Buchsbaum D, Khazaeli M B, Liu T, Bright S, Richardson K, Jones M, Meredith R
Department of Radiation Oncology, University of Alabama at Birmingham 35233, USA.
Cancer Res. 1995 Dec 1;55(23 Suppl):5881s-5887s.
Radiolabeled monoclonal antibodies (MoAbs) have been used for radioimmunotherapy (RIT) of human colon cancer xenografts in an attempt to develop promising clinical approaches to improving therapy success. Several strategies have been investigated to accomplish this task while decreasing toxicity. The CC49 antibody was selected for the present studies because of its relatively high affinity constant (16.2 x 10(9) M-1) for the high molecular weight TAG-72 mucinous antigen secreted by human colon cancer cells. In previous studies, when CC49 was labeled with 131I, it demonstrated a substantial therapeutic advantage over the lower affinity antibody (B72.3) reactive with TAG-72. One of the chief problems in achieving cures with RIT is that hematological toxicity limits the quantity of radionuclide that can be administered. In other studies of dose fractionation using athymic nude mice and 131I-labeled intact MoAbs reactive with human colon cancer xenografts, multiple administrations at approximately 1-week intervals were found to produce more prolonged tumor growth inhibition and less toxicity than single administrations. The purpose of this study was to investigate the therapeutic efficacy and toxicity of 131I-labeled CC49 MoAb administered with short fractionation schedules against human colon cancer xenografts to determine the optimal treatment schedule, with the ultimate aim of applying this approach in clinical trials. The results reported here demonstrate that in an animal colon cancer xenograft model, RIT delivered in a fractionated schedule clearly presents a therapeutic advantage. For example, one administration of 600 microCi 131I-labeled CC49 to LS174T tumor-bearing mice was lethal to approximately 25% of mice but produced no tumor regressions. Fractionation of this dose to two administrations of 300 microCi 131I-labeled CC49 at a 3-day interval resulted in tumor regression in approximately 30% of the animals, accompanied by a similar 25% death rate. The administration of 300 microCi 131I-labeled CC49 at a 7-day interval resulted in 15% animal lethality, but no complete tumor regressions. When three administrations of 300 microCi 131I-labeled CC49 were given over a 1-week period on days 0, 3, and 7, tumor regressions occurred in approximately 40% of the animals, accompanied by a 30% death rate. Moreover, three administrations of 300 microCi 131I-labeled CC49 resulted in 20% tumor recurrence, whereas two administrations of 131I-labeled CC49 resulted in 60% tumor recurrence.(ABSTRACT TRUNCATED AT 400 WORDS)
放射性标记的单克隆抗体（MoAbs）已用于人结肠癌异种移植瘤的放射免疫治疗（RIT），试图开发出有望提高治疗成功率的临床方法。为了完成这一任务并降低毒性，人们研究了几种策略。本研究选择CC49抗体，是因为它对人结肠癌细胞分泌的高分子量TAG-72粘蛋白抗原有相对较高的亲和常数（16.2×10⁹ M⁻¹）。在先前的研究中，当用¹³¹I标记CC49时，它比与TAG-72反应的低亲和力抗体（B72.3）显示出显著的治疗优势。用RIT实现治愈的主要问题之一是血液学毒性限制了可给药的放射性核素量。在其他使用无胸腺裸鼠和与人类结肠癌异种移植瘤反应的¹³¹I标记完整MoAbs进行剂量分割的研究中，发现每隔约1周多次给药比单次给药能产生更长时间的肿瘤生长抑制且毒性更小。本研究的目的是研究短分割方案给予¹³¹I标记的CC49单克隆抗体对人结肠癌异种移植瘤的治疗效果和毒性，以确定最佳治疗方案，最终目标是将这种方法应用于临床试验。此处报告的结果表明，在动物结肠癌异种移植瘤模型中，分割给药的RIT明显具有治疗优势。例如，给荷LS174T肿瘤的小鼠一次注射600微居里¹³¹I标记的CC49，约25%的小鼠死亡，但未出现肿瘤消退。将此剂量分割为间隔3天两次注射300微居里¹³¹I标记的CC49，约30%的动物出现肿瘤消退，死亡率约为25%。间隔7天注射300微居里¹³¹I标记的CC49导致15%的动物死亡，但没有完全的肿瘤消退。当在第0、3和第7天的1周内分三次注射300微居里¹³¹I标记的CC49时，约40%的动物出现肿瘤消退，死亡率为30%。此外，三次注射300微居里¹³¹I标记的CC49导致20%的肿瘤复发，而两次注射¹³¹I标记的CC49导致60%的肿瘤复发。（摘要截短至400字）
