Antiangiogenic versus cytotoxic therapeutic approaches in a mouse model of pancreatic cancer: an experimental study with a multitarget tyrosine kinase inhibitor (sunitinib), gemcitabine and radiotherapy.
This work evaluated SU11248 (sunitinib) as a potential therapeutic agent, alone or in combination with the cytotoxic agent gemcitabine or radiotherapy in a murine model of pancreatic cancer. Panc02 cells were injected subcutaneously into HsdOla/MF1 mice (n=222). Treatment was administered during 1 week: sunitinib (SUN), gemcitabine (GEM), radiotherapy (RT), RT+SUN and GEM+SUN. Mice were sacrificed 14 days after treatment. The effect on microvessel density (MVD) was measured by CD31 staining. Apoptosis (sFAS, cleaved caspase-3) and proangiogenic proteins (VEGF, PlGF, EGF) were measured with ELISA and immunohistochemistry. At day 14, tumors in all groups increased significantly despite treatment. Only after RT/SUN treatment tumor growth slowed down, although the accretion was still significant (P=0.033). Highest levels of apoptosis were seen in GEM/SUN, RT/SUN and RT treated mice (respectively P<0.001, P<0.01 and P<0.05 compared to placebo). MVD was lowest in RT/SUN treated mice [compared to placebo (P<0.05), GEM (P<0.05) and GEM/SUN (P<0.01)]. Highest VEGF levels were seen after RT and RT/SUN treatment [vs. placebo (P<0.001) and vs. other treatments (P<0.01 for all comparisons)]. GEM and SUN in monotherapy lead to an up-regulation of PlGF and EGF, respectively. In conclusion, the combination treatments RT/SUN and GEM/SUN result in a more potent anti-angiogenic and antitumor effect when compared to either treatment alone. Multitargeted angiogenesis inhibitor therapy with sunitinib combined with either radiotherapy or gemcitabine may be a novel approach for human pancreatic cancer.
Casneuf
Veerle F
VF
Department of Gastroenterology, Ghent University Hospital, Gent, Belgium. veerle.casneuf@ugent.be
Demetter
Pieter
P
Boterberg
Tom
T
Delrue
Louke
L
Peeters
Marc
M
Van Damme
Nancy
N
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004815:Epidermal Growth Factor / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D055806:Microvessels / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D018714:Radiotherapy, Adjuvant; D000077210:Sunitinib; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D000093542:Gemcitabine
D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; C491899:Fas protein, mouse; D007211:Indoles; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D019014:fas Receptor; C467480:vascular endothelial growth factor A, mouse; D003841:Deoxycytidine; D000072483:Placenta Growth Factor; D004815:Epidermal Growth Factor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D000077210:Sunitinib; D000093542:Gemcitabine