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

Citation
Jy. Chang et al., Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4 beta-amino-4'-O-demethylepipodophyllotoxin conjugates, BIOCH PHARM, 59(5), 2000, pp. 497-508
Citations number
55
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
59
Issue
5
Year of publication
2000
Pages
497 - 508
Database
ISI
SICI code
0006-2952(20000301)59:5<497:UBCAAA>2.0.ZU;2-B
Abstract
Two compounds having a camptothecin(CPT) analog conjugated to the 4 beta-am ino-4'-O demethylepipodophyllotoxin analog were evaluated for their:biochem ical and biological activities. W1 [camptothecin-(para)-4 beta-amino-4'-O-d emethylepipodoyhyllotoxin] had no activity against topoisomerase II (TOP II ), but inhibited topoisomerase I (TOP I) with an IC50 value 2-fold higher t han CPT. W2 [camptothecin-(ortho) -4 beta-amino-4'-O-demethylepipodophyllot oxin] 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 simi lar 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 thos e of W1. No cross-resistance with the two conjugates was seen in a VP-16-re sistant KB subline, which showed down-regulation of TOP II and overexpressi on 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 anothe r mechanism that occurs post-PLDB formation, was partially resistant to bot h compounds. W1 was nor, affected by this post-PLDB resistance mechanism. C ell cycle analysis demonstrated that W1 and W2 had similar cell cycle effec ts on KB and KB CPT 100 cells, which accumulated in S-phase upon drug treat ment. These results suggested that W1 and W2 exerted their cytotoxicity thr ough TOP I. In CPT-resistant cells, however, an unidentified target also ma y be involved in the cytotoxic action of W1, and TOP II may still be a targ et for W2. In vivo, W1 was more effective against the growth of human prost ate cancer cells in nude mice than VP-16, CPT, or W2. Given its antitumor a ctivity and unique biochemical mechanism of action, W1 warrants exploration as an antitumor compound. (C) 2000 Elsevier Science Inc.