DEOXYCOFORMYCIN IN LYMPHOID MALIGNANCIES

腺苷脱氨酶（ADA），一种重要的嘌呤核苷酶 代谢是细胞分化和增殖所必需的。 脱氧共形霉素（dCF）对这种酶的药理学抑制作用已被证实。 探索其在淋巴增生性疾病中的化疗潜力 恶性肿瘤 在以下患者中观察到对DCF的客观反应： 晚期慢性淋巴细胞白血病（CLL）和皮肤T细胞淋巴瘤 （CTCL）在无毒的剂量下。 dCF诱导的拟议机制 肿瘤细胞的细胞毒性直接涉及细胞内积累的 脱氧腺苷（dAdo）和dATP。 dATP的增加抑制了 核糖核苷酸还原酶，从而损害DNA合成。 的 dAdo的增加将抑制S-腺苷高半胱氨酸水解酶（SAHH） 活性，并可能干扰重要的细胞内 甲基化反应。 这项研究将集中在确定已知的生化 对于实现和维持细胞内池重要的参数 晚期CLL患者肿瘤细胞中dATP的水平， CTCL。 从外周血、可触及淋巴中分离出的肿瘤细胞 结节或皮肤肿瘤的特征将由两个标准表面 标记物和单克隆抗体，以确定治疗前 患者样本中存在的肿瘤细胞。 比活性 将通过放射化学测定法测定下列酶中的 肿瘤细胞：ADA，脱氧腺苷激酶，胞质5'核苷酸酶， 治疗前后的SAHH。 细胞内脱氧核糖核苷酸 和核糖核苷酸将通过DNA聚合酶定量， DCF前后的高效液相色谱法 局 这些特定生化参数的相关性 观察到的临床反应。 患者将在基线时测定放射性标记的 dCF转运到肿瘤细胞中。 将努力确定 无反应或复发患者的耐药机制 患者 在耐药疾病患者中，肿瘤细胞将被 再次测量DCF细胞内转运的速率， 测定耐药细胞中ADA的比活性，并 使用dADO和dADO定量抗性细胞中ADA的Km， 腺苷作为底物。 本研究将定义一个 生化预测模型，用于测试患者的药物敏感性 淋巴恶性肿瘤

Adenosine deaminase (ADA), an enzyme important in purine nucleoside metabolism, is essential for cell differentiation and proliferation. Pharmacologic inhibition of this enzyme by deoxycoformycin (dCF) has been explored for its chemotherapeutic potential in lymphoproliferative malignancy. Objective responses to dCF have been observed in patients with advanced chronic lymphocytic leukemia (CLL) and cutaneous T-cell lymphoma (CTCL) at doses which are nontoxic. The proposed mechanism of dCF induced tumor cell cytotoxicity directly involves the intracellular accumulation of both deoxyadenosine (dAdo) and dATP. The increase in dATP inhibits ribonucleotide reductase with consequent impairment in DNA synthesis. The increase in dAdo will inhibit S-adenosylhomocysteine hydrolase (SAHH) activity and potentially will interfere with important intracellular methylation reactions. This study will focus on a determination of the known biochemical parameters that are important to achieve and maintain an intracellular pool of dATP in the neoplastic cells from patients with either advanced CLL or CTCL. Neoplastic cells isolated from the peripheral blood, palpable lymph nodes, or skin tumors will be characterized by both standard surface markers and monoclonal antibodies before treatment to define the percentage of neoplastic cells present in the patient sample. The specific activity of the following enzymes will be determined by radiochemical assay in the neoplastic cells: ADA, deoxyadenosine kinase, cytoplasmic 5' nucleotidase, and SAHH before and after treatment. Intracellular deoxyribonucleotides and ribonucleotides will be quantitated by DNA polymerase and high performance liquid chromatography methods before and after dCF administration. A correlation of these specific biochemical parameters with the observed clinical response will be accomplished. Patients will have a baseline determination of the rate of radiolabelled dCF transport into the neoplastic cells. An effort will be made to define the mechanism of drug resistance in the non-responsing or relapsed patients. In patients with resistant disease, neoplastic cells will be procured to again measure the rate of dCF intracellular transport, to determine the specific activity of ADA in the resistant cells, and to quantitate the Km for ADA in the resistant cells using both dADO and adenosine as substrates. This study will define the utility of a biochemical predictive model for testing drug sensitivity in patients with lymphoid malignancies.