title: Gene expression profiling upon (212) Pb-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model.
abstract: Recent studies have demonstrated that therapy with (212) Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of (212) Pb-TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to (212) Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to (212) Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45α, GADD45γ, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45α, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by (212) Pb-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by (212) Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by (212) Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using α-particle emitters.
authors.affiliation: Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kwon J
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: Young-Seung
authors.initials: YS
authors.lastname: Kim
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007856:Lead Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology; D016499:Radioimmunotherapy / Q000379:methods*; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D000068878:Trastuzumab; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000502:physiology; D015854:Up-Regulation / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D000097642:GADD45 Proteins
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007856:Lead Radioisotopes; D009687:Nuclear Proteins; D000068878:Trastuzumab; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse
keywords: 212Pb-TCMC-trastuzumab; disseminated intraperitoneal disease; gene expression