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Emerging Role of Platelet-Derived Growth Factor Receptor-ß Inhibition in Radioimmunotherapy of Experimental Pancreatic Cancer

Authors' Affiliations: ¹ Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, Nebraska and ² Saiseikai Kumamoto Hospital, Kumamoto City, Japan

Requests for reprints: Janina Baranowska-Kortylewicz, Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, 986850 Nebraska Medical Center, Omaha, NE 68198-6850. Phone: 402-559-8906; Fax: 402-559-9127; E-mail: jbaranow{at}unmc.edu.

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-ß. 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 (T_Q) of 40.8 days. ¹³¹ICC49 alone and imatinib alone also delayed the tumor growth to T_Q 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 T_Q 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 multimodality treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-ß inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.