Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth.
Cyclooxygenase, involved in tumor growth and angiogenesis, converts arachidonic acid to prostaglandin (PG)H(2), which is immediately converted to bioactive prostanoids including PGE(2), PGD(2), thromboxane (TX)A(2) and PGI(2). To test the hypothesis that changes in the prostanoid profile alter cancer growth, we transduced the retroviral vectors carrying TXA(2) synthase cDNA or PGI(2) synthase cDNA to colon-26 adenocarcinoma cells and subsequently inoculated each transformant to syngeneic BALB/c mice. Tumors derived from TXA(2) synthase transformants grew faster (280%, day 8, versus null-vector control; P < 0.05) and showed more abundant vasculature (204%, versus null-vector control; P < 0.01), whereas tumors from PGI(2) synthase transformants presented opposite effects. These effects by the transgenes were reversed by administration of specific inhibitors. These results suggest that the profile of downstream metabolites of cyclooxygenase in cancer cells can be a determinant for tumor development.
Pradono
Prasenohadi
P
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
Tazawa
Ryushi
R
Maemondo
Makoto
M
Tanaka
Masashi
M
Usui
Kazuhiro
K
Saijo
Yasuo
Y
Hagiwara
Koichi
K
Nukiwa
Toshihiro
T
D000230:Adenocarcinoma / Q000098:blood supply / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D000818:Animals; D002455:Cell Division / Q000235:genetics; D003110:Colonic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D013930:Thromboxane-A Synthase / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods
D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase