Re-186 Therapeutic Radiopharmaceutical for Bone Pain Palliation in Malignant Bone Tumor or Bone Metastases : Biological Basis on Osteoblastic and Osteolytic Bone Metastases

Re-186 治疗性放射性药物用于缓解恶性骨肿瘤或骨转移的骨痛：成骨细胞和溶骨性骨转移的生物学基础

• 批准号: 11670883
• 负责人: HORIUCHI(SUZUKI) Kazuko
• 金额: $ 2.18万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670883/
• 关键词: Radiotherapeutic agent; Bone pain palliation; ^<186>Re (V)-DMS; pH sensitive drug; Cancer bone metastases; Osteoclastic cells; ^<99m>Tc (V)-DMS; Osteolytic metastases; ^<186>Re(V)-DMS; ^<99m>Tc(V)-DMS

Advances have been made in cancer therapy that prolong life expectancy, however, in primary bone tumor or bone metastases, the presence of pain, compromise patients' quality of life. Progress on bone research indicates presence of bone resorption and formation types of osteoclastic (OC) and osteoblastic (OB) metastases, respectively. Early differential diagnosis of bone metastases is desirable but radiotherapeutical agent would help a breakthrough to cancer pain palliation. In the applicant laboratory, a new pH sensitive tumor agent, the polynuclear pentavalent technetium-99m complex of dimercaptosuccinic acid (^<99m>Tc (V)-DM) has been developed and clinical trials indicated its accumulation in bone tumors, bone metastases, Paget's diseases. On those basis, synthesis of a therapeutical agent with a Tc congener, the beta emitter, rhenium-186 (Re-186) was estimated. Studies on various labeling parameters, made the ^<186>Re (V)-DMS available, and its longer half-life allowed basic histom … More orphological studies. Then, to learn about the pH sensitive ^<99m>Tc (V) -DMS character, biodistribution changes in mice under variable conditions of acidosis, induced by glucose or ammonium chloride were compared with the conventional bisphosphonated Tc-bone agent (Tc-BP). Response on radioactivity bone uptake, detected only with ^<99m>Tc (V)-DMS ; autoradiographic and histological bone tissue studies revealed high radioactivity regions overlaying osteoclastic activity rich areas. Further studies on cultured bone cells, namely, OC and OB cells showed, 10-50 times higher accumulation of ^<99m>Tc (V)-DMS in OC than OB cells, with Tc-BP accumulated in OB cells although at low rate. Significant effect of acid pH incubation media detected only with ^<99m>Tc (V) -DMS.Thus, characterization of its uptake mechanism using various cell membrane transport system inhibitors revealed the involvement of Cl-/HCO3-exchanger and phosphate transporter system. The gathered data during the provided grant offered basic in-vivo and in-vitro knowledge for understanding clinical bone disease problems, related to OC, opening a road not only to new diagnostic resources for osteolytic metastases but a breakthrough to bone pain palliation in cancer patient. Less

癌症治疗已经取得了进展，延长了预期寿命，然而，在原发性骨肿瘤或骨转移，疼痛的存在，损害患者的生活质量。骨研究的进展表明，存在骨吸收和骨转移（OC）和成骨细胞（OB）的形成类型分别。骨转移的早期鉴别诊断是可取的，但放射治疗剂将有助于癌症疼痛缓解的突破。在申请人的实验室中，已经开发了一种新的pH敏感性肿瘤剂，即二巯基琥珀酸的多核五价锝-99 m络合物（^<99m>Tc（V）-DM），临床试验表明其在骨肿瘤、骨转移、佩吉特病中蓄积。在此基础上，估计了用Tc同系物β发射体Re-186（Re-186）合成治疗剂的可能性。对各种标记参数的研究使得^<186>Re（V）-DMS可用，其较长的半衰期允许碱性组织化学染色。 ...更多信息 形态学研究然后，为了了解pH敏感性^<99m>Tc（V）-DMS特性，将由葡萄糖或氯化铵诱导的不同酸中毒条件下小鼠中的生物分布变化与常规双膦酸化Tc-骨剂（Tc-BP）进行比较。放射性骨摄取反应，仅用^<99m>Tc（V）-DMS检测;放射自显影和组织学骨组织研究显示高放射性区域覆盖骨细胞活性丰富区域。对培养的骨细胞（即OC和OB细胞）的进一步研究显示，<99m>OC中^ Tc（V）-DMS的积累比OB细胞高10-50倍，Tc-BP在OB细胞中积累，尽管速率较低。因此<99m>，使用各种细胞膜转运系统抑制剂表征其摄取机制揭示了Cl-/HCO 3-交换和磷酸盐转运系统的参与。在所提供的资助期间收集的数据为理解与OC相关的临床骨病问题提供了基本的体内和体外知识，不仅为溶骨性转移的新诊断资源开辟了道路，而且为癌症患者的骨痛缓解提供了突破。少

项目成果

Horiuchi Kazuko: "Carrier Effect on Radiolabeling the Polunuclear Pentavalent Rhenium-186 Complex of Dimercaptosuccinic Acid at Alkaline pH : 186Re(V)-DMS"Nuclear Medicine and Biology. 26. 771-778 (1999)

Horiuchi Kazuko：“碱性 pH 值下对二巯基丁二酸多核五价铼-186 复合物放射性标记的载体效应：186Re(V)-DMS”核医学和生物学。

Horiuchi Kazuko: "Strategies of Development of Functional Biomimetic 99mTc-radiopharma-ceutics."Radiochemistry. 42. 499-501 (2000)

堀内和子：“功能仿生 99mTc-放射性药物的开发策略。”放射化学。

K.Horiuchi, H.Saji and A.Yokoyama: "Carrier Effect on Radiolabeling the Polynuclear Pentavalent Rhenium-186 Complex of Dimercaptosuccinic Acid at Alkaline pH : ^<186>Re (V)-DMS"Nuclear Medicine and Biology. 26. 771-779 (1999)

K.Horiuchi、H.Saji 和 A.Yokoyama：“碱性 pH 值下对二巯基丁二酸多核五价铼-186 复合物放射性标记的载体效应：^<186>Re (V)-DMS”核医学和生物学。

Horiuchi Kazuko: "Carrier Effect on Radiolabeling the Polynuclear Pentavalent Rhenium-186 Complex of Dimercaptosuccinic Acid at Alkaline pH :186Re(V)-DMS"Nuclear Medicine and Biology. 26. 771-779 (1999)

堀内和子：“碱性 pH 值：186Re(V)-DMS 对二巯基丁二酸多核五价铼-186 复合物放射性标记的载体效应”核医学和生物学。

Horiuchi Kazuko: "Strategies of Development of Functional Biomimetic 99mTc-radiopharmaceuticals"Radiochemistry. 42. 499-501 (2000)

堀内和子：“功能仿生99mTc-放射性药物的开发策略”放射化学。