In vivo reversal of multidrug resistance by two new dihydropyridine derivatives, S16317 and S16324.
Two new dihydropyridine derivatives with low calcium channel affinity, S16317 and S16324, were found to fully overcome multidrug resistance in vitro. These two compounds increased doxorubicin cytotoxicity on the human COLO 320DM cell line and completely reversed the vincristine resistance of murine P388/VCR cells. In vivo, S16324 administered p.o. (200 mg/kg on days 1 to 4) or i.p. (50 mg/kg on days 1, 5, 9) in combination with vincristine (i.p.) restored the antitumor activity of vincristine in P388/VCR-bearing mice. S16317 showed a reversing activity when administered p.o., i.v. (days 1 to 4) or i.p. (days 1, 5, 9) at the same dose (25 mg/kg), suggesting a remarkable bioavailability. Moreover, these two compounds potentiated the antitumor activity of vincristine in the sensitive P388 leukemia, increasing the number of long-term survivors. These results suggest that combination chemotherapy using S16317 or S16324 would be effective not only in circumventing multidrug resistance but also in preventing the emergency of a population of resistant tumor cells in sensitive tumors.
Kraus-Berthier
L
L
Division de Cancérologie Expérimentale, Institut de Recherches Servier, Suresnes, France.
Guilbaud
N
N
Peglion
J L
JL
Leonce
S
S
Lombet
A
A
Pierre
A
A
Atassi
G
G
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015736:Felodipine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D015220:Calcium Channels; D004095:Dihydropyridines; C090516:S 16324; C090515:S 16317; D014750:Vincristine; C038806:1,4-dihydropyridine; D004317:Doxorubicin; D015736:Felodipine