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

癌症治疗取得了进展，延长了预期寿命，然而，在原发性骨肿瘤或骨转移中，疼痛的存在降低了患者的生活质量。骨研究的进展表明，骨吸收和形成类型的破骨细胞（OC）和成骨细胞（OB）转移分别存在。骨转移的早期鉴别诊断是必要的，但放射治疗药物将有助于缓解癌症疼痛的突破。申请人实验室研制了一种新的pH敏感肿瘤药物，二巯基琥珀酸多核五价锝-99m复合物（^<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，估计合成了一种具有Tc同系物，β发射器，铼-186 （Re-186）的治疗剂。通过对各种标记参数的研究，得到了^<186>Re (V)-DMS，其较长的半衰期使得基本组织学研究成为可能。然后，为了了解pH敏感性^<99m>Tc (V) -DMS的特征，比较葡萄糖或氯化铵诱导的不同酸中毒条件下小鼠体内生物分布的变化。放射性骨摄取的响应，仅用^<99m>Tc (V)-DMS检测；放射自显影和骨组织组织学研究显示，高放射性区域覆盖破骨细胞活性丰富的区域。对培养的骨细胞，即OC和OB细胞的进一步研究表明，OC细胞中^<99m>Tc (V)-DMS的积累量比OB细胞高10-50倍，OB细胞中Tc- bp的积累量虽低，但也有积累。仅用^<99m>Tc (V) -DMS检测酸性pH培养基效果显著。因此，利用各种细胞膜转运系统抑制剂表征其摄取机制揭示了Cl-/ hco3交换剂和磷酸盐转运体系统的参与。在提供的资助期间收集的数据为了解与OC相关的临床骨病问题提供了基本的体内和体外知识，不仅为溶骨转移开辟了新的诊断资源，而且为癌症患者骨痛缓解开辟了突破。少

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