Open AccessJournal Article
Modulation of Radiation Response after Epidermal Growth Factor Receptor Blockade in Squamous Cell Carcinomas: Inhibition of Damage Repair, Cell Cycle Kinetics, and Tumor Angiogenesis
Shyhmin Huang,Paul M. Harari +1 more
Reads0
Chats0
TLDR
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.Abstract:
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 mm 3 ) and well-established (100
mm 3 ) 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 (G 1 ,
G 2 -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.read more
Citations
More filters
Journal ArticleDOI
Intracytoplasmic epidermal growth factor receptor shows poor response to the cetuximab antitumor effect in irradiated non-small cell lung cancer cell lines
Seung-Hee Ryu,Sang-wook Lee,Youn-Joo Yang,Si Yeol Song,Jong Hoon Kim,Eun Kyung Choi,Seung Do Ahn +6 more
TL;DR: The findings suggest that localization of EGFR is related to the sensitivity/resistance of cells to a combination of cetuximab and radiation, and radiosensitivity was increased solely in A549 cells.
Journal ArticleDOI
Combined EGFR1 and PARP1 Inhibition Enhances the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Models.
Barbara Frederick,Barbara Frederick,Rohit Gupta,Amandla Atilano-Roque,Tin Tin Su,David Raben +5 more
TL;DR: A proof-of-concept study using Detroit562 HNSCC cells, which are proficient for DNA repair by both HR and non-homologous end joining (NHEJ) mechanisms, demonstrates a potential for combining biologically-based therapies that might optimize radiosensitization in HNS CC.
Journal ArticleDOI
Genetic manipulation of radiosensitivity.
Adrian C. Begg,Conchita Vens +1 more
TL;DR: The present paper will concentrate on other pathways thought to be one of the principal potentially lethal lesions induced by ionizing radiation, and it will become clear that these can also markedly influence radiosensitivity.
Journal ArticleDOI
Current status of intensified neo-adjuvant systemic therapy in locally advanced rectal cancer.
TL;DR: The addition of other chemotherapeutical drugs and biologic agents as radiation sensitizers to neo-adjuvant 5-FU based chemoradiotherapy (CRT) has been recently investigated, the role of those agents is however questionable as first results from phase III data do not show improvement on pathologic complete remission and circumferential resection margin negative resection rates as compared to 5-fu based CRT, nevertheless an increased toxicity.
Journal ArticleDOI
Combination epidermal growth factor receptor inhibition and radical radiotherapy for NSCLC.
TL;DR: The current challenges of discovering how best to use these new anticancer therapies are addressed, with particular emphasis on the enhancement of existing therapeutic strategies such as radical radiotherapy, factors relating to patient selection and prediction of clinical response.
References
More filters
Journal ArticleDOI
Principles and practice of radiation oncology
Carlos A. Perez,Luther W. Brady +1 more
TL;DR: The principles and practice of radiation oncology are studied in detail in a systematic manner in the context of cancer diagnosis and treatment.
Journal Article
Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.
Alicia M. Viloria Petit,Janusz Rak,Mien Chie Hung,Patricia Rockwell,Neil I. Goldstein,Brian M. Fendly,Robert S. Kerbel +6 more
TL;DR: Therapeutic disruption of EGFR or ErbB2/neu protein function in vivo may result in partial suppression of angiogenesis, a feature that could enhance the therapeutic index of such agents in vivo and endow them with anti-tumor effects, the magnitude of which may be out of proportion with their observed cytostatic effects in monolayer tissue culture.
Journal Article
Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck.
TL;DR: Examination of C225 effects on radiation response in SCCs demonstrates enhancement in radiosensitivity and amplification of radiation-induced apoptosis, and C225 represents a promising growth-inhibitory agent that can influence cellular proliferation, apoptosis and radiosensitivity in S CCs of the head and neck.
Journal ArticleDOI
Combined effects of angiostatin and ionizing radiation in antitumour therapy
Helena J. Mauceri,Nader Hanna,Michael A. Beckett,David H. Gorski,M J Staba,Kerri Anne Stellato,Kevin Bigelow,Ruth Heimann,Stephen T. Gately,Mohanraj Dhanabal,Gerald A. Soff,Vikas P. Sukhatme,Donald Kufe,Ralph R. Weichselbaum +13 more
TL;DR: The results show an antitumour interaction between ionizing radiation and angiostatin for four distinct tumour types, at doses of radiation that are used in radiotherapy.
Journal Article
Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice.
Paul Perrotte,Takashi Matsumoto,Keiji Inoue,Hiroki Kuniyasu,Beryl Y. Eve,Daniel J. Hicklin,Robert Radinsky,Colin P.N. Dinney +7 more
TL;DR: Therapy with anti-EGFR MAb C225 has a significant antitumor effect mediated, in part, by inhibition of angiogenesis, and down-regulation of these angiogenic factors preceded the involution of blood vessels.