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Pharmacokinetic Studies of Internal Radiation Therapy with Radionuclide-labeled Tumor Specific Substances

放射性核素标记的肿瘤特异性物质体内放射治疗的药代动力学研究

基本信息

批准号：
63480254
负责人：
KUBO Atsushi
金额：
$ 4.03万
依托单位：
Keio 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：
1988
资助国家：
日本
起止时间：
1988 至 1990
项目状态：
已结题

项目摘要

The internal radiation therapy has been exclusively studied since some tumor-specific substances, such as monoclonal antibodies associated with cancer, have been well developed. Comparing with the external radiation therapy, this method is superior in the point that the radiation dose in normal organs should be quite small. However, this theory has not worked out well in clinical practice because radionuclide-conjugates administered are influenced by many factors before they reach tumor sites. The aim of this project is to investigate how some factors infuence the biodisteibution of radionuclide-labeled monoclonal antibodies from pharmacokinetic point of view. As the number of monoclonal antibodies which were used for patients were regulated by the committee, we have not investigated clinical radioimmunodetection enough to evaluate factors which have been studied by experimental animals. neverthless, we have concluded that pharmacokinetic characterization of In-111-labeled anti-CEA mon … More oclonal antibody, ZCE-025 in patients with colorectal cancer were relatively similar each other. Using experimental animals, we have found that injected antibody coupled with the circulating antigens, and thereby became unavailable for reaction with tumor associated antigen, and/or circulating antigen enhanced the degradation of the infected antibody in the plasma before it reached the tumor sites. However, the results obtained from athymic mice were not cases in clinical findings. Circulating antigens have not affected the visualization of tumors, the blood clearance and urine excretion of In-111-ZCE-025. Some other factors, such as vascularity or permeability, which made discrepancies between experimental animals and humans results must be considered very carefully. The fact that the absolute amount of antibody accumulated in tumors of patients was quite small should also be concerned in immunoscintigraphy as well as in radioimmunotherapy. We proposed here that the administration of interferon could improve the localization of antibody in tumors. Several researchers in the U. S. A. have now treated patients who underwent immunoscinitigraphy and/or radioimmunotherapy with interferon under the protocol we proposed. Treatment of iron-chelating agent as well as interferon has incceased the blood clearance of In-111. The interesting results were that effects of iron- or iron-chelating agents on the biodistribution of In-111-ZCE-025 were remarkably different between tumor-bearing and normal mice. This fact should be especially focused on here since similar situation would happen to patients who are on the way to being cured by receiving antibody. We still need investigate not only factors which should influence radioimmunodetection but also mechanisms which should clarify discrepancies of results between from experimental animals and from patients before applying radionuclide-labeled antibody to patients for the purpose of therapy. Less

由于一些肿瘤特异性物质，如与癌症相关的单克隆抗体，已经得到了很好的开发，因此内部放射治疗一直被专门研究。与外照射相比，该方法的上级之处在于正常器官所受的辐射剂量很小。然而，这一理论在临床实践中并没有很好地发挥作用，因为施用的放射性核素缀合物在到达肿瘤部位之前受到许多因素的影响。本课题的目的是从药物动力学的角度研究影响放射性核素标记单克隆抗体生物分布的因素。由于用于患者的单克隆抗体的数量由委员会规定，我们尚未对临床放射免疫检测进行足够的研究，以评估实验动物研究的因素。尽管如此，我们得出结论，In-111标记的抗CEA单克隆抗体的药代动力学特征， ...更多信息单克隆抗体ZCE-025在结直肠癌患者中的表达相对相似。使用实验动物，我们发现注射的抗体与循环抗原偶联，从而变得不能与肿瘤相关抗原反应，和/或循环抗原在血浆中感染的抗体到达肿瘤部位之前增强了其降解。然而，从无胸腺小鼠中获得的结果在临床发现中并非个例。循环抗原不影响肿瘤的可视化、In-111-ZCE-025的血液清除和尿液排泄。必须非常仔细地考虑其他一些因素，例如血管分布或渗透性，这些因素导致实验动物和人类结果之间存在差异。事实上，抗体的绝对量积累在病人的肿瘤是相当小的，也应该关注的免疫闪烁显像以及在放射免疫治疗。我们认为干扰素的应用可以改善抗体在肿瘤中的定位。美国的几位研究人员说，S. A.现在已经治疗了根据我们提出的方案进行免疫显像和/或用干扰素进行放射免疫治疗的患者。铁螯合剂和干扰素的治疗增加了In-111的血液清除率。结果表明，不同铁螯合剂对In-111-ZCE-025在荷瘤小鼠和正常小鼠体内分布的影响存在显著差异。这一事实应该特别关注，因为类似的情况也会发生在那些通过接受抗体而治愈的患者身上。在将放射性核素标记的抗体应用于患者治疗之前，我们不仅需要研究影响放射免疫检测的因素，而且还需要研究机制，以澄清实验动物和患者结果之间的差异。少