Emerging role of platelet-derived growth factor receptor-beta inhibition in radioimmunotherapy of experimental pancreatic cancer.
OBJECTIVE
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.


METHODS
Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on (131)ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-beta. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of (131)ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy.


RESULTS
Biodistribution studies revealed a 50% improvement in the tumor uptake of (131)ICC49 in mice treated with imatinib. Tumor development was practically arrested for approximately 3 weeks in response to the treatment composed of (131)ICC49 and imatinib with tumor quadrupling time (T(Q)) of 40.8 days. (131)ICC49 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-beta inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.
Baranowska-Kortylewicz
Janina
J
Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, Nebraska 68198-6850, USA. jbaranow@unmc.edu
Abe
Michio
M
Nearman
Jessica
J
Enke
Charles A
CA
D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D010190:Pancreatic Neoplasms / Q000628:therapy*; D010879:Piperazines / Q000494:pharmacology; D011312:Pressure; D011743:Pyrimidines / Q000494:pharmacology; D016499:Radioimmunotherapy / Q000379:methods*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D013997:Time Factors
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta