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

自从一些肿瘤特异性物质，如与癌症相关的单抗得到很好的发展以来，内放射治疗一直是专门研究的。与体外放射治疗相比，这种方法的优势在于正常器官的辐射剂量应该很小。然而，这一理论在临床实践中并没有得到很好的应用，因为在放射性核素结合物到达肿瘤部位之前，它们受到许多因素的影响。本项目的目的是从药代动力学的角度研究一些因素对放射性核素标记的单抗生物分布的影响。由于用于患者的单抗的数量受到委员会的监管，我们没有对临床放射免疫检测进行足够的调查，以评估已由实验动物研究的因素。然而，我们得出的结论是，In-111标记的抗CEA在…上的药代动力学特征多克隆抗体ZCE-025在结直肠癌患者中彼此比较相似。利用实验动物，我们发现注射的抗体与循环抗原偶联，从而不能与肿瘤相关抗原反应，和/或循环抗原促进了感染抗体在到达肿瘤部位之前在血浆中的降解。然而，在无瘤小鼠身上所得到的结果在临床上是不成立的。循环抗原不影响In-111-ZCE-025的肿瘤显影、血液清除和尿液排泄。其他一些因素，如血管或渗透性，导致实验动物和人类结果之间的差异，必须非常仔细地考虑。患者肿瘤中累积的抗体绝对量很小，这一事实在免疫核素成像和放射免疫治疗中也应引起关注。我们在这里提出，给予干扰素可以改善抗体在肿瘤中的定位。根据我们提出的方案，美国的几位研究人员现在已经用干扰素治疗了接受免疫示波和/或放射免疫治疗的患者。铁络合剂和干扰素的治疗增加了In-111的血液清除。有趣的结果是，铁或铁络合剂对In-111-ZCE-025在荷瘤小鼠和正常小鼠体内的生物分布的影响明显不同。这里应该特别关注这一事实，因为类似的情况也会发生在通过接受抗体治愈的患者身上。在将放射性核素标记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，还需要研究澄清实验动物和患者结果之间差异的机制。较少

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