MOLECULAR STUDIES OF DRUG RESISTANCE IN CHRONIC LYMPHOCY

慢性淋巴细胞白血病（CLL）是成人白血病最常见的形式。这种疾病患者的肿瘤细胞由于程序性细胞死亡缺陷而积累。在对标准化疗药物的反应中，通常会产生耐药性。增加对这种相对化疗耐药的分子基础的理解和特定肿瘤细胞亚群的异质性将促进创新治疗策略的发展。可以潜在地绕过已知的耐药机制的新药物正在被引入临床。该提案将侧重于确定特定的患者群体，这些患者将最终以基于其白血病细胞的分子特征的新型治疗药物为目标，以预测对标准化疗药物的反应或失败。此外，使用替代的体外预测试验也将有助于识别那些可能对标准药物没有反应或短暂反应的患者，从而使这些患者避免不必要的毒性。最后，cDNA微阵列的强大技术进步将用于检测白血病细胞中药物诱导凋亡相关基因的差异表达。这些观察结果将与已知的染色体畸变和恶性细胞内特定水平的蛋白质表达相关。我们对药物敏感性和耐药性的理解可能会从这项基因组研究中得到实质性的增加。

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.