Activities of novel nonglycosidic epipodophyllotoxins in etoposide-sensitive and -resistant variants of human KB cells, P-388 cells, and in vivo multidrug-resistant murine leukemia cells.
Previous structure-activity studies of the antitumor compound etoposide (VP-16) have suggested that replacement of the glycoside moiety could afford therapeutically active analogues with different biochemical determinants for cellular accumulation and drug resistance. In the present report, 10 analogues of VP-16 in which the glycosidyl moiety was replaced with alkyl or arylamino substituents exhibited 5-10-fold better binding affinity for topoisomerase II/DNA complex in human KB cells. A similar increase in the binding affinity was observed in an isolated-nuclei model. The analogues displayed greater or comparable potency to VP-16 in cell growth-inhibition studies and were less affected by cell membrane-associated drug resistance mechanisms, as exemplified by overexpressions of P-glycoprotein multidrug-resistance gene or multidrug resistance-associated protein. Interestingly, in animal studies, analogues least affected by the membrane transport-deficiency phenotypes exhibited low therapeutic index values, thus suggesting that highly efficient modulation of cellular membrane transport defects could perturb the selectivity of antitumor agents for cancer cells. This report also suggests a new method of quantifying drug-induced protein-linked DNA breaks by graphically determining the apparent dissociation-inhibition constant (Kdi) for the inhibitors.
Anyanwutaku
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IO
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Guo
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X
Chen
H X
HX
Ji
Z
Z
Lee
K H
KH
Cheng
Y C
YC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004249:DNA Damage; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007624:KB Cells; D007941:Leukemia P388 / Q000188:drug therapy; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D011034:Podophyllotoxin / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011034:Podophyllotoxin