A non-P-glycoprotein-mediated mechanism of vincristine transport which is affected by resistance modifiers and present in chemosensitive cells.
The accumulation and cytotoxicity of vincristine (Vcr), etoposide (VP16), and daunorubicin (Dau) and effect of the resistance modifiers (RM) verapamil (Ver; 10 microM) and cyclosporin A (CyA; 3 microM) were studied in isolated rat cardiac myocytes, peripheral lymphocytes from seven patients with chronic lymphocytic leukemia (CLL), in the human leukemic cell line K562 and its two Vcr resistant mdr1 gene expressing sublines, K562/Vcr30, K562/Vcr150. Both RMs increased the accumulation and cytotoxic effect of Vcr and Dau in the resistant sublines. In K562 cells, lymphocytes from patients with CLL and rat cardiac myocytes, which all were mdr1 RNA negative RMs increased the cellular accumulation and potentiated the cytotoxic effect of Vcr but not that of Dau. K562/Vcr30 and K562/Vcr150 were cross resistant to Dau but not to VP16 and RMs had no effect on the cytotoxicity of VP16 in any of cell lines. The results indicate that chemosensitive cells also have a transport mechanism, not mediated by P-glycoprotein, which transports Vcr but not Dau and VP16. This suggests that addition of RMs to Vcr-containing chemotherapy may enhance the antineoplastic effect also by inhibition of non-P-glycoprotein mediated transport mechanisms.
Gruber
A
A
Department of Internal Medicine, Karolinska Hospital, Stockholm, Sweden.
Larsson
R
R
Nygren
P
P
Björkholm
M
M
Peterson
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000633:toxicity; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D006321:Heart / Q000187:drug effects; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism; D008214:Lymphocytes / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000493:pharmacokinetics* / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D014750:Vincristine; D016572:Cyclosporine; D014700:Verapamil; D003630:Daunorubicin