Adenoviral gene transfer of angiostatic ATF-BPTI inhibits tumour growth.
BACKGROUND
The outgrowth of new vessels--angiogenesis--in the tumour mass is considered to be a limiting factor of tumour growth. To inhibit the matrix lysis that is part of the tumour angiogenesis, we employed the chimeric protein mhATF-BPTI, composed of the receptor binding part of the urokinase (ATF) linked to an inhibitor of plasmin (BPTI).


METHODS
For delivery, recombinant adenovirus encoding the transgene of interest was injected intravenously or locally into the tumour. The anti tumour effect of this compound was compared to that of human endostatin and of mhATF alone in two different rat bronchial carcinomas growing either as subcutaneous implants or as metastases.


RESULTS
Significant inhibition of the tumour growth and decrease of the number of lung metastasis was achieved when the concentration of mhATF-BPTI at the tumour site was above 400 of ng/g tissue. This concentration could be achieved via production by the liver, only if permissive to the recombinant adenovirus. When the tumour cells could be transduced, local delivery of the vector was enough to obtain a response. In the case of metastasis, the capacity of the lung tissue to concentrate the encoded protein was essential to reach the required therapeutic levels. Further, endostatin or mhATF could not reproduce the effects of mhATF-BPTI, at similar concentrations (mhATF) and even at 10-fold higher concentration (endostatin).


CONCLUSIONS
The ATF-BPTI was shown to inhibit tumour growth of different rat lung tumours when critical concentration was reached. In these tumour models, endostatin or ATF induce almost no tumour response.
Lefesvre
Pierre
P
Crucell BV, Leiden, The Netherland. p.lefesvre@crucell.com
Attema
Joline
J
van Bekkum
Dirk
D
D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000235:genetics*; D000818:Animals; D007611:Aprotinin / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use; D002283:Carcinoma, Bronchogenic / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D003094:Collagen / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods; D043169:Endostatins; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D008297:Male; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator
D020533:Angiogenesis Inhibitors; D043169:Endostatins; C524898:PLAUR protein, human; D010446:Peptide Fragments; C524900:Plaur protein, rat; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D015842:Serine Proteinase Inhibitors; D003094:Collagen; D007611:Aprotinin; D014568:Urokinase-Type Plasminogen Activator