Treatment of colorectal and hepatocellular carcinomas by adenoviral mediated gene transfer of endostatin and angiostatin-like molecule in mice.
OBJECTIVE
In this study, we explored the responsiveness of different tumour entities (colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), and the murine Lewis lung carcinoma (LLC)) to angiostatic antitumour treatment with two recombinant adenoviral vectors encoding angiostatin-like molecule (AdK1-3) and endostatin (Adendo).


RESULTS
AdK1-3 and Adendo exerted inhibitory biological functions on endothelial cell proliferation, migration, and tube formation in vitro. AdK1-3 inhibited significantly endothelial cell infiltration in vascular endothelial growth factor embedded Matrigel plugs in mice whereas Adendo showed only minor effects. Both AdK1-3 and Adendo induced similar antitumour effects in the LLC tumour model in immune competent C57BL/6 mice but AdK1-3 had stronger inhibitory effects in athymic mice. Furthermore, AdK1-3 inhibited tumour growth in a murine CRC and human HCC model but was ineffective in a human CRC model. In contrast, Adendo did not reduce tumour progress in either of these tumour models although AdK1-3 and Adendo effectively reduced intratumoral microvessel density in LLC tumours.


CONCLUSIONS
Our data demonstrate that angiostatic gene therapy may form a feasible strategy for the treatment of established hepatocellular carcinomas and that in vivo antitumour efficacy of angiostatic proteins is tumour specific.
Schmitz
V
V
Division of Hepatology and Gene Therapy, Department of Medicine, Medical School, University of Navarra, Pamplona, Spain. Volker.Schmitz@ukb.uni-bonn.de
Wang
L
L
Barajas
M
M
Gomar
C
C
Prieto
J
J
Qian
C
C
D000256:Adenoviridae / Q000235:genetics; D043168:Angiostatins / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy*; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000628:therapy; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D043169:Endostatins / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D014407:Tumor Cells, Cultured
D043169:Endostatins; D043168:Angiostatins