PMID- 10873065
OWN - NLM
STAT- MEDLINE
DCOM- 20001207
LR  - 20211203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 6
IP  - 6
DP  - 2000 Jun
TI  - Modulation of radiation response after epidermal growth factor receptor blockade 
      in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, 
      and tumor angiogenesis.
PG  - 2166-74
AB  - We have recently demonstrated that molecular blockade of the epidermal growth 
      factor receptor with the anti-epidermal growth factor receptor (EGFR) monoclonal 
      antibody C225 enhances the in vitro radiosensitivity of human squamous cell 
      carcinomas (SCCs) derived from the head and neck. In the present study, we 
      further investigated the capacity of C225 to modulate the in vitro and in vivo 
      radiation response of human SCC tumor cells and xenografts, and we examined 
      several potential mechanisms that may contribute to the enhanced radiation 
      response induced by C225. Tumor xenograft studies demonstrated complete 
      regression of both newly established (20 mm3) and well-established (100 mm3) SCC 
      tumors over a 55-100 day follow-up period in athymic mice treated with the 
      combination of C225 (i.p. injection) and radiation. Cell cycle analysis via flow 
      cytometry confirmed that combined treatment with C225 and radiation induced an 
      accumulation of cells in the more radiosensitive cell cycle phases (G1, G2-M) 
      with concurrent reduction in the proportion of cells in the more radioresistant S 
      phase. Results from sublethal damage repair and potentially lethal damage repair 
      analyses in cultured SCC cells demonstrated a strong inhibitory effect of C225 on 
      postradiation damage repair. Further, exposure of SCC cells to C225 induced a 
      redistribution of DNA-dependent protein kinase from the nucleus to the cytosol, 
      suggesting one potential mechanism whereby C225 may influence the cellular 
      response to radiation. Immunohistochemical analysis of SCC tumor xenografts after 
      systemic administration of C225 demonstrated inhibition of the in vivo expression 
      of tumor angiogenesis markers, including vascular endothelial growth factor and 
      Factor VIII. Taken together, the collective data suggest that the profound in 
      vivo antitumor activity identified in the xenograft setting when C225 is combined 
      with radiation derives from more than simply the antiproliferative and cell cycle 
      effects of EGFR system inhibition. In addition to antiproliferative growth 
      inhibition, EGFR blockade with C225 appears to influence the capacity of human 
      SCCs to effect DNA repair after exposure to radiation, and to express classic 
      markers of tumor angiogenesis.
FAU - Huang, S M
AU  - Huang SM
AD  - Department of Human Oncology, University of Wisconsin School of Medicine and 
      Comprehensive Cancer Center, Madison 53792-0600, USA.
FAU - Harari, P M
AU  - Harari PM
LA  - eng
GR  - CA 66786/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Lymphokines)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proliferating Cell Nuclear Antigen)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 9001-27-8 (Factor VIII)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PRKDC protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*therapeutic use
MH  - Carcinoma, Squamous Cell/*drug therapy/*pathology/*radiotherapy
MH  - Cell Cycle/*drug effects/radiation effects
MH  - Cell Nucleus/metabolism
MH  - Cetuximab
MH  - Cytosol/metabolism
MH  - DNA Repair/drug effects/radiation effects
MH  - DNA-Activated Protein Kinase
MH  - *DNA-Binding Proteins
MH  - Dose-Response Relationship, Radiation
MH  - Endothelial Growth Factors/biosynthesis
MH  - ErbB Receptors/antagonists & inhibitors
MH  - Factor VIII/biosynthesis
MH  - Female
MH  - Flow Cytometry
MH  - Head and Neck Neoplasms/*drug therapy/*pathology/*radiotherapy
MH  - Humans
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Kinetics
MH  - Lymphokines/biosynthesis
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - *Neovascularization, Pathologic
MH  - Nuclear Proteins
MH  - Proliferating Cell Nuclear Antigen/biosynthesis
MH  - Protein Serine-Threonine Kinases/biosynthesis
MH  - Radiation Tolerance
MH  - Recombinant Fusion Proteins/therapeutic use
MH  - Subcellular Fractions/metabolism
MH  - Time Factors
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2000/06/29 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/06/29 11:00
PHST- 2000/06/29 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/06/29 11:00 [entrez]
PST - ppublish
SO  - Clin Cancer Res. 2000 Jun;6(6):2166-74.