Newly synthesized dihydropyridine derivatives as modulators of P-glycoprotein-mediated multidrug resistance.
Newly synthesized 1,4-dihydropyridine derivatives possessing alkyl chains at the 4-position screened whether they could overcome P-glycoprotein-mediated multidrug resistance in cultured cancer cells and also leukemia-bearing animals. Of these derivatives, some could overcome drug resistance to doxorubicin and vincristine in multidrug resistant human cancer cell lines. Combined administration of vincristine and some of the derivatives significantly increased the life span of P-glycoprotein overexpressing multidrug-resistant P388 leukemia-bearing mice. The calcium antagonistic activities, an undesirable effects, were weaker than that of verapamil. These results suggested that the introduction of alkyl groups at the 4-position were effective for both overcoming multidrug resistance and reducing the calcium antagonistic activity.
Tanabe
H
H
Omiya Research Laboratory, Nikken Chemicals Co. Ltd., Saitama, Japan.
Tasaka
S
S
Ohmori
H
H
Gomi
N
N
Sasaki
Y
Y
Machida
T
T
Iino
M
M
Kiue
A
A
Naito
S
S
Kuwano
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity; D015195:Drug Design; D018432:Drug Resistance, Multiple; D006801:Humans; D007624:KB Cells; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000493:pharmacokinetics / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014750:Vincristine; D004317:Doxorubicin