Emerging role of platelet-derived growth factor receptor-β inhibition in radioimmunotherapy of experimental pancreatic cancer

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Abstract

Purpose: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. Experimental Design: Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on 131ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-β. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of 131ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. Results: Biodistribution studies revealed a 50% improvement in the tumor uptake of 131ICC49 in mice treated with imatinib. Tumor development was practically arrested for ∼3 weeks in response to the treatment composed of 131ICC49 and imatinib with tumor quadrupling time (TQ) of 40.8 days. 131ICC49 alone and imatinib alone also delayed the tumor growth to TQ of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d, for 3 days. Xenografts in control mice receiving injection of PBS had TQ of 23 days. Conclusions: The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodatity treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-β inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.

Original languageEnglish (US)
Pages (from-to)299-306
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2007

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Radioimmunotherapy
Platelet-Derived Growth Factor Receptors
Pancreatic Neoplasms
Neoplasms
Heterografts
Therapeutics
Extracellular Fluid
Imatinib Mesylate
Disease Progression
Adenocarcinoma
Research Design
Animal Models
Monoclonal Antibodies
Pressure
Injections

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "Emerging role of platelet-derived growth factor receptor-β inhibition in radioimmunotherapy of experimental pancreatic cancer",
abstract = "Purpose: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. Experimental Design: Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on 131ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-β. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of 131ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. Results: Biodistribution studies revealed a 50{\%} improvement in the tumor uptake of 131ICC49 in mice treated with imatinib. Tumor development was practically arrested for ∼3 weeks in response to the treatment composed of 131ICC49 and imatinib with tumor quadrupling time (TQ) of 40.8 days. 131ICC49 alone and imatinib alone also delayed the tumor growth to TQ of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d, for 3 days. Xenografts in control mice receiving injection of PBS had TQ of 23 days. Conclusions: The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodatity treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-β inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.",
author = "Janina Baranowska-Kortylewicz and Michio Abe and Jessica Nearman and Enke, {Charles Arthur}",
year = "2007",
month = "1",
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doi = "10.1158/1078-0432.CCR-06-1702",
language = "English (US)",
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T1 - Emerging role of platelet-derived growth factor receptor-β inhibition in radioimmunotherapy of experimental pancreatic cancer

AU - Baranowska-Kortylewicz, Janina

AU - Abe, Michio

AU - Nearman, Jessica

AU - Enke, Charles Arthur

PY - 2007/1/1

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N2 - Purpose: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. Experimental Design: Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on 131ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-β. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of 131ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. Results: Biodistribution studies revealed a 50% improvement in the tumor uptake of 131ICC49 in mice treated with imatinib. Tumor development was practically arrested for ∼3 weeks in response to the treatment composed of 131ICC49 and imatinib with tumor quadrupling time (TQ) of 40.8 days. 131ICC49 alone and imatinib alone also delayed the tumor growth to TQ of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d, for 3 days. Xenografts in control mice receiving injection of PBS had TQ of 23 days. Conclusions: The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodatity treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-β inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.

AB - Purpose: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. Experimental Design: Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on 131ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-β. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of 131ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. Results: Biodistribution studies revealed a 50% improvement in the tumor uptake of 131ICC49 in mice treated with imatinib. Tumor development was practically arrested for ∼3 weeks in response to the treatment composed of 131ICC49 and imatinib with tumor quadrupling time (TQ) of 40.8 days. 131ICC49 alone and imatinib alone also delayed the tumor growth to TQ of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d, for 3 days. Xenografts in control mice receiving injection of PBS had TQ of 23 days. Conclusions: The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodatity treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-β inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.

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