Inhibition of metastatic brain tumor growth by intramuscular administration of the endostatin gene.
The cancer patients suffering from brain metastases are basically incurable. The conventional tumoricidal strategies frequently cause severe side effects instead of life prolongation of such patients. On the other hand, antiangiogenic therapy seems to be a promising strategy to avoid such unfavorable effects. In the present study, we experimentally investigated tumor dormancy effect of the excessively produced endostatin, a potent angiostatic factor, by intramuscular administration of the endostatin gene against primary cancer and metastatic brain tumor. For this purpose, we established a model system in which FM3A P-15 cells, a high metastatic mouse breast cancer cell line, were inoculated simultaneously into the brain as an artificially metastatic brain tumor (herein referred as "metastatic brain tumor") and the mammary pad as a primary cancer (referred as "primary breast cancer"), and utilized a non-viral system to deliver an expression plasmid encoding a secretable form of mouse endostatin into muscle tissues. The plasmid vector formulated with the synthetic polymer, polyvinylpyrrolidone, was administrated at 3 and 10 days after the inoculation of FM3A P-15 cells. A significant increase in the serum level of endostatin was achieved at 7 days after second administration of the plasmid vector (p=0.0066). Consequently, the growth of metastatic brain tumor was significantly retarded (p=0.0455), while no significant change in the weight of primary breast cancer was observed (p=0.1531). Intratumoral microvessel density in metastatic brain tumor but not in primary cancer as revealed by Factor VIII immunohistochemistry was significantly decreased in the endostatin gene-administrated group (p=0.0027). In conclusion, the present study demonstrates the potential efficacy of intramuscular delivery of antiangiogenic gene for treatment of metastatic brain tumor.
Oga
Masaru
M
Div. of Neurosurgery, Chiba Cancer Center Research Institute, 666-2, Nitona-cho, Chuo-ku, Chiba 260-8717, Japan. moga@chiba-cc.pref.chiba.jp
Takenaga
Keizo
K
Sato
Yasuo
Y
Nakajima
Hideki
H
Koshikawa
Nobuko
N
Osato
Katsunobu
K
Sakiyama
Shigeru
S
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D043169:Endostatins / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D008279:Magnetic Resonance Imaging; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D008957:Models, Genetic; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D010957:Plasmids / Q000378:metabolism; D011205:Povidone / Q000737:chemistry; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D012333:RNA, Messenger; D011205:Povidone