MOLECULAR STUDIES OF DRUG RESISTANCE IN CHRONIC LYMPHOCY

慢性淋巴细胞耐药性的分子研究

• 批准号: 6027183
• 负责人: MICHAEL R GREVER
• 金额: $ 44.34万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-06 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6027183
• 关键词: apoptosis; chronic lymphocytic leukemia; clinical research; complementary DNA; drug resistance; fludarabine; fluorescent in situ hybridization; gene expression; human subject; microarray technology; molecular oncology; nucleic acid sequence

Chronic Lymphocytic Leukemia (CLL) is the most common form of adult leukemia. The neoplastic cells in patients with this disease accumulate as a result of defective programmed cell death. In response to standard chemotherapeutic agents, drug resistance routinely develops. An increased understanding of the molecular basis for this relative chemoresistance and heterogeneity of specific tumor cell sub-populations will facilitate development of innovative therapeutic strategies. New agents which can potentially circumvent the recognized mechanisms of resistance are being introduced into the clinic. This proposal will focus on identifying specific patient populations who will be ultimately targeted for novel therapeutic agents based upon the molecular characterization of their leukemic cells to predict either response or failure to standard chemotherapeutic agents. Furthermore, the use of alternatives in vitro predictive assays will also facilitate recognition of those who are likely to have either no response or a transient response to standard agents, and thus enable these patients to avoid unnecessary toxicity. Finally, the availability of powerful technological advances in cDNA microarrays will be used to examine the differential expression of genes relevant to drug- induced apoptosis in leukemic cells. These observations will be correlated with known chromosomal aberrations and specified levels of protein expression within the malignant cell. A substantial increment in our understanding of drug sensitivity and resistance will potentially result from this genomic research.

慢性淋巴细胞性白血病（CLL）是成人白血病的最常见形式。 由于程序性细胞死亡缺陷，该疾病患者的肿瘤细胞积累。 为了响应标准的化学治疗剂，耐药性通常会发展。 对特定肿瘤细胞亚群的这种相对化学抗性和异质性的分子基础的理解将有助于发展创新的治疗策略。 可能会绕过公认的抗药性机制的新药物正在引入诊所。 该建议将集中于确定特定的患者人群，这些患者人群最终将基于其白血病细胞的分子表征来预测对标准化学治疗剂的反应或失败的新治疗剂。 此外，在体外预测测定中使用替代方法还将促进识别那些可能对标准药物没有反应或短暂反应的人的识别，从而使这些患者避免不必要的毒性。 最后，将使用cDNA微阵列中强大的技术进步的可用性来检查与药物诱导的白血病细胞中与药物诱导的凋亡相关的基因的差异表达。 这些观察结果将与已知的染色体畸变和恶性细胞内的蛋白质表达水平相关。 我们对药物敏感性和耐药性的理解将有可能是由这项基因组研究产生的。