In pre-clinical studies, targeted radioimmunotherapy using 212Pb-TCMC-trastuzumab as an in vivo generator of the high energy α-particle emitting radionuclide 212Bi is proving an efficacious modality for the treatment of disseminated peritoneal cancers. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T i.p. xenografts were treated with 212Pb-TCMC-trastuzumab and compared to the non-specific control 212Pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. 212Pb-TCMC-trastuzumab treatment induced significantly more apoptosis and DNA double stranded breaks (DSBs) at 24 h. Rad51 protein expression was down-regulated, indicating delayed DNA double strand damage repair compared to 212Pb-TCMC-HuIgG, the non-specific control. 212Pb-TCMC-trastuzumab treatment also caused G2/M arrest, depression of the S phase fraction and depressed DNA synthesis that persisted beyond 120 h. In contrast, the effects produced by 212Pb-TCMC-HuIgG appeared to rebound by 120 h. In addition, 212Pb-TCMC-trastuzumab treatment delayed open chromatin structure and expression of p21 until 72 h, suggesting a correlation between induction of p21 protein and modification in chromatin structure of p21 in response to 212Pb-TCMC-trastuzumab treatment. Taken together, increased DNA DSBs, impaired DNA damage repair, persistent G2/M arrest, and chromatin remodeling were associated with 212Pb-TCMC-trastuzumab treatment and may explain its increased cell killing efficacy in the LS-174T i.p. xenograft model for disseminated intraperitoneal disease.
- Received September 1, 2011.
- Revision received December 20, 2011.
- Accepted January 3, 2012.
- Copyright © 2012, American Association for Cancer Research.