title: Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4beta-amino-4'-O-demethylepipodophyllotoxin conjugates.
abstract: Two compounds having a camptothecin (CPT) analog conjugated to the 4beta-amino-4'-O-demethylepipodophyllotoxin analog were evaluated for their biochemical and biological activities. W1[camptothecin-(para)-4beta-amino-4'-O-demethylepipodophyllotoxin] had no activity against topoisomerase II (TOP II), but inhibited topoisomerase I (TOP I) with an IC(50) value 2-fold higher than CPT. W2 [camptothecin-(ortho)-4beta-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with IC(50) 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 W1 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 W1. 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: J Y
authors.initials: JY
authors.lastname: Chang
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: H X
authors.initials: HX
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Jiang
authors.forename: Q
authors.initials: Q
authors.lastname: Fu
authors.forename: H K
authors.initials: HK
authors.lastname: Wang
authors.forename: K F
authors.initials: KF
authors.lastname: Bastow
authors.forename: X K
authors.initials: XK
authors.lastname: Zhu
authors.forename: J
authors.initials: J
authors.lastname: Guan
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin; C072088:4'-demethylepipodophyllotoxin; D002166:Camptothecin