Ballangrud A M, Yang W H, Charlton D E, McDevitt M R, Hamacher K A, Panageas K S, Ma D, Bander N H, Scheinberg D A, Sgouros G
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 2001 Mar 1;61(5):2008-14.
A theoretical drawback to alpha-particle therapy with 213Bi is the short range of the particle track coupled with the short half-life of the radionuclide, thereby potentially limiting effective cytotoxicity to rapidly accessible, disseminated individual tumor cells (e.g., as in leukemia). In this work, a prostate carcinoma spheroid model was used to evaluate the feasibility of targeting micrometastatic clusters of tumor cells using 213Bi-labeled anti-prostate-specific membrane antigen (PSMA) antibody, J591. In prostate cancer, vascular dissemination of tumor cells or tumor cell clusters to the marrow constitutes an important step in the progression of this disease to widespread skeletal involvement, an incurable state. Such prevascularized clusters are ideal targets for radiolabeled antibodies because the barriers to antibody penetration that are associated with the capillary basal lamina have not yet formed. Beta- and gamma-emitting radionuclides such as 131I, which are widely used in radioimmunotherapy, are not expected to be effective when targeting single cells or small cell clusters. This is because the range of the emissions is one to two orders of magnitude greater than the target size, and the energy deposited per traversal is insufficient to produce any significant radiobiological effect. Spheroids of the prostate cancer cell line, LNCaP-LN3, were used as a model of prevascularized micrometastases; their response to an anti-PSMA antibody, J591, radiolabeled with the alpha-particle emitter 213Bi (T(1/2), 45.6 min.) has been measured. The time course of spheroid volume reductions was found to be sensitive to the initial spheroid volume. J591 labeled with 0.9 MBq/ml 213Bi resulted in a 3-log reduction in spheroid volume on day 33, relative to control, for spheroids with an initial diameter of 130 microm; 1.8 MBq/ml were required to achieve a similar response for spheroids with an initial diameter of 180 microm. Equivalent spheroid responses were observed after 12 Gy of acute external beam photon irradiation. Monte Carlo-based microdosimetric analyses of the 213Bi decay distribution in individual spheroids of 130-microm diameter yielded an average alpha-particle dose of 3.7 Gy to the spheroids, resulting in a relative biological effectiveness factor of 3.2 over photon irradiation. The activity concentrations used in the experiments were clinically relevant, and this work supports the possibility of using 213Bi-labeled antibodies not only for disseminated single tumor cells, as found in patients with leukemia, but also for micrometastatic tumor deposits up to 180 microm in diameter (1200 cells).
用²¹³Bi进行α粒子治疗存在一个理论缺陷，即粒子径迹范围短且放射性核素半衰期短，从而可能将有效的细胞毒性作用局限于可快速到达、播散的单个肿瘤细胞（如白血病中的情况）。在本研究中，使用前列腺癌球体模型来评估用²¹³Bi标记的抗前列腺特异性膜抗原（PSMA）抗体J591靶向肿瘤细胞微转移簇的可行性。在前列腺癌中，肿瘤细胞或肿瘤细胞簇向骨髓的血管播散是该疾病进展至广泛骨转移（一种无法治愈的状态）的重要步骤。这种预血管化的簇是放射性标记抗体的理想靶点，因为与毛细血管基膜相关的抗体渗透屏障尚未形成。广泛用于放射免疫治疗的发射β和γ射线的放射性核素，如¹³¹I，在靶向单个细胞或小细胞簇时预计无效。这是因为发射范围比靶标尺寸大1至2个数量级，且每次穿过沉积的能量不足以产生任何显著的放射生物学效应。前列腺癌细胞系LNCaP-LN3的球体被用作预血管化微转移灶的模型；已测量了它们对用α粒子发射体²¹³Bi（半衰期T(1/2)为45.6分钟）标记的抗PSMA抗体J591的反应。发现球体体积减小的时间进程对初始球体体积敏感。对于初始直径为130微米的球体，用0.9 MBq/ml²¹³Bi标记的J591在第33天相对于对照导致球体体积减少3个对数；对于初始直径为180微米的球体，需要1.8 MBq/ml才能达到类似反应。在12 Gy的急性外照射光子照射后观察到了等效的球体反应。基于蒙特卡洛的微剂量分析对直径130微米的单个球体中²¹³Bi衰变分布进行分析，得出球体的平均α粒子剂量为3.7 Gy，相对于光子照射，其相对生物效应因子为3.2。实验中使用的活度浓度与临床相关，并且这项研究支持不仅在白血病患者中发现的播散单个肿瘤细胞，而且对于直径达180微米（1200个细胞）的微转移肿瘤沉积物使用²¹³Bi标记抗体的可能性。
