Inhibition of tumor growth correlates with the expression level of a human angiostatin transgene in transfected B16F10 melanoma cells.
Although the therapeutic value of angiostatin, a proteolytic fragment of plasminogen, has been recognized for the treatment of cancer, the production of bioactive angiostatin remains a difficult task. Here we report that expression of a cDNA encoding a secreted, four-kringle human angiostatin inhibited tumor growth of B16F10 melanoma cells in mice but did not suppress tumor cell growth in culture. After transfection and selection, stable expression of the angiostatin cDNA was demonstrated in several B16F10 clones by quantitative mRNA analysis using the Taqman method. Cells that expressed angiostatin at either a low, medium, or high level were injected into C57BL/6 mice. s.c. Growth of B16F10 tumors was diminished by the angiostatin transgene, and the inhibition was directly proportional to the expression level of angiostatin in the transfected cells. However, suppression of s.c. tumor growth was transient, and eventually, tumors emerged with a strongly decreased expression of the transgene. Angiostatin expression also reduced lung metastasis from i.v.-injected B16F10 cells. Our data indicate that a cDNA encoding bioactive human angiostatin is potentially useful for gene therapy of human cancers, but the delivery of the transgene may require repeated dosing to achieve sustained dormancy of primary tumors and cancer metastases.
Ambs
S
S
Valentis Inc., Burlingame, California 94010, USA.
Dennis
S
S
Fairman
J
J
Wright
M
M
Papkoff
J
J
D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D018076:DNA, Complementary / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018082:Kringles; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D010957:Plasmids / Q000627:therapeutic use; D010958:Plasminogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D014162:Transfection; D019076:Transgenes; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen