Modulation of expression of multidrug resistance gene (mdr-1) by adriamycin.
The acquired resistance to various drugs in cancer is mediated by P-glycoprotein (P-gp) which is encoded by the mdr-1 gene. An increased level of mdr-1/P-gp was demonstrated after chemotherapy administered to treat cancer in humans. To clarify the direct effect of anticancer drugs on mdr-1/P-gp expression, we investigated the change in transport of adriamycin (ADR), and the expression of the mdr-1 gene and P-gp in an ADR-treated, multidrug-resistant leukemic cell line (K562/ADR500). The addition of ADR induced the over-expression of mdr-1/P-gp, which led to a transient decrease in the intracellular accumulation of ADR although the difference was not statistically significant. A maximal effect was observed after 4 h incubation, returning to the baseline level after further incubation for 12-24 h. The phosphorylation of P-gp was inversely correlated with the levels of P-gp. These observations suggest that ADR itself modulates both the expression and function of P-gp. Determination of the optimal schedule for administering adriamycin is essential to achieving the optimal effect in treating cancer.
Kato
S
S
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Nishimura
J
J
Yufu
Y
Y
Ideguchi
H
H
Umemura
T
T
Nawata
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D005786:Gene Expression Regulation; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D012313:RNA / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D015345:Oligonucleotide Probes; D012313:RNA; D004317:Doxorubicin