New Pharmaceutical Treatment of Gastric MALT Lymphoma: Anti-angiogenesis Treatment using VEGF Receptor Antibodies and Celecoxib

Masahiko      Nakamura; Tetsufumi      Takahashi; Hidenori      Matsui; Shinichi      Takahashi; Somay   Y.   Murayama; Hidekazu      Suzuki; Kanji      Tsuchimoto

Abstract

In addition to eradication of Helicobacter pylori, chemotherapy with anticancer agents, and radiation therapy, the treatment with molecular target drugs including rituximab, a CD20 antagonist, is one of the promising new regimens. The mucosa-associated lymphoid tissue (MALT) lymphoma is histologically characterized by rich distribution of the microvascular network consisting of the immature capillaries, lymphatics and venules, and this microvascular network could be the target of the new pharmacotherapy in addition to the direct action on the accumulated B lymphocytes. We have established the animal model of the gastric MALT lymphoma by the Helicobacter heilmannii (H. heilmannii) peroral infection of C57BL/6 mice. The disease induced by this model is very similar to the human counterpart, because of the lymphoepithelial lesion characteristic of the human MALT lymphoma as well as the rich vascularization and localization of vascular endothelial growth factor (VEGF) and its receptors, Flt-1, Flk-1 and Flt-4. By administering VEGF receptor antibodies or celecoxib, one of the cyclooxygenase 2 inhibitors, we were able to induce a significant decrease in the size of the tumor and the apoptotic changes of the endothelial cells of the microvascular network. These antiangiogenic strategies were suggested to be candidates for the new pharmacological treatment of gastric MALT lymphoma, when other treatments are not effective.

Keywords: Gastric MALT lymphoma, angiogenesis, lymphangiogenesis, VEGF, Flt-1, Flk-1, Flt-4, celecoxib.