The mechanism of the enhanced vascular permeability and retention (EPR) effect seen in solid tumors was investigated with sarcoma 180 (S-180) in mice by using the bradykinin receptor antagonist d-Arg-[Hyp3,Thi5,d-Tic7,Oic8]bradykinin] (HOE 140), the nitric oxide (NO) scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), and the cyclooxygenase (prostaglandin synthase) inhibitor indomethacin. In the S-180 solid tumor model, administration of HOE 140 (0.65 or 1.3 µg/kg/8 h, s.c.), PTIO (167 mg/kg/2 h, four times/8 h, i.p.), or indomethacin (5 or 10 mg/kg/day, three times, i.p.) significantly suppressed the EPR effect in the tumor, and the combined administration of these agents achieved a stronger inhibition of the EPR effect than did each compound alone. Indomethacin (10 mg/kg/day, three times) plus PTIO (167 mg/kg/2 h, four times) given i.p. had the greatest inhibition (70%) on the EPR effect. When HOE 140 was administered s.c. at a dose of 13 µg/kg/12 h for 2 weeks after tumor inoculation, growth of the solid tumor was also suppressed by 32%, by tumor weight. In the ascitic form of S-180, i.p. administration of HOE 140 at 13 µg/kg/12 h initiated immediately after tumor inoculation significantly suppressed formation of S-180 tumor ascites; the life span of ascitic S-180 tumor-bearing mice was prolonged at the same dose of HOE 140. The expression of inducible NO synthase mRNA and of cyclooxygenase 2 mRNA in S-180 tumor tissue was highly elevated, as evidenced by Northern blotting and reverse transcription-PCR and by Southern blot analyses. These results indicate that bradykinin, NO, and prostaglandins play an important role in enhanced vascular permeability in tumor tissue and sustain tumor growth. More importantly, bradykinin antagonists such as HOE 140 may be beneficial for the inhibition of tumor growth.
This work was supported by Grant-in-Aid 06282247 for Research on Cancer from the Ministry of Education, Culture, Sports and Science of Japan (Monbusho). J. W. is a grantee of a Japanese Government (Monbusho) Scholarship.