title: (212)Pb-radioimmunotherapy induces G(2) cell-cycle arrest and delays DNA damage repair in tumor xenografts in a model for disseminated intraperitoneal disease.
abstract: In preclinical studies, targeted radioimmunotherapy using (212)Pb-TCMC-trastuzumab as an in vivo generator of the high-energy α-particle emitting radionuclide (212)Bi 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 (212)Pb-TCMC-trastuzumab and compared with the nonspecific control (212)Pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. (212)Pb-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 (212)Pb-TCMC-HuIgG, the nonspecific control. (212)Pb-TCMC-trastuzumab treatment also caused G(2)-M arrest, depression of the S phase fraction, and depressed DNA synthesis that persisted beyond 120 hours. In contrast, the effects produced by (212)Pb-TCMC-HuIgG seemed to rebound by 120 hours. In addition, (212)Pb-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 (212)Pb-TCMC-trastuzumab treatment. Taken together, increased DNA DSBs, impaired DNA damage repair, persistent G(2)-M arrest, and chromatin remodeling were associated with (212)Pb-TCMC-trastuzumab treatment and may explain its increased cell killing efficacy in the LS-174T intraperitoneal xenograft model for disseminated intraperitoneal disease.
authors.affiliation: Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Kwon Joong
authors.initials: KJ
authors.lastname: Yong
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000627:therapeutic use; D017879:Isothiocyanates / Q000737:chemistry; D007856:Lead Radioisotopes / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: C410212:2-(4-isothiocyanatobenzyl)-1,4,7,10--tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)cyclododecane; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006571:Heterocyclic Compounds; D007074:Immunoglobulin G; D017879:Isothiocyanates; D007856:Lead Radioisotopes; D000068878:Trastuzumab