Acivicin with glutaminase regulates proliferation and invasion of human MCF-7 and OAW-42 cells--an in vitro study.

Tumor cells intensely utilize glutamine as the major source of respiratory fuel. Glutamine-analogue acivicin inhibits tumor growth and tumor-induced angiogenesis in Ehrlich ascites carcinoma. In the present study, antitumor properties of acivicin in combination with glutaminase enzyme is reported. Acivicin along with E. coli glutaminase synergistically reduced in vitro proliferation and matrigel invasion of human MCF-7 and OAW-42 cells. Effects of single and combined treatments with acivicin and glutaminase on angiogenic factors were also analyzed in these cell lines. Co-administration of the treatment agents inhibits the release of VEGF and MMP-9 by cells in culture supernatant significantly than single agent treatments. The result suggests that combination of acivicin with glutaminase may provide a better therapeutic option than either of them given separately for treating human breast and ovarian cancer. However, further studies are required to be conducted in vivo for its confirmation.

Modulation of metastatic potential of B16F10 melanoma cells by acivicin: synergistic action of glutaminase and potentiation of cisplatin cytotoxicity.

Treatment for metastatic melanoma has mostly been unsatisfactory despite advances in ongoing medical research. Here we investigated the role of acivicin, a glutamine analogue, singly and in combination with either E. coli glutaminase or cisplatin, on the growth, angiogenic activity and invasiveness of B16F10 cells in vitro and after allografting in C57BL/6 mice. B16F10 melanoma colonization in the lungs of mice was measured by monitoring colony counts. Host toxicity was assessed with reference to tumor bearing host's weight and survivability. Acivicin promoted melanoma dormancy and reduced melanoma associated angiogenic factors like VEGF level and vessel diameter. Acivicin in combination with glutaminase significantly suppressed tumor growth by 66.7% and increased life-span by 43.5% without host toxicity. Tumor VEGF content was significantly lowered by combination therapy as assessed by ELISA. Accelerated cytotoxicity, reduced invasion and enhanced apoptosis of melanoma cells were exhibited in vitro by combined than by single agent treatment. Moreover, invasion of melanoma cells through matrigel chambers was reduced in presence of acivicin and glutaminase combination. These findings support future studies of acivicin in combination with other anticancer agents for prevention of melanoma metastasis.

Effect of glutamine analogue-acivicin on tumor induced angiogenesis in Ehrlich ascites carcinoma.

The inhibition of tumor growth and tumor induced angiogenesis by the glutamine antimetabolite acivicin was evaluated in 6-7 weeks old male Swiss albino mice bearing Ehrlich ascites carcinoma (EAC) transplanted by intraperitoneal (ip) injections of EAC cells. Treatment involving ip injections with two different doses of acivicin (0.05 and 0.41microg/g body weight/day) in saline revealed decrease in tumor volumes and reduced number of blood vessels on peritoneal wall after 10 and 15 days of treatment when compared to control (i.e. injected with saline only). Vascular hyperpermeability was found to be lesser in the treated groups of mice than the control as indicated by the FITC- D and colloidal carbon assay. Serum VEGF level was found to decrease in the drug treated groups both after 10 and 15 days of treatment. The results thus suggest that acivicin may suppress tumoral angiogenesis through regulation of VEGF level.