MECHANISMS OF HEMATOLOGICAL TOXICITY OF ANTIAIDS DRUGS

描述（改编自摘要）：这一竞争的目标 续签申请是要继续调查机制 与艾滋病治疗中药物诱导的血液学毒性相关。 的 齐多夫定（AZT）的血液学毒性仍然是 艾滋病的临床管理，往往是唯一最重要的 最终需要停止治疗的并发症。 此外，本发明还提供了一种方法， 造血功能受损也是与造血功能异常相关的主要异常之一。 HIV-1感染。 本申请中包含的初步数据 提示HIV-1的反式激活蛋白（达特）可能会降低 调节造血祖细胞中的γ-珠蛋白基因表达 并且还可以增强AZT诱导的对红系分化的抑制。 因此，主要研究者假设， HIV-1达特与药物一起引起的细胞和分子效应， 诱导作用可导致增强的造血毒性。 测试 这一假说，他提出：（1）研究Tat诱导的作用， AZT和其他2 '，3'-双脱氧核苷的骨髓抑制增强作用 （ddN）诱导的人造血分化抑制 造血细胞系（K-562）和人骨髓CD 34+细胞;（2） 为了检测达特对跨膜信号传导的影响， 涉及酪氨酸的促红细胞生成素（EPO）-EPO受体复合物 磷酸化和蛋白激酶C在增殖过程中， 红系祖细胞的分化;（3）确定作用 TAT诱导的细胞因子，TNF α和β以及TGF β， 人混合骨髓细胞的微环境，在调节 在存在和不存在AZT和其他ddN的情况下的分化;（4） 为了确定达特对原癌基因c-myc表达的作用， c-fos和c-raf在存在和不存在 （5）检测达特和/或AZT对人肝癌细胞凋亡的影响。 通过监测DNA片段化和利用视频 成像技术;和6）开发新的治疗方法， 克服HIV-1达特和AZT诱导的骨髓毒性， 潜在的机制。 为了实现这些具体目标， 研究者深入了解机制 与艾滋病患者的血液学毒性相关， 开发有效的治疗方法，以克服 血液抑制

DESCRIPTION (adapted from Abstract): The objectives of this competing renewal application is to continue to investigate the mechanisms associated with drug-induced hematological toxicity in AIDS therapy. The hematological toxicity of zidovudine (AZT) remains a limiting factor in clinical management of AIDS and is often the single most important complication ultimately requiring cessation of therapy. In addition, impaired hematopoiesis is also one of the major abnormalities associated with HIV-1 infection. The preliminary data included in this application would suggest that the trans-activator protein (Tat) of HIV-1 may down regulate gamma-globin gene expression in hematopoietic progenitor cells and also may enhance AZT-induced inhibition of erythroid differentiation. The Principal Investigator, therefore, hypothesizes that a combination of cellular and molecular effects caused by HIV-1 TAT together with drug- induced effects may lead to an enhanced hematopoietic toxicity. To test this hypothesis, he proposes: (1) to study the role of Tat-induced myelosuppression in enhancing the AZT and other 2',3'-dideoxynucleoside (ddN)-induced inhibition of hematopoietic differentiation in human hematopoietic cell line (K-562) and in human bone marrow CD34+ cells; (2) to examine the effect of Tat on transmembrane signalling by erythropoietin (EPO)-EPO receptor complex involving tyrosine phosphorylation and protein kinase C during proliferation and differentiation of erythroid progenitor cells; (3) to determine the role of TAT-induced cytokines, TNF alpha and beta and TGF beta, in the microenvironment of human mixed bone marrow cells, in modulating differentiation in the presence and absence of AZT and other ddNs; (4) to determine the role of Tat on the expression of proto-oncogenes c-myc, c-fos, and c-raf in the progenitor cells in the presence and absence of AZT; (5) to examine the effects of Tat and/or AZT on apoptosis in progenitor cells by monitoring DNA fragmentation and utilizing video imaging techniques; and 6) to develop new therapeutic approaches to overcome the HIV-1 Tat and AZT-induced bone marrow toxicity based upon the underlying mechanisms. In completing these specific aims, the Investigator to gain an in-depth understanding of the mechanisms associated with hematological toxicity in AIDS patients, and a basis for development of effective therapeutic approaches to overcome the hematological suppression.