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一种。这种疾病患者的肿瘤细胞是由于有缺陷的程序性细胞死亡而积累的。作为对标准化疗药物的反应，耐药性通常会产生。对这种特定肿瘤细胞亚群的相对化疗耐药和异质性的分子基础的进一步了解将有助于创新治疗策略的发展。新的药物可以潜在地绕过已知的耐药性机制，正在被引入临床。这项建议将侧重于确定特定的患者群体，他们将最终成为新的治疗药物的靶点，基于他们的白血病细胞的分子特征来预测对标准化疗药物的反应或失败。此外，在体外预测分析中使用替代物也将有助于识别那些可能对标准药物无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，强大的技术进步的可获得性将被用来检查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异常和恶性细胞内特定水平的蛋白质表达相关联。这项基因组研究可能会大大提高我们对药物敏感性和耐药性的理解。

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.