Abbas Rizvi Syed M, Li Yong, Song Emma Yan Jun, Qu Chang Fa, Raja Chand, Morgenstern Alfred, Apostolidis Christos, Allen Barry J
Center for Experimental Radiation Oncology (CERO), Division of Cancer Services, St. George Hospital, Gray Street, Kogarah, NSW 2217, Australia.
Cancer Biol Ther. 2006 Apr;5(4):386-93. doi: 10.4161/cbt.5.4.2478. Epub 2006 Apr 4.
The key objective of the study was to determine the single and multiple dose toxicity and efficacy of Bismuth-213 labeled PAI2 based targeted alpha therapy by selectively targeting uPA and uPAR in regressing prostate cancer in a nude mouse model. Targeted alpha therapy (TAT) is an experimental therapeutic modality for cancer. Another objective was to compare the in vivo pharmacokinetics using two different chelators to form the radioisotope-protein construct.
The single and multiple intra-peritoneal (IP) dose toxicity and efficacy of 213BiPAI2 was investigated in nude mice and its toxicity in rabbits. CD 31 staining for vasculature and uPA expression were measured at different stages of tumor growth. The pharmacokinetics of the chelators cDTPA and CHX-A'' were measured.
All TAT regimes were well tolerated in mice and rabbits on biochemical and haematological examination. Capillaries became evident at six days post-cell inoculation. uPA expression was positive at all stages of tumour growth. No significant differences were observed between cDTPA and CHX-A. '' Inhibition of tumour growth was observed at 947 and 1421 MBq/kg single dose injection at three days post-PC3 cell inoculation. The three day post-inoculation multiple dose regime gave complete tumour growth inhibition at a total dose of 947 MBq/kg given on five successive days. Mice treated at 6, 12 and 18 days post-inoculation showed significantly slower tumour growth compared to controls.
The efficacy of single and multiple dose TAT in mice was demonstrated within tolerance limits, the multiple dose regime being no more toxic than the single dose. Either of the two chelators could be used for 213Bi studies.
本研究的主要目的是通过在裸鼠模型中选择性靶向uPA和uPAR来确定铋 - 213标记的PAI2基于靶向α疗法在消退前列腺癌中的单剂量和多剂量毒性及疗效。靶向α疗法（TAT）是一种用于癌症的实验性治疗方式。另一个目的是比较使用两种不同螯合剂形成放射性同位素 - 蛋白质构建体的体内药代动力学。
研究了213BiPAI2在裸鼠中的单剂量和多剂量腹腔内（IP）毒性及疗效以及在兔中的毒性。在肿瘤生长的不同阶段测量血管的CD 31染色和uPA表达。测量了螯合剂cDTPA和CHX - A''的药代动力学。
在生化和血液学检查中，所有TAT方案在小鼠和兔中耐受性良好。细胞接种后六天毛细血管变得明显。uPA表达在肿瘤生长的所有阶段均为阳性。cDTPA和CHX - A''之间未观察到显著差异。在PC3细胞接种后三天，单剂量注射947和1421 MBq/kg时观察到肿瘤生长受到抑制。接种后三天的多剂量方案在连续五天给予总剂量947 MBq/kg时实现了完全的肿瘤生长抑制。接种后6、12和18天治疗的小鼠与对照组相比肿瘤生长明显减慢。
在耐受限度内证明了单剂量和多剂量TAT在小鼠中的疗效，多剂量方案的毒性不比单剂量大。两种螯合剂中的任何一种都可用于213Bi研究。
