TY - JOUR
T1 - Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4β-amino-4'-O-demethylepipodophyllotoxin conjugates
AU - Chang, Jang Yang
AU - Guo, Xin
AU - Chen, Hong Xing
AU - Jiang, Zaoli
AU - Fu, Qin
AU - Wang, Hui Kang
AU - Bastow, Kenneth F.
AU - Zhu, Xiao Kang
AU - Guan, Jian
AU - Lee, Kuo Hsiung
AU - Cheng, Yung Chi
N1 - Funding Information:
The authors would like to thank Rocco Carbone for technical assistance and Chris Gaj for assistance in preparing and reviewing this manuscript. This work was supported by NCI Grant CA63477
PY - 2000/3/1
Y1 - 2000/3/1
N2 - Two compounds having a camptothecin (CPT) analog conjugated to the 4β-amino-4'-O-demethylepipodophyllotoxin analog were evaluated for their biochemical and biological activities. W1 [camptothecin-(para)-4β-amino-4'-O-demethylepipodophyllotoxin] 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)-4β-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with IC50 values 1.5-fold higher than either CPT or etoposide (VP-16). Both conjugates had similar cytotoxicity 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 CPT-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 not 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. Copyright (C) 2000 Elsevier Science Inc.
AB - Two compounds having a camptothecin (CPT) analog conjugated to the 4β-amino-4'-O-demethylepipodophyllotoxin analog were evaluated for their biochemical and biological activities. W1 [camptothecin-(para)-4β-amino-4'-O-demethylepipodophyllotoxin] 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)-4β-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with IC50 values 1.5-fold higher than either CPT or etoposide (VP-16). Both conjugates had similar cytotoxicity 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 CPT-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 not 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. Copyright (C) 2000 Elsevier Science Inc.
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U2 - 10.1016/S0006-2952(99)00363-9
DO - 10.1016/S0006-2952(99)00363-9
M3 - Article
C2 - 10660116
AN - SCOPUS:0033966496
VL - 59
SP - 497
EP - 508
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 5
ER -
