Growth-Inhibitory Effects of Human Anti-Insulin-Like Growth Factor-I Receptor Antibody (A12) in an Orthotopic Nude Mouse Model of Anaplastic Thyroid Carcinoma

Autor: Samar A. Jasser, Zhuoying Wang, Yasemin D. Yazici, Seungwon Kim, Geetika Chakravarty, Jeffrey N. Myers, Adel K. El-Naggar, Maher N. Younes, Corazon D. Bucana, Alfredo A. Santillan
Rok vydání: 2006
Předmět:
Male
Cancer Research
medicine.medical_specialty
Transplantation
Heterologous
Mice
Nude
Antineoplastic Agents
Apoptosis
Methylation
Receptor
IGF Type 1
Antigen-Antibody Reactions
Thyroid carcinoma
Mice
Structure-Activity Relationship
Nude mouse
Insulin-Like Growth Factor II
In vivo
Cell Line
Tumor
Internal medicine
medicine
Animals
Humans
Thyroid Neoplasms
Anaplastic carcinoma
Insulin-Like Growth Factor I
Thyroid cancer
Cell Proliferation
Dose-Response Relationship
Drug
Neovascularization
Pathologic
biology
Cell growth
business.industry
Carcinoma
Thyroid
Antibodies
Monoclonal
Cancer
medicine.disease
biology.organism_classification
Xenograft Model Antitumor Assays
Disease Models
Animal
Endocrinology
medicine.anatomical_structure
Oncology
Cancer research
Drug Screening Assays
Antitumor
business
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Clinical Cancer Research. 12:4755-4765
ISSN: 1557-3265
1078-0432
DOI: 10.1158/1078-0432.ccr-05-2691
Popis: Purpose: The insulin-like growth factor-I receptor (IGF-IR) and its ligands have been implicated in the pathogenesis and progression of various cancers, including those arising in the thyroid gland. We therefore evaluated whether the IGF-IR could serve as a potential target for therapy of anaplastic thyroid carcinoma (ATC). Experimental Design: The expression and activation of the IGF-IR and some of its downstream signaling pathway components were evaluated in both human thyroid cancer specimens and thyroid cancer cell lines. The therapeutic potential of a humanized monoclonal antibody (A12) directed against IGF-IR was assessed in vitro and in vivo in an orthotopic model of ATC. Tumor volume and overall survival time were analyzed to evaluate the efficacy of A12 in vivo. Results: IGF-IR was overexpressed in 94% of the thyroid cancers. Blockade of IGF-IR with A12 was effective in attenuating IGF-IR signaling both in vitro and in vivo. However, the inhibitory effects of A12 on cell proliferation were cell line dependent, as those ATC cell lines that had detectable levels of pIGF-IR were more sensitive to A12 treatment. A12 was equally effective in vivo, where it brought ∼57% (P = 0.041) inhibition in tumor volume. The concomitant use of A12 and irinotecan produced additive effects and resulted in a 93% (P < 0.001) reduction in tumor volume. Blocking IGF-IR blocked Akt phosphorylation and decreased proliferation and microvessel density but increased apoptosis within the tumor xenografts. Our results also highlighted a previously undefined IGF-IR-mediated antiangiogenic effect on tumor-associated endothelium in thyroid cancers. Conclusion: Blocking the IGF-IR with A12 seems to be a potential avenue for treating patients with ATC by its direct antitumor effects and its effects on the tumor vasculature.
Databáze: OpenAIRE
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