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http://ir.nhri.org.tw/handle/3990099045/2711
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| Title: | Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4 beta-amino-4'-O-demethylepipodophyllotoxin conjugates |
| Other Titles: | Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4β-amino-4′-O-demethylepipodophyllotoxin conjugates |
| Authors: | Chang, JY;Guo, X;Chen, HX;Jiang, ZL;Fu, Q;Wang, HK;Bastow, KF;Zhu, XK;Guan, J;Lee, KH;Cheng, YC |
| Contributors: | National Institute of Cancer Research |
| Abstract: | 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. |
| Keywords: | Pharmacology & Pharmacy |
| Date: | 2000-03-01 |
| Relation: | 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 |
| Appears in Collections: | [張俊彥] 期刊論文
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| 000084899600006.pdf | | 498Kb | Adobe PDF | 600 | View/Open |
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