New purines and purine analogs as modulators of multidrug resistance.
A series of 36 purine and purine analog derivatives have been synthesized and tested for their ability to modulate multidrug resistance in vitro (P388/VCR-20 and KB-A1 cells) and in vivo (P388/VCR leukemia). Compounds were compared to S9788, a triazine derivative which has already shown some activity during phase 1 clinical trials and also a limiting cardiovascular side effect possibly linked to its calcium channel affinity. The fact that active compounds increase adriamycin accumulation in the resistant KB-A1 cells, and not in the sensitive KB-3-1 cells, suggests they act predominantly by inhibiting the P-glycoprotein-catalyzed efflux of cytotoxic agents. No direct relation was found between the affinity for the phenylalkylamine binding site of the calcium channel and in vitro sensitization of resistant cells. In vivo, when administered po in association with vincristine (0.25 mg/kg), five compounds (3, 4, 9, 25, and 26), of very differing calcium channel affinities (Ki from 5 to 560 nM), fully restored (T/V > or = 1.4) the sensitivity of P388/VCR leukemia to vincristine.
Dhainaut
A
A
Institut de Recherches Servier, Suresnes, France.
Regnier
G
G
Tizot
A
A
Pierre
A
A
Leonce
S
S
Guilbaud
N
N
Kraus-Berthier
L
L
Atassi
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000627:therapeutic use; D011687:Purines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014227:Triazines / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000627:therapeutic use
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D015220:Calcium Channels; D010880:Piperidines; D011687:Purines; D014227:Triazines; C077022:S 9788; D014750:Vincristine; D004317:Doxorubicin