Enhancement of antitumour activity of etoposide by dihydropyridines on drug-sensitive and drug-resistant leukaemia in mice.
We recently reported that six 1,4-dihydropyridine derivatives out of 57 screened effectively over-came vincristine (VCR)-resistance in VCR-resistant (P388/VCR) leukaemia-bearing mice when the dihydropyridines and VCR were administered intraperitoneally (i.p.). Furthermore, among the six dihydropyridine derivatives, two compounds, NK-250 and NK-252, most effectively overcame VCR-resistance while exhibiting relatively low calcium antagonistic activity and toxicity. In this study, we examined whether NK-250 and NK-252 could potentiate the antitumour activities of etoposide in mice with drug-sensitive (P388/S) or VCR-resistant (P388/VCR) leukaemia cells when the anticancer agents and tumour cells were administered by various routes. In both groups of mice inoculated i.p. with P388/S- and P388/VCR-leukaemia cells, the oral (p.o.) administration of NK-250 combined with i.p. or intravenously (i.v.) administration of etoposide (ip-po-ip trials and ip-po-iv trials) dramatically potentiated the antitumour activity of etoposide. Although etoposide alone was less effective in treating mice inoculated i.v. with P388/S- and P388/VCR-leukaemia cells, p.o. administration of NK-250 combined with i.p. or i.v. administration of etoposide (iv-po-ip trials and iv-po-iv trials) potentiated the antitumour activity of etoposide to similar levels as in treating mice inoculated i.p. with leukaemia cells. These 1,4-dihydropyridines were therefore highly effective in potentiating anticancer drugs against both drug-sensitive and drug-resistant tumours.
Kiue
A
A
Omiya Research Laboratory, Nikken Chemicals Co. Ltd., Saitama, Japan.
Sano
T
T
Naito
A
A
Okumura
M
M
Kohno
K
K
Kuwano
M
M
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002460:Cell Line; D004095:Dihydropyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D004147:Dioxins / Q000008:administration & dosage / Q000627:therapeutic use*; D004351:Drug Resistance; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007941:Leukemia P388 / Q000188:drug therapy*; D008297:Male; D051379:Mice
D004095:Dihydropyridines; D004147:Dioxins; C066457:NK 250; C066458:NK 252; D005047:Etoposide