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

Anticancer Drugs. 2000 Jun;11(5):385-92. doi: 10.1097/00001813-200006000-00009.


Combretastatin A-4 (CA-4) is one of a family of compounds isolated from the South African willow tree Combretum caffrum. CA-4 was found to be active against murine melanoma and a variety of other human solid tumors. For the first 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), diffuse 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 all 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 92% in WSU-WM. When used against the WSU-DLCL2 cell line, this same concentration of CA-4 was completely toxic. Morphological examination showed CA-4 induced the formation of giant, multinucleated cells, a phenomenon commonly found in mitotic catastrophe. Only minimal numbers of cells showing characteristics of apoptosis were detected. In WSU-DLCL2 cells, CA-4 (3 nM) induced 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 cells for 24 h to 5 nM CA-4 induced 19, 28, 57 and 75% G2/M arrest, as determined by flow cytometry, respectively. Based on these preliminary studies, we believe that mitotic catastrophe is the predominant mechanism by which CA-4 induces cell death rather than apoptosis. Further studies to elucidate the mechanisms of CA-4 activity in vitro and in vivo are currently under investigation in our laboratory.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Annexin A5 / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • DNA, Neoplasm / drug effects
  • Flow Cytometry
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Mitosis / drug effects
  • Prodrugs / pharmacology*
  • Stilbenes / pharmacology*
  • Tumor Cells, Cultured / drug effects*
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology


  • Annexin A5
  • Antineoplastic Agents, Phytogenic
  • DNA, Neoplasm
  • Prodrugs
  • Stilbenes
  • fosbretabulin