title: Sensitization of tumor to ²¹²Pb radioimmunotherapy by gemcitabine involves initial abrogation of G2 arrest and blocked DNA damage repair by interference with Rad51.
abstract: OBJECTIVE
  To elucidate the mechanism of the therapeutic efficacy of targeted α-particle radiation therapy using (212)Pb-TCMC-trastuzumab together with gemcitabine for treatment of disseminated peritoneal cancers.
  
  
  METHODS
  Mice bearing human colon cancer LS-174T intraperitoneal xenografts were pretreated with gemcitabine, followed by (212)Pb-TCMC-trastuzumab and compared with controls.
  
  
  RESULTS
  Treatment with (212)Pb-TCMC-trastuzumab increased the apoptotic rate in the S-phase-arrested tumors induced by gemcitabine at earlier time points (6 to 24 hours). (212)Pb-TCMC-trastuzumab after gemcitabine pretreatment abrogated G2/M arrest at the same time points, which may be associated with the inhibition of Chk1 phosphorylation and, in turn, cell cycle perturbation, resulting in apoptosis. (212)Pb-TCMC-trastuzumab treatment after gemcitabine pretreatment caused depression of DNA synthesis, DNA double-strand breaks, accumulation of unrepaired DNA, and down-regulation of Rad51 protein, indicating that DNA damage repair was blocked. In addition, modification in the chromatin structure of p21 may be associated with transcriptionally repressed chromatin states, indicating that the open structure was delayed at earlier time points.
  
  
  CONCLUSIONS
  These findings suggest that the cell-killing efficacy of (212)Pb-TCMC-trastuzumab after gemcitabine pretreatment may be associated with abrogation of the G2/M checkpoint, inhibition of DNA damage repair, and chromatin remodeling.
authors.affiliation: Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1088, 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 / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002843:Chromatin / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy / Q000379:methods; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D016195:G2 Phase / Q000502:physiology / Q000528:radiation effects; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D017879:Isothiocyanates / Q000494:pharmacology*; D007856:Lead Radioisotopes / Q000494:pharmacology*; D018499:Linear Energy Transfer / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000528:radiation effects; D010534:Peritoneal Neoplasms / Q000532:radiotherapy; D010766:Phosphorylation / Q000528:radiation effects; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016499:Radioimmunotherapy / Q000379:methods*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine
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; C493956:CDKN1A protein, human; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006571:Heterocyclic Compounds; D017879:Isothiocyanates; D007856:Lead Radioisotopes; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D051135:Rad51 Recombinase; D000068878:Trastuzumab; D000093542:Gemcitabine