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Fundamental study of combination treatment of fibrinolytic agents, radiohypersensitizer and repair-inhibitor of DNA to enhance radiation effects on experimental tumor in mice and rabbits.

纤溶剂、放射增敏剂和DNA修复抑制剂联合治疗增强对小鼠和兔实验性肿瘤的放射作用的基础研究。

基本信息

批准号：
02454562
负责人：
MIYOSHI Takeyoshi
金额：
$ 1.98万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

To strengthen radiation effects on tumors, each one of fibrinolytic agents and radiohypersensitizers have been used jointly with radiation,however this approach has not always produced good results in cancer patients. Fibrinolytic agents can not improve blood flow in capillary vessels in which micro-thrombus become old and fibrotic. While, radiohypersensitizers are unable to permeate deeply and sufficiently in hypoxic and anoxic areas of large tumor, because this agents have neuro-toxic effects when administered in large amounts.We carried out a combination treatment with fibrinolytic agents (a mixture of Low Molecular Weight Dextran and Urokinase) and a radiohypersensitizer(misonidazol) to supply deficiencys of these agents. In our studies on mouse Ehrlich solid tumor, we found the same result could be obtained with 300 mg/kg of misonidazol as with 500 mg/kg of misonidazol in case of misonidazol, alone a reduction of 40%. However, the effect of this combination treatment had been redu … More ced in experiments when large sized Vx-2 tumors on rabbits were used, and it was thought that permeation of misonidazol was not sufficient in wide hypoxic and anoxic areas of large tumors. In other studies, we foundthat low doses of TNF(Tumor Necrosis Factor) remarkably increased drug accumulation in tumor tissures. From these results, a new combination treatment of fibrinolytic agents, TNF and misonidazol was studied on large Vx-2 tumor. By this new treatment, radiation effects were greatly enhanced, and the effective dosage of misonidazol reduced to 200 mg/kg.By this combination treatment system, RK-28( an improved type substance of misonidazol ) was studied instead of misonidazol, and the same result were obtained. To further augment radiation effects, at the same time, Ara-A( as a repair-inhibitor of damaged DNA ) was studied with this systemic combination treatment of fibrinolytic agents, TNF and RK-28, but it failed to show enhancement of radiation effects.These results indicated that our combination treatment of fibrinolytic agents, TNF and radiohypersensitizers is worthy of clinical trial for cancer therapy. Less

为了加强对肿瘤的辐射作用，纤维蛋白溶解剂和放射增敏剂中的每一种都与辐射联合使用，但这种方法并不总是对癌症患者产生良好的效果。纤溶药物不能改善毛细血管内的血流，微血栓会老化和纤维化。然而，放射增敏剂不能在大肿瘤的缺氧和缺氧区域充分渗透，因为这些药物在大量给药时具有神经毒性作用，我们进行了纤溶剂（低分子量葡聚糖和尿激酶的混合物）和放射增敏剂（misonidazol）的联合治疗，以补充这些药物的不足。在我们对小鼠埃利希实体瘤的研究中，我们发现使用300 mg/kg的米索咪唑可以获得与使用500 mg/kg的米索咪唑相同的结果，仅减少40%。然而，这种联合治疗的效果已经降低， ...更多信息在实验中，当使用兔的大尺寸Vx-2肿瘤时，发现米索咪唑在大肿瘤的宽缺氧和缺氧区域中的渗透是不充分的。在其他研究中，我们发现低剂量的TNF（肿瘤坏死因子）显著增加肿瘤组织中的药物蓄积。根据这些结果，研究了纤溶剂、TNF和米索咪唑对大Vx-2肿瘤的新的组合治疗。采用该组合处理体系，研究了RK-28（一种改良型的咪唑类物质）替代咪唑的效果，并获得了相同的结果。为进一步增强放射效应，同时研究了Ara-A（作为DNA损伤修复抑制剂）与纤溶剂、TNF和RK-28的全身联合治疗，但未显示出增强放射效应的作用，提示纤溶剂、TNF和放射增敏剂的联合治疗对肿瘤的治疗是值得临床试验的。少