DEOXYCOFORMYCIN IN LYMPHOID MALIGNANCIES

腺苷脱氨酶(ADA)--嘌呤核苷的重要酶 新陈代谢是细胞分化和增殖所必需的。 脱氧辅酶甲霉素(DCF)对该酶的药理抑制作用 探讨其在淋巴增生性疾病中的化疗潜力 恶毒。已观察到对DCF的客观反应 晚期慢性淋巴细胞白血病与皮肤T细胞淋巴瘤 (CTCL)的剂量为无毒。DCF诱导机制的研究进展 肿瘤细胞的细胞毒性直接涉及到细胞内的蓄积 脱氧腺苷(DAO)和dATP。DATP的增加抑制了 核糖核苷酸还原酶导致DNA合成受损。这个 DAO的增加将抑制S同型半胱氨酸腺苷水解酶 并有可能干扰重要的细胞内活动 甲基化反应。 这项研究将集中在已知生化物质的测定上。 对于实现和维护细胞内池非常重要的参数 晚期慢性淋巴细胞性白血病患者肿瘤细胞中dATP的表达 CTCL。从外周血、可触及的淋巴中分离出肿瘤细胞 结节或皮肤肿瘤的特征将既有标准表面 标记物和单抗在治疗前确定百分比 病人样本中存在的肿瘤细胞。具体活动 以下酶的含量将通过放射化学分析在 肿瘤细胞：AdA、脱氧腺苷激酶、胞浆5‘核苷酸酶、 治疗前后SAHH。细胞内脱氧核糖核苷酸 而核糖核苷酸将通过DNA聚合酶和高密度的 DCF前后的高效液相色谱方法 行政管理。这些特定生化参数之间的相关性 根据观察到的临床反应将完成。 患者将有一个放射性标记比率的基线测定 DCF转运到肿瘤细胞中。我们将努力界定 无反应或复发患者的耐药机制 病人。在抗药性疾病的患者中，肿瘤细胞将被 需要再次测量DCF的细胞内转运速率，以 测定抗性细胞中ADA的比活性，并 用DADO和DATO定量测定抗性细胞中ADA的Km 腺苷作为底物。这项研究将定义一种 慢性粒细胞白血病患者药敏试验的生化预测模型 淋巴样恶性肿瘤。

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.