Endostatin, an antiangiogenic drug, induces tumor stabilization after chemotherapy or anti-CD20 therapy in a NOD/SCID mouse model of human high-gradenon-Hodgkin lymphoma

Both chemotherapy and chimeric anti-CD20 monoclonal antibodies are effectiv e agents against B-cell non-Hodgkin lymphoma (NHL). However, patients achie ving remission are at risk of relapse. To evaluate the effect of the antian giogenic drug endostatin used alone and after the administration of cycloph osphamide (CTX) or the anti-CD20 antibody rituximab, we generated a new mod el of human NHL by transplanting Namalwa cells intraperitoneally into nonob ese diabetic/severe combined immunodeficient (NOD/SCID) mice. First, we det ermined the most effective treatment schedule for the drugs assessed. When administered alone, CTX (3 courses of 75 mg/kg of body weight given intrape ritoneally), rituximab (3 courses of 25 mg/kg given intraperitoneally), and endostatin (5 courses of 50 mu g given subcutaneously) delayed tumor growt h, and CTX was the most effective in controlling bulky disease. When given after chemotherapy or immunotherapy, endostatin effectively induced tumor s tabilization. When mice given CTX or rituximab on days 3, 5, and 7 after tr ansplantation were randomly assigned to receive endostatin or phosphate-buf fered saline on days 15 to 19, tumor growth was prevented in endostatin-tre ated mice as long as the drug was administered. Furthermore, administration of endostatin on days 25 to 29 after tumor regrowth still induced signific ant tumor regression, whereas CTX and rituximab were not effective. The spe cific antiangiogenic action of endostatin was confirmed by in vitro and in vivo studies indicating that the drug inhibited proliferation and induced a poptosis of endothelial (but not of NHL) cells. In conclusion, sequential a dministration of chemotherapy and endostatin seems promising for treating b ulky NHL, and the less toxic sequential administration of rituximab and end ostatin is promising for treating limited disease. (Blood. 2000;96:282-287) (C) 2000 by The American Society of Hematology.