Reversal of multidrug resistance by new dihydropyridines with low calcium antagonist activity.
The clinical use of Ca++ antagonist agents as modulators of multidrug resistance is limited by their strong vasodilator activity. This study reports data obtained by testing a series of new 1,4 dihydropyridine derivatives (DHPs) for their in vitro resistance modulating activity and their Ca++ antagonist effect. All the tested DHPs are active to increase doxorubicin activity with dose modifying factor values ranging between 2 and 47 on P388/DX cells and 12 and 36 on LoVo/DX cells. Their resistance modulating action is exerted through an increase of DX intracellular level. The Ca++ antagonist activity of DHPs, evaluated as capacity to inhibit the KCl-induced contractions in isolated Guinea pig ileum strips, is not related to their resistance modulating activity. This finding makes it possible to select, for further in vivo evaluations, compounds IX, X and XI, which have strong ability to overcome multidrug resistance and low Ca++ antagonist effect.
Capolongo
L
L
Pharmacia-Farmitalia Carlo Erba, Research Center R.&D., Business Area Oncology, Oncology Lab. Nerviano, Italy.
Amboldi
N
N
Ballinari
D
D
Cozzi
P
P
Melegaro
G
G
Ripamonti
M
M
Vaghi
F
F
Grandi
M
M
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors*; D004095:Dihydropyridines / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007941:Leukemia P388 / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004095:Dihydropyridines; D004317:Doxorubicin; D002118:Calcium