DEOXYCOFORMYCIN IN LYMPHOID MALIGNANCIES

脱氧福霉素治疗淋巴恶性肿瘤

• 批准号: 3173885
• 负责人: MICHAEL R GREVER
• 金额: $ 5.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3173885
• 关键词: DNA directed DNA polymerase; adenosine deaminase; adenosine triphosphate; cell differentiation; deoxyadenosines; human T cell leukemia; human tissue; lymphocytic leukemia; lymphoma; methylation; neoplastic cell; nucleotide metabolism; purine nucleosides

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.

腺苷脱氨酶 (ADA)，一种重要的嘌呤核苷酶 代谢，对于细胞分化和增殖至关重要。 脱氧考福霉素（dCF）对该酶的药理学抑制作用已被证实 探索其在淋巴增殖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）的剂量是无毒的。 所提出的 dCF 诱导机制 肿瘤细胞的细胞毒性直接涉及细胞内的积累 脱氧腺苷 (dAdo) 和 dATP。 dATP 的增加抑制 核糖核苷酸还原酶，从而损害 DNA 合成。 这 dAdo 的增加会抑制 S-腺苷同型半胱氨酸水解酶 (SAHH) 活性并可能会干扰重要的细胞内 甲基化反应。 本研究将重点确定已知的生化物质 对于实现和维持细胞内池很重要的参数 晚期 CLL 患者肿瘤细胞中 dATP 的含量 CTCL。 从外周血中分离出肿瘤细胞，可触及淋巴 节点或皮肤肿瘤将通过标准表面来表征 治疗前标记物和单克隆抗体以确定百分比 患者样本中存在的肿瘤细胞的数量。 具体活动 下列酶中的一种将通过放射化学测定法测定 肿瘤细胞：ADA、脱氧腺苷激酶、胞质 5' 核苷酸酶、 以及治疗前后的SAHH。 细胞内脱氧核糖核苷酸 核糖核苷酸将通过 DNA 聚合酶和高通量进行定量 dCF 之前和之后的高效液相色谱方法 行政。 这些特定生化参数的相关性 随着观察到的临床反应的完成。 患者将对放射性标记率进行基线测定 dCF 转运至肿瘤细胞中。 将努力定义 无反应或复发的耐药机制 患者。 在患有耐药性疾病的患者中，肿瘤细胞将被 再次测量 dCF 细胞内转运的速率，以 确定耐药细胞中 ADA 的比活性，并 使用 dADO 和 dADO 定量耐药细胞中 ADA 的 Km 腺苷作为底物。 这项研究将定义一个 用于测试患者药物敏感性的生化预测模型 淋巴系统恶性肿瘤。