Metronomic chemotherapy in combination with antiangiogenic treatment induces mosaic vascular reduction and tumor growth inhibition in hepatocellular carcinoma xenografts.

BACKGROUND

In addition to sprouting angiogenesis, other mechanisms, such as mosaic tumor vessel formation, have been recognized to contribute to tumor vascularization. We sought to examine vascular alteration as well as tumor growth inhibition after treatment with antiangiogenic therapy, chemotherapy alone or in combination.

METHODS

Hepatocellular carcinoma cells (Hep3B) expressed green fluorescent protein were utilized to establish orthotopic xenograft model in nude mice. The formation and distribution of mosaic vessels was analyzed quantitatively by immunolabeling. Next, changes in tumor microcirculation and therapeutic effects on tumor growth were evaluated in several different treatment groups: control, conventional doxorubicin, metronomic doxorubicin, bevacizumab, bevacizumab plus conventional doxorubicin, and bevacizumab plus metronomic doxorubicin. In addition, we examined the effects of combined regimens on lung metastasis using a highly metastatic human hepatocellular carcinoma (HCCLM3) mouse model.

RESULTS

Approximately 62 % of the vessels were present in the central part or near the midsection of the tumor and were mosaic. Only the combined antiangiogenic treatment and chemotherapy (metronomic schedule, P = 0.00; conventional schedule, P = 0.02) had a significant effect on the degree of mosaic vasculature. Metronomic doxorubicin in combination with bevacizumab had an even more profound effect than bevacizumab plus conventional doxorubicin (P < 0.05) on tumor growth inhibition and survival. However, bevacizumab plus metronomic doxorubicin failed to inhibit lung metastasis compared with antiangiogenic monotherapy.

CONCLUSIONS

Metronomic chemotherapy in combination with antiangiogenic treatment results in the reduction of mosaic tumor vasculature, inhibition of tumor growth, and enhanced survival of mice. Further investigation of drug scheduling is required to optimize antitumor activity.