Time course of MDR gene amplification during in vivo selection for doxorubicin-resistance and during reversal in murine leukemia L 1210.
MDR gene expression in murine leukemia L 1210 cells was investigated during treatment in vivo with 0.5 mg doxorubicin/kg body weight (BW). Drug resistance (measured by an in vitro short-term test and immunohistochemistry) increased with the number of treatments and the maximum resistance reached after 8 treatments was similar with that of an established multidrug- resistant cell line (20 treatments, 2 mg/kg BW). Southern-blot and DNA dot-blot analyses show that development of MDR is associated with MDR-gene amplification and correlates with the degree of drug resistance and P-glycoprotein-expression. After cessation of doxorubicin treatment, resistance decreased continuously and disappeared after 20 passages. This decrease in resistance is accompanied by a loss of MDR gene amplification and P-glycoprotein expression. Furthermore, P-glycoprotein expression was analyzed in the first hours after treatment with doxorubicin in vivo (0.5 mg/kg BW). Expression was markedly increased and peaked at about 24 hours after treatment. In contrast, only slightly increased resistance and no MDR gene amplification could be detected.
Volm
M
M
Department of Experimental Pathology, German Cancer Research Center, Heidelberg.
Mattern
J
J
Pommerenke
E W
EW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000911:Antibodies, Monoclonal; D015139:Blotting, Southern; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D007150:Immunohistochemistry; D007700:Kinetics; D007939:Leukemia L1210 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; D004317:Doxorubicin