CARBORANYL NUCLEOTIDES-POTENTIAL DNA PROBES FOR BNCT

碳酰基核苷酸 - BNCT 的潜在 DNA 探针

• 批准号: 3198506
• 负责人: ALBERT H SOLOWAY
• 金额: $ 16.67万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-01 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3198506
• 关键词: boranes; cellular oncology; combination cancer therapy; cyclic nucleoside monophosphate; drug design /synthesis /production; glioma; laboratory mouse; laboratory rat; melanoma; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; neoplastic cell; neutron radiation; nonhuman therapy evaluation; nucleic acid chemical synthesis; nucleic acid probes; nucleotide analog; prodrugs; radiobiology; radiopharmacology; tritium

The treatment of tumors by Boron Neutron Capture Therapy (BNCT) requires the development of nontoxic boron compounds which will attain a differential boron concentration between tumor and normal tissues of at least 5 to 10:1. Such compounds should show persistence for a sufficient period of time that would ultimately allow for the delivery of a fractionated radiation dose to the tumor permitting repair from low linear energy transfer (LET) radiation in contiguous normal tissue. Ideally, the compounds should be localized in the cell nucleus since the radiobiological effectiveness is at least twice as great as it would be if the compounds were confined to the cytoplasm. The overall objective of this proposal is to synthesize and biologically evaluate boron-containing nucleic acid precursors such as carboranyl nucleotides and oligonucleotides that may possess a strong proclivity for malignant cells. The specific aims are: 1. To develop the methodology to synthesize carboranyl nucleosides and nucleotides with the boron moiety on the carbohydrate portion of the molecule. 2. To synthesize carboranyl nucleosides and cyclic nucleotides of adenine, guanine cytosine, thymine and other purine/pyrimidine bases. 3. Masking of the phosphate moiety of nucleotides to enhance cellular uptake and concentration by tumors. 4. To undertake the incorporation of carboranyl nucleotides into oligonucleotides as potential chemoradiotherapeutic agents. 5. To develop the methodology for radiolabeling these nucleic acid precursors. 6. To determine the in vitro cellular uptake and persistence of these boron-containing nucleosides and nucleotides in melanoma and glioma cells. 7. To study the in vivo pharmacokinetics and tumor-localizing properties of these compounds in tumor-bearing rats and mice. 8. To assess the tumorcidal activity both in vitro and in vivo of carboranyl nucleic acid precursors following thermal neutron irradiation.

通过硼中子捕获疗法（BNCT）对肿瘤的治疗需要 无毒硼化合物的发展，这将达到 肿瘤与正常组织之间的差异硼浓度 至少5至10：1。 这样的化合物应表现出足够的持久性 最终允许交付的时间 允许从低线性修复的肿瘤的辐射剂量 连续正常组织中的能量转移（LET）辐射。 理想情况下， 由于放射生物学，化合物应位于细胞核中 有效性至少是化合物的两倍 被局限于细胞质。 该提议的总体目标是 合成和生物学评估含硼的核酸 前体，例如Carboranyl核苷酸和寡核苷酸，可能 对恶性细胞具有很强的倾向。 具体目的是： 1。开发合成Carboranyl核苷的方法论 核苷酸在碳水化合物部分上的硼部分 分子。 2。合成carboranyl核苷和环核苷酸的循环核苷酸 腺嘌呤，鸟嘌呤胞嘧啶，胸腺嘧啶和其他嘌呤/嘧啶碱。 3。核苷酸磷酸盐部分的掩盖以增强 细胞摄取和肿瘤浓度。 4。将碳酸核苷酸掺入中 寡核苷酸作为潜在的化学核治疗剂。 5。开发用于放射标记的方法论这些核酸 前体。 6。确定体外细胞的摄取和持久性 这些含硼的核苷和黑色素瘤和神经胶质瘤中的核苷酸 细胞。 7。研究体内药代动力学和肿瘤定位 这些化合物在肿瘤大鼠和小鼠中的性质。 8。在体外和体内评估肿瘤活性 热中子辐照后的碳纤维核酸前体。