國家衛生研究院 NHRI:Item 3990099045/2711
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    题名: Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4 beta-amino-4'-O-demethylepipodophyllotoxin conjugates
    其它题名: Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4β-amino-4′-O-demethylepipodophyllotoxin conjugates
    作者: Chang, JY;Guo, X;Chen, HX;Jiang, ZL;Fu, Q;Wang, HK;Bastow, KF;Zhu, XK;Guan, J;Lee, KH;Cheng, YC
    贡献者: National Institute of Cancer Research
    摘要: Two compounds having a camptothecin(CPT) analog conjugated to the 4 beta-amino-4'-O demethylepipodophyllotoxin analog were evaluated for their:biochemical and biological activities. W1 [camptothecin-(para)-4 beta-amino-4'-O-demethylepipodoyhyllotoxin] had no activity against topoisomerase II (TOP II), but inhibited topoisomerase I (TOP I) with an IC50 value 2-fold higher than CPT. W2 [camptothecin-(ortho) -4 beta-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with Ic,, values 1.5-fold higher than either CPT or etoposide (VP-16). Both conjugates had similar cptotoxicity against the KB cell line, although the protein-linked DNA breaks (PLDBs) generated by W2 in KB cells were about 4-fold more than those of W1. No cross-resistance with the two conjugates was seen in a VP-16-resistant KB subline, which showed down-regulation of TOP II and overexpression of the multiple drug resistance-associated protein, or in a vincristine-resistant KB subline with overexpression of gp-170/mdr-1. The CIT-resistant KB variant (KB CPT 100), which has a reduction in TOP I content and another mechanism that occurs post-PLDB formation, was partially resistant to both compounds. W1 was nor, affected by this post-PLDB resistance mechanism. Cell cycle analysis demonstrated that W1 and W2 had similar cell cycle effects on KB and KB CPT 100 cells, which accumulated in S-phase upon drug treatment. These results suggested that W1 and W2 exerted their cytotoxicity through TOP I. In CPT-resistant cells, however, an unidentified target also may be involved in the cytotoxic action of W1, and TOP II may still be a target for W2. In vivo, W1 was more effective against the growth of human prostate cancer cells in nude mice than VP-16, CPT, or W2. Given its antitumor activity and unique biochemical mechanism of action, W1 warrants exploration as an antitumor compound. (C) 2000 Elsevier Science Inc.
    关键词: Pharmacology & Pharmacy
    日期: 2000-03-01
    關聯: Biochemical Pharmacology. 2000 Mar;59(5):497-508.
    Link to: http://dx.doi.org/10.1016/S0006-2952(99)00363-9
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0006-2952&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000084899600006
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0033966496
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