MOLECULAR STUDIES OF DRUG RESISTANCE IN CHRONIC LYMPHOCY

慢性淋巴细胞白血病（CLL）是成人白血病中最常见的形式。 由于有缺陷的程序性细胞死亡，患有这种疾病的患者中的肿瘤细胞积聚。 在对标准化疗剂的反应中，通常会产生耐药性。 对这种相对化学抗性和特定肿瘤细胞亚群异质性的分子基础的进一步理解将促进创新治疗策略的开发。 可以潜在地规避已认识到的耐药机制的新药剂正在被引入临床。 该提案将侧重于确定特定的患者群体，这些患者群体将根据其白血病细胞的分子特征最终成为新型治疗药物的目标，以预测对标准化疗药物的反应或失败。 此外，使用替代体外预测测定也将有助于识别那些可能对标准药物无反应或有短暂反应的患者，从而使这些患者能够避免不必要的毒性。 最后，cDNA微阵列技术的强大进步将被用于检测白血病细胞中与药物诱导的细胞凋亡相关的基因的差异表达。 这些观察结果将与恶性细胞内已知的染色体畸变和特定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从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.