Introduction: It has been suggested that nitric oxide (NO) promotes angiogenesis and tumor progression and CXC Chemokine Recepter-4 (CXCR4) is involved in cell migration in cancer metastasis. Efficacy of single agent or combination chemotherapy of NO synthase (NOS) inhibitor and CXCR4 antagonist was examined using xenograft mouse models of human adenoid cystic carcinoma.
Materials and methods: ACCIM (derived from cervical metastastic lesion of human adenoid cystic carcinoma in a nude mouse) was implanted subcutaneously in nude mice. N G -nitro- l -arginine-methyl ester ( l -NAME) was used as an NOS inhibitor, dihydrochloride (1400W) as an inducible NOS inhibitor, and AMD3100 as a CXCR4 antagonist. From day 19 when tumor formed reached 5 mm in diameter, mice were received these agents by intraperitoneal injection. Mice were sacrificed on day 35.
Results: AMD3100, l -NAME and 1400W as single agent inhibited tumor growth by 20%, 27% and 54%, respectively. Combined treatment ( l -NAME and AMD3100, 1400W and AMD3100) inhibited tumor growth by 50% and 52%. The immunohistochemical examination demonstrated decreased expression of iNOS or CXCR4 in tumor cells treated with 1400W or AMD3100. 1400W and combined treatment reduced the microvessel density and increased apoptosis in tumor stroma and parenchyma. Treatment with 1400W or AMD3100 and combined treatment significantly reduced lung metastasis.
Conclusion: Treatment with 1400W and combined therapy induced apoptosis and significant inhibitory effect for tumor-induced angiogenesis and proliferation of ACCIM. Blocking CXCR4 and iNOS inhibited lung metastasis of ACCIM, suggesting that CXCR4 and iNOS may become molecular targets to inhibit tumor progression.
Conflict of interest: None declared.