Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA.
Despite recent advances in neurosurgery, radiation, and chemotherapy, the prognosis of patients with malignant gliomas remains dismal. Based on the observation that solid tumor growth is angiogenic dependent, and gliomas are among the most angiogenic of all tumors, therapeutic strategies aimed at inhibiting angiogenesis are theoretically attractive. Angiostatin, an internal peptide fragment of plasminogen, has recently been shown to potently inhibit endothelial proliferation in vitro and tumor growth in vivo. Long-term systemic delivery of proteins, however, poses a number of difficult logistic and pharmacological problems and may not be necessary or optimal for treating locally aggressive tumors such as gliomas. We now demonstrate that retroviral and adenoviral vectors that transduce the angiostatin cDNA can be used to inhibit endothelial cell growth in vitro and angiogenesis in vivo. Vector-mediated inhibition of tumor-associated angiogenesis results in increased apoptotic tumor cell death, leading to inhibition of tumor growth. These studies support a potential role of vector-mediated transduction of the cDNA encoding angiostatin as a potential novel therapeutic strategy for the treatment of malignant brain tumors and confirm the antitumor activity of angiostatin and the concept of dormancy therapy.
Laboratory of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
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Tanaka
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Cao
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Folkman
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Fine
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D043168:Angiostatins; D000818:Animals; D015152:Blotting, Northern; D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D002455:Cell Division / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D005910:Glioma / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000628:therapy*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics*; D010958:Plasminogen / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection
D018076:DNA, Complementary; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen