| Reference | 1. Int J Oncol. 2008 Nov;33(5):1107-13.
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Co-targeting the EGFR and IGF-IR with anti-EGFR monoclonal antibody ICR62 and the
IGF-IR tyrosine kinase inhibitor NVP-AEW541 in colorectal cancer cells.
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Cunningham MP(1), Thomas H, Marks C, Green M, Fan Z, Modjtahedi H.
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Author information: <br>
(1)Division of Oncology, Postgraduate Medical School, Guildford, UK.
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The aberrant expression of the epidermal growth factor receptor (EGFR) has been
reported in a wide range of epithelial tumours. In some studies, co-expression of
insulin-like growth factor receptor-I (IGF-IR) have been associated with
resistance to the EGFR inhibitors. Here, we investigated the sensitivity of a
panel of human colorectal tumour cell lines, including two newly established
lines Colo2 and Colo13, to treatment with anti-EGFR mAb ICR62 and IGF-IR tyrosine
kinase inhibitor NVP-AEW541 alone and in combination. We also determined the
association between the expression levels of EGFR and IGF-IR with their responses
to ICR62 and/or NVP-AEW541. In contrast to DiFi cells, which contained high
levels of EGFR but lower level of IGF-IR, the remaining 11 colorectal tumour
cells expressed low levels of both EGFR and IGF-IR and such cells were relatively
resistant to ICR62 or NVP-AEW-541 when used alone. Interestingly, compared to the
results with the single agent, the effect of combination of NVP-AEW541 and ICR62
was found to be additive on inhibiting the growth of Colo13, CCL235, CCL244 cells
but antagonistic in other (CCL218) cells. While overexpression of the EGFR seems
to be associated with response to ICR62, no clear correlation was found between
the expression levels of EGFR and IGF-IR, or the levels of phosphorylated EGFR
and response to treatment with NVP-AEW541, in single or combination setting with
ICR62. Our results suggest that combining EGFR and IGF-IR inhibitors may enhance
antitumour response in a fraction of colorectal cancer cells and warrants further
study in colorectal cancer.
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2. Leukemia. 2007 May;21(5):886-96. Epub 2007 Mar 15.
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The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces
apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like
growth factor-I secretion.
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Tazzari PL(1), Tabellini G, Bortul R, Papa V, Evangelisti C, Grafone T,
Martinelli G, McCubrey JA, Martelli AM.
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Author information: <br>
(1)Servizio di Immunoematologia e Trasfusionale, Policlinico S.Orsola-Malpighi,
Bologna, Italy.
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Insulin-like growth factor-I (IGF-I) and its receptor (IGF-IR) have been
implicated in the pathophysiology of many human cancers, including those of
hematopoietic lineage. We investigated the therapeutic potential of the novel
IGF-IR tyrosine kinase activity inhibitor, NVP-AEW541, on human acute myeloid
leukemia (AML) cells. NVP-AEW541 was tested on a HL60 cell subclone, which is
dependent on autocrine secretion of IGF-I for survival and drug resistance, as
well as primary drug resistant leukemia cells. NVP-AEW541 treatment (24 h)
induced dephosphorylation of IGF-IR. NVP-AEW541 also caused Akt dephosphorylation
and changes in the expression of key regulatory proteins of the cell cycle. At
longer incubation times (48 h), NVP-AEW541-induced apoptotic cell death, as
demonstrated by caspase-3 cleavage. Apoptosis was accompanied by decreased
expression of anti-apoptotic proteins. NVP-AEW541 enhanced sensitivity of HL60
cells to either cytarabine or etoposide. Moreover, NVP-AEW541 reduced the
clonogenic capacity of AML CD34(+) cells cultured in the presence of IGF-I.
Chemoresistant AML blasts displayed enhanced IGF-I secretion, and were sensitized
to etoposide-induced apoptosis by NVP-AEW541. Our findings indicate that
NVP-AEW541 might be a promising therapeutic agent for the treatment of those AML
cases characterized by IGF-I autocrine secretion.
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3. Cancer Cell. 2004 Mar;5(3):231-9.
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In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor
of the IGF-IR kinase.
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García-Echeverría C(1), Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao
J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG,
Liebetanz J, Martiny-Baron G, Ruetz S, Hofmann F.
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Author information: <br>
(1)Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002
Basel, Switzerland.
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IGF-IR-mediated signaling promotes survival, anchorage-independent growth, and
oncogenic transformation, as well as tumor growth and metastasis formation in
vivo. NVP-AEW541 is a pyrrolo[2,3-d]pyrimidine derivative small molecular weight
kinase inhibitor of the IGF-IR, capable of distinguishing between the IGF-IR
(IC50 = 0.086 microM) and the closely related InsR (IC50 = 2.3 microM) in cells.
As expected for a specific IGF-IR kinase inhibitor, NVP-AEW541 abrogates
IGF-I-mediated survival and colony formation in soft agar at concentrations that
are consistent with inhibition of IGF-IR autophosphorylation. In vivo, this
orally bioavailable compound inhibits IGF-IR signaling in tumor xenografts and
significantly reduces the growth of IGF-IR-driven fibrosarcomas. Thus, NVP-AEW541
represents a class of selective, small molecule IGF-IR kinase inhibitors with
proven in vivo antitumor activity and potential therapeutic application.
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