Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4β-amino-4'-O-demethylepipodophyllotoxin conjugates

Jang-Yang Chang, Xin Guo, Hong Xing Chen, Zaoli Jiang, Qin Fu, Hui Kang Wang, Kenneth F. Bastow, Xiao Kang Zhu, Jian Guan, Kuo Hsiung Lee, Yung Chi Cheng

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Abstract

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.

Original languageEnglish
Pages (from-to)497-508
Number of pages12
JournalBiochemical Pharmacology
Volume59
Issue number5
DOIs
Publication statusPublished - 2000 Mar 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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    Chang, J-Y., Guo, X., Chen, H. X., Jiang, Z., Fu, Q., Wang, H. K., Bastow, K. F., Zhu, X. K., Guan, J., Lee, K. H., & Cheng, Y. C. (2000). Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4β-amino-4'-O-demethylepipodophyllotoxin conjugates. Biochemical Pharmacology, 59(5), 497-508. https://doi.org/10.1016/S0006-2952(99)00363-9