Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

Wachsberger, Phyllis; Burd, Randy; Ryan, Anderson J.; Daskalakis, Constantine; Dicker, Adam P.

doi:10.1016/j.ijrobp.2009.06.016

Cited by 14 publications

(11 citation statements)

References 37 publications

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“…However, the combined treatment with vandetanib, cisplatin and radiation showed the most marked reduction in OSC-19-luc and HN5 tumor growth and prolongation of survival in orthotopic oral tongue tumor models compared with not only control but also when compared to all of the other treatments. Similar results with significant tumor inhibition by the combination of vandetanib, cytotoxic chemotherapy and radiation have been reported for other xenograft tumor models (42, 43). …”

Section: Discussionsupporting

confidence: 88%

Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

Sano

Matsumoto

Valdecanas

et al. 2011

Clinical Cancer Research

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Purpose: We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC).Experimental Design: OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data.Results: Vandetanib plus cisplatin radiosensitized HNSCC cells in vitro and in vivo. The combination treatment with vandetanib, cisplatin, and radiation was superior to the rest of treatments (including the double combinations) in antitumoral effects, prolonging survival, decreasing cervical lymph node metastases in vivo. It also increased both tumor and tumor-associated endothelial cell apoptosis and decreased microvessel density in vivo. An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo. All vandetanib-containing treatments inhibited EGFR and Akt phosphorylation in vitro and in vivo.Conclusion: The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC. Further study of this regimen in clinical trials may be warranted.

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Section: Discussionsupporting

confidence: 88%

Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

Sano

Matsumoto

Valdecanas

et al. 2011

Clinical Cancer Research

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“…Consistent with the dramatic effect in vitro, RIP1-knockdown HT29-derived xenograft models showed no response to irinotecan treatment, while the expected growth delay (49,50) was observed in parental cells. These findings prompt the analysis of RIP1 expression in human tumor samples derived from irinotecan studies to determine whether RIP1 may be a marker of response.…”

Section: Discussionsupporting

confidence: 61%

“…These findings prompt the analysis of RIP1 expression in human tumor samples derived from irinotecan studies to determine whether RIP1 may be a marker of response. In glioblastoma, RIP1 expression appears to be a marker of poor prognosis (50), and a relationship with expression of a variant EGFR was reported (18). A possible relationship to outcome of therapy in colorectal cancer is being explored.…”

Section: Discussionmentioning

confidence: 99%

TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma

Cabal-Hierro

O’Dwyer

2017

Molecular Cancer Research

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Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Changes in levels of RIP1 and RIP3 occurred following monotherapy with SN38 or in combination with TNF. Downregulation of RIP1 resulted in increased resistance to SN38, implying a requirement for RIP1 in mediating cytotoxicity through the TNF/TNFR signaling pathway. Downregulation of RIP1 in a xenograft model impaired tumor growth inhibition from SN38 treatment, suggesting the potential of RIP1 to determine the clinical outcome of irinotecan treatment. These results indicate that TNF plays a key role in determining the cytotoxic effectiveness of SN38 in colorectal cancer and suggests a re-evaluation of TNF-based interventions to enhance therapeutic efficacy. The capacity of RIP1 to influence drug sensitivity suggests RIP1 may have biomarker potential. .

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“…The association of CLM3 with SN-38, the active metabolite of irinotecan, showed a marked synergistic effect on endothelial and cancer cells, placing our compound on the same level as those currently being tested for combination chemotherapy regimens, such as vandetanib [48], pazopanib [49] and axitinib [39]. In order to improve the antineoplastic activity of CLM3, we presently investigated the effects of CLM3 in combination with SN-38 in EGFR and VEGFR-2 expressing human endothelial cell line HMVEC-d and in EGFR and RET expressing human thyroid cancer cell 8305C [50].…”

Section: Discussionmentioning

confidence: 87%

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

Bocci¹,

Fioravanti²,

Motta³

et al. 2011

Biochemical Pharmacology

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Aims. To demonstrate the antiproliferative and pro-apoptotic activity of the novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone and in combination with SN-38 (the active metabolite of irinotecan), on endothelial and tumour cells and to show its mechanism of action.Methods. Proliferation and apoptotic assays were performed on microvascular endothelial (HMVECd) and lung (A549) and thyroid cancer (8305C, TT) cell lines exposed to CLM3 and to the simultaneous combination with SN38 for 72h. Cell-based phospho-VEGFR-2, phospho-EGFR and phospho-RET inhibition assays were performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Conclusions.The pyrazolopyrimidine derivative CLM3 demonstrated a highly significant and promising antiproliferative and proapoptotic activity, alone and in combination with SN-38, for activated endothelial and cancer cell cells. These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signalling pathways.

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Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

Cited by 14 publications

References 37 publications

Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

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