Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Camptothecin (CPT) has been recognized as a topoisomerase I (Topo I) inhibitor. However, the mechanism of cytotoxicity of this agent remains unknown. In the present study, we analyzed the kinetics of Topo I-mediated DNA single-strand breaks and internucleosomal DNA cleavage produced by CPT and its derivative, 7-ethyl-10-hydroxycamptothecin (SN-38), in HL-60 cells. DNA single-strand breaks were detected using alkaline sucrose gradient centrifugation when HL-60 cells were incubated with 10 microM CPT or 10 microM SN-38 for 30 min. These DNA single-strand breaks were rapidly repaired after drug removal, while the cytotoxic action of these drugs was sustained. Treatment of HL-60 cells with CPT or SN-38 for 3 h produced extensive degradation of DNA. Agarose gel electrophoresis showed a ladder of DNA fragments consisted of multimers of approximately 200 base pairs, characteristic of apoptosis. Interestingly, this type of DNA fragmentation was also induced within 4 h after repair of DNA single-strand breaks, and subsequently loss of cell viability was observed. When zinc ion, a potent inhibitor of endonuclease, was added to drug-free medium after treatment with CPT or SN-38, internucleosomal DNA cleavage was abolished. Furthermore, addition of zinc ion reduced the loss of cell viability. These data suggest that Topo I-mediated DNA single-strand breaks may be necessary but are not sufficient for cell death, and the endonuclease involved in induction of internucleosomal DNA cleavage may play an important role in HL-60 cell death induced by Topo I inhibitor.
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PMID:DNA damage and cell killing by camptothecin and its derivative in human leukemia HL-60 cells. 839 26

Irinotecan Hydrochloride (CPT-11) and 7-ethyl-10-hydroxycamptothecin (SN-38), which are both topoisomerase I inhibitors with potent antitumor effects in vivo and in vitro, were tested for the induction of programmed cell death (PCD) in leukemia/lymphoma cell lines. When the human T-cell leukemia cell line HUT-102 and the human promyelocytic leukemia 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 that of CPT-11. Besides inducing PCD in HUT-102 and HL-60 cells, SN-38 also induced PCD in the human erythroblast leukemia cell line K-562, which was resistant to CPT-11. Induction of PCD by SN-38 and CPT-11 was dose- and time-dependent. PCD in HUT-102 cells induced by SN-38 was prevented neither by aurintricarboxylic acid (ATA), an endonuclease inhibitor, as determine by DNA electrophoretic profiles and the number of viable cells, nor by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA). The present data suggest that the topoisomerase I inhibitors, SN-38 and CPT-11 exert antitumor activity through induction of PCD in involved cells, at least in part. The PCD-inducing activity of the topoisomerase II inhibitor VP-16 was also tested in the above three cell lines and compared with CPT-11 and SN-38.
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PMID:A new derivative of camptothecin, irinotecan hydrochloride (cpt-11) induces programmed cell-death in leukemia-lymphoma cell-lines. 2157 18