Qu Chang F, Songl Yan J, Rizvi Syed M A, Li Yong, Smith Ross, Perkins Alan C, Morgenstern Alfred, Brechbiel Martin, Allen Barry J
Centre for Experimental Radiation Oncology, Cancer Care Centre, St George Hospital, New South Wales, Australia.
Cancer Biol Ther. 2005 Aug;4(8):848-53. doi: 10.4161/cbt.4.8.1892.
The aim of this study was to investigate the effect of targeted alpha therapy for the control of in vitro pancreatic cancer cell clusters and micrometastatic cancer lesions in vivo.
The expression of tumor-associated antigen MUC-1 on three pancreatic cancer cell clusters and animal xenografts was detected by indirect immmunostaining. Monoclonal antibodies C595 (test) and A2 (non-specific control) were labeled with 213Bi using the chelator CHX.A" to form the alpha-immunoconjugate (AIC). Cell clusters were incubated with AIC and examined at 48 h. Apoptosis was documented using the TUNEL assay. In vivo, an antiproliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AIC by regional or systemic administration. Changes in tumor progression were assessed by tumor size.
MUC-1 is strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The AICs can target and kill cancer cell clusters (100 mm) in vitro. Some 73-81 % of cells were TUNEL positive cells in the clusters after incubation with AIC. At two days post- cell inoculation in mice, a single local injection of 74 and 148 MBq/kg of AIC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of AIC cause significant tumor growth delay after 16 weeks, compared with the nonspecific control providing 333 MBq/kg after 16 weeks.
CFPAC-1, PANC-1 and CAPAN-1 pancreatic cancer cell clusters and pancreatic tumor xenografts show high expression of the MUC-1 target antigen. 213Bi-C595 can specifically target and regress pancreatic cancer cell clusters in vitro, and delay and inhibit tumor growth in vivo. 213Bi-C595 may be a useful agent for the treatment of micrometastatic pancreatic cancer with overexpression of MUC 1 antigen in post-surgical patients with minimal residual disease.
本研究旨在探讨靶向α治疗对体外胰腺癌细胞簇及体内微转移癌病灶的控制效果。
采用间接免疫染色法检测三种胰腺癌细胞簇及动物异种移植瘤中肿瘤相关抗原MUC-1的表达。使用螯合剂CHX.A”将单克隆抗体C595（测试）和A2（非特异性对照）用213Bi标记，形成α免疫偶联物（AIC）。将细胞簇与AIC孵育，并在48小时后进行检测。使用TUNEL法记录细胞凋亡情况。在体内，于皮下接种细胞两天后测试对肿瘤的抗增殖作用。通过区域或全身给药向小鼠注射不同浓度的AIC。通过肿瘤大小评估肿瘤进展的变化。
MUC-1在CFPAC-1、PANC-1上强烈表达，在CAPAN-1细胞簇和肿瘤异种移植瘤中表达中等。AICs可在体外靶向并杀死癌细胞簇（100毫米）。与AIC孵育后，细胞簇中约73 - 81%的细胞为TUNEL阳性细胞。在小鼠接种细胞两天后，单次局部注射74和148 MBq/kg的AIC可导致肿瘤生长完全抑制。与16周后提供33 MBq/kg的非特异性对照相比，全身注射111、222和333 MBq/kg的AIC在16周后可导致肿瘤生长显著延迟。
CFPAC-1、PANC-1和CAPAN-1胰腺癌细胞簇及胰腺肿瘤异种移植瘤显示MUC-1靶抗原高表达。213Bi-C595可在体外特异性靶向并使胰腺癌细胞簇消退，并在体内延迟和抑制肿瘤生长。213Bi-C595可能是治疗术后残留疾病极少且MUC 1抗原过表达的微转移胰腺癌患者的有用药物。
