Plasminogen fragment K1-5 improves survival in a murine hepatocellular carcinoma model.
BACKGROUND
The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, and new alternative treatments are needed.


OBJECTIVE
To comparatively test the angiostatic and antitumour effects of adenoviral gene transfer of angiostatin (PlgK1-4, amino acids 1-440) and full kringles 1-5 (PlgK1-5, amino acids 1-546) in a model of subcutaneously transferred HCC in mice.


METHODS
PlgK1-4 and PlgK1-5 were generated from human WtPlg cDNA and used for adenovirus construction. Vector function and angiostatic effects were confirmed in vitro and in vivo. Antitumoral efficacies of intratumoral vector injections were studied in a model of subcutaneously transferred HCC model.


RESULTS
Cell supernatants containing PlgK1-4 and PlgK1-5 reduced endothelial tube formation in vitro by about 30%, whereas WtPlg exerted no inhibitory effect. Endothelial cell infiltration in vivo was decreased by about 60%, but not in AdWtPlg-treated animals. Intratumoral treatment of subcutaneous HCC tumours inhibited growth by 40% for AdPlgK1-4 and 63% for AdPlgK1-5 in surviving mice 12 days after initiation of treatment, whereas treatment with AdWtPlg even led to accelerated growth. Although PlgK1-4 and PlgK1-5 have similar inhibitory effects on intratumoral microvessels, PlgK1-5 markedly improved the survival time compared with PlgK1-4.


CONCLUSIONS
PlgK1-5 and PlgK1-4 effectively inhibited HCC growth. As PlgK1-5 could also prolong the survival time, inducing complete tumour elimination in half of the AdPlgK1-5-treated mice, PlgK1-5 might be the most potential plasminogen fragment for treatment of experimental HCC.
Schmitz
Volker
V
Department of Internal Medicine I, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. volker.schmitz@ukb.uni-bonn.de
Raskopf
Esther
E
Gonzalez-Carmona
Maria Angeles
MA
Vogt
Annabelle
A
Rabe
Christian
C
Leifeld
Ludger
L
Kornek
Miroslaw
M
Sauerbruch
Tilman
T
Caselmann
Wolfgang H
WH
D020533:Angiogenesis Inhibitors / Q000235:genetics; D043168:Angiostatins / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000032:analysis; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000235:genetics; D001973:Bromodeoxyuridine / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000235:genetics*; D010958:Plasminogen / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen; D001973:Bromodeoxyuridine