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

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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
Issue number5
Publication statusPublished - Mar 2000
Externally publishedYes


  • Antitumor
  • Camptothecin
  • Conjugates
  • Topoisomerase
  • VP-16

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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