In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 11, No. 3 ( 2012-03-01), p. 639-648
Abstract:
In preclinical 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 intraperitoneal xenografts were treated with 212Pb-TCMC-trastuzumab and compared with the nonspecific control 212Pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. 212Pb-TCMC-trastuzumab treatment induced significantly more apoptosis and DNA double-strand breaks (DSB) at 24 hours. Rad51 protein expression was downregulated, indicating delayed DNA double-strand damage repair compared with 212Pb-TCMC-HuIgG, the nonspecific control. 212Pb-TCMC-trastuzumab treatment also caused G2-M arrest, depression of the S phase fraction, and depressed DNA synthesis that persisted beyond 120 hours. In contrast, the effects produced by 212Pb-TCMC-HuIgG seemed to rebound by 120 hours. In addition, 212Pb-TCMC-trastuzumab treatment delayed open chromatin structure and expression of p21 until 72 hours, 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 intraperitoneal xenograft model for disseminated intraperitoneal disease. Mol Cancer Ther; 11(3); 639–48. ©2012 AACR.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.MCT-11-0671
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2062135-8
SSG:
12
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