Blockade of an angiotensin type I receptor enhances effects of radiation on tumor growth and tumor-associated angiogenesis by reducing vascular endothelial growth factor expression.
OBJECTIVE
Angiogenesis, the formation of new capillary blood vessels, is essential for tumor progression. We had reported that Type 1 angiotensin receptor (AT1-R) antagonist reduced tumor-associated angiogenesis. Since antiangiogenic agents were reported to enhance efficacy of radiation therapy, we tested here whether or not AT1-R blockade facilitates the effects of radiation.


METHODS
1 x 10(6) LLC cells were injected into the subcutaneous tissue of male C57BL/6 mice, and when the average tumor volume reached around 0.1 cm(3), radiation doses (3, 5, 10, and 15 Gy) were given on day 1.


RESULTS
The mean tumor volumes at day 22 were 6.39 (3 Gy), 6.15 (5 Gy), 5.15 (10 Gy), and 3.07 (15 Gy) cm(3), respectively. Combination of 10 Gy radiation with AT1R antagonist TCV-116 (30 mg/kg) significantly inhibited tumor growth by 83% (1.47 +/- 0.11 cm(3), P < 0.01) in comparison with its inhibition of control tumors (8.81 +/- 0.45 cm(3)). The same was true for mean vessel density, and the combination therapy markedly reduced tumor-associated angiogenesis. This was confirmed by the reduced expression of CD31. LLC tumor growth was blocked by neutralizing antibody against vascular endothelial growth factor (VEGF). Real-time PCR analysis of VEGF disclosed a marked reduction in the mice under combination therapy, compared with control mice.


CONCLUSIONS
These results suggest that combination of radiation with AT1-R blockade markedly reduced the LLC growth rate, and that this was due to reduction of neovascularization by reducing VEGF levels. Combination therapy consisting of radiation and AT1R blockade may become an effective novel strategy for cancer treatment.
Ohnuma
Yuichiro
Y
Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan.
Toda
Masaya
M
Fujita
Mamoru
M
Hosono
Kanako
K
Suzuki
Tatsunori
T
Ogawa
Yasuhumi
Y
Amano
Hideki
H
Kitasato
Hidero
H
Hayakawa
Kazushige
K
Majima
Masataka
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000532:radiotherapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D016133:Polymerase Chain Reaction; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000528:radiation effects
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011838:Radiation-Sensitizing Agents; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C077793:candesartan cilexetil