Verapamil potentiation of VP-16-213 in acute lymphatic leukemia and reversal of pleiotropic drug resistance.
Verapamil, the calcium-influx-blocking agent, has previously been shown to have favorable interactions with antineoplastic drugs. Our study of human T cell acute lymphatic leukemia (ALL) GM3639 indicates that verapamil enhances the in vitro cytotoxicity of VP-16-213 against drug-sensitive ALL by reducing the concentration of VP-16-213, resulting in 50% cell viability from 104.5 +/- 26.6 nM to 46.0 +/- 2.7 nM (P less than 0.05). The addition of verapamil to VP-16-213 treatment of BDF/1 mice bearing L1210 leukemia increases their mean survival from 21.2 +/- 3.6 to 50.4 +/- 4.3 days (P less than 0.01) and the survival of CD2F/l mice bearing P388 leukemia from 27.8 +/- 3.7 to 49.1 +/- 5.0 days (P less than 0.01). The 30-day survival is significantly increased in L1210 and P388 leukemia mice, and 60-day survival is significantly increased in P388 leukemic mice by verapamil. We developed a vincristine (VCR)-resistant subline of GM3639 T cell ALL, L23, by continuous exposure of drug-sensitive cells to VCR. This subline demonstrates pleiotropic cross resistance to VP-16-213 and daunorubicin. The addition of verapamil to VCR, to VP-16-213, and to daunorubicin completely restores responsiveness to these drugs, as indicated by the normalization of the VCR and VP-16-213 concentrations required for cytotoxicity and the concentration of daunorubicin required for inhibition of thymidine incorporation.
Slater
L M
LM
Murray
S L
SL
Wetzel
M W
MW
Sweet
P
P
Stupecky
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003630:Daunorubicin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects; D004357:Drug Synergism; D005047:Etoposide / Q000627:therapeutic use*; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D007942:Leukemia, Experimental / Q000188:drug therapy*; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use*; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D014750:Vincristine; D005047:Etoposide; D014700:Verapamil; D011034:Podophyllotoxin; D003630:Daunorubicin