Effects of Combretastatin A-4 prodrug against a panel of malignant human B-lymphoid cell lines

Combretastatin A-4 (CA-4) is one of a family of compounds isolated from the South African willow tree Combretum caffrom, CA-4 was found to be active a gainst murine melanoma and a variety of other human solid tumors. For the f irst time, we report the effect of CA-4 against a panel of malignant human B-lymphoid cell lines [early pre-B acute lymphoblastic leukemia (Reh), diff use large cell lymphoma (WSU-DLCL2), chronic lymphocytic leukemia (WSU-CLL) and Waldenstrom's macroglobulinemia (WSU-WM)]. Our results indicate, using the prodrug form of CA-4, a concentration-dependent growth inhibition in a ll tested cell lines, although WSU-DLCL2 was more sensitive. Exposure to 4 nM CA-4 for 96 h induced 77% growth inhibition in Reh, 86% in WSU-CLL and 9 2% in WSU-WM. When used against the WSU-DLCL2 cell line, this game concentr ation of CA-4 was completely toxic. Morphological examination showed CA-4 i nduced the formation of giant, multinucleated cells, a phenomenon commonly found In mitotic catastrophe. Only minimal numbers of cells showing charact eristics of apoptosis were detected. In WSU-DLCL2 cells, CA-4 (3 nM) induce d the highest apoptosis (5%) after 48 h, while the percentage of dead cells was approximately 47%. Exposure of Reh, WSU-CLL, WSU-WM and WSU-DLCL2 cell s for 24 h to 5 nM CA-4 induced 19, 28, 57 and 75% G(2)/M arrest, as determ ined by flow cytometry, respectively. Based on these preliminary studies, w e believe that mitotic catastrophe is the predominant mechanism by which CA -4 induces cell death rather than apoptosis, Further studies to elucidate t he mechanisms of CA-4 activity in vitro and in vivo are currently under inv estigation in our laboratory, [(C) 2000 Lippincott Williams & Wilkins.].