A NEW DERIVATIVE OF CAMPTOTHECIN, IRINOTECAN HYDROCHLORIDE (CPT-11) INDUCES PROGRAMMED CELL-DEATH IN LEUKEMIA-LYMPHOMA CELL-LINES

Irinotecan Hydrochloride (CPT-11) and 7-ethyl-10-hydroxycamptothecin ( SN-38), which are both topoisomerase I inhibitors with potent antitumo r effects in vivo and in vitro, were tested for the induction of progr ammed cell death (PCD) in leukemia/lymphoma cell lines. When the human T-cell leukemia cell line HUT-102 and the human promyelocytic leukemi a cell line HL-60 cells were exposed to CPT-11, PCD characterized by a DNA fragmentation ladder of 180-200 bp in agarose gel electrophoresis and loss of cell viability was induced. The PCD inducing activity of SN-38, an active metabolite of CPT-11, was much more powerful than tha t of CPT-11. Besides inducing PCD in HUT-102 and HL-60 cells, SN-38 al so induced PCD in the human erythroblast leukemia cell line K-562, whi ch was resistant to CPT-11. Induction of PCD by SN-38 and CPT-11 was d ose- and time-dependent. PCD in HUT-102 cells induced by SN-38 was pre vented neither by aurintricarboxylic acid (ATA), an endonuclease inhib itor, as determine by DNA electrophoretic profiles and the number of v iable cells, nor by the protein kinase C (PKC) activator phorbol 12-my ristate 13-acetate (PMA). The present data suggest that the topoisomer ase I inhibitors, SN-38 and CPT-11 exert antitumor activity through in duction of PCD in involved cells, at least in part. The PCD-inducing a ctivity of the topoisomerase II inhibitor VP-16 was also tested in the above three cell lines and compared with CPT-11 and SN-38.