SYNERGY OF CD95 LIGAND AND TENIPOSIDE - NO ROLE OF CLEAVABLE COMPLEX-FORMATION AND ENHANCED CD95 EXPRESSION

Teniposide (VM26) enhanced the anti-glioma activity of the cytotoxic c ytokine, CD95 ligand. Synergy was observed at concentrations of tenipo side that were insufficient for cleavable DNA topoisomerase II complex formation. CD95 ligand did not modulate the formation or removal of s uch complexes after teniposide treatment. These processes were also un affected by ectopic expression of bcl-2. Teniposide enhanced CD95 expr ession in a glioma cell line with wild-type p53 (LN-229) but not in tw o p53 mutant cell lines (T98G, LN-308). Forced expression of a transdo minant negative p53 mutant prevented the teniposide induced augmentati on of CD95 expression in LN-229 cells but did not prevent the synergy of CD95 ligand and teniposide. Teniposide did not alter CD95 ligand ex pression, and forced expression of CD95 did not modulate sensitivity t o VM26. Thus, teniposide-induced DNA lesions and alterations in CD95 o r CD95 ligand are not necessary for teniposide-induced sensitization o f human malignant glioma cells to CD95-mediated apoptosis. (C) 1998 Pu blished by Elsevier Science B.V.