并提供紫杉醇抗性， 这些细胞。 然而，在第一阶段的临床试验中，我们只看到 低水平MDR转导。 我们现在建议找到更多 利用人造血干细胞（HSC）的有效方法 人MDR基因，以在体内建立耐药骨髓。 这些研究可能导致允许更高剂量的 对晚期癌症患者进行化疗， 血液学毒性、较长缓解期或潜在治愈 患者

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.