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.
Department of Experimental Pathology, German Cancer Research Center, Heidelberg.
M
M
Volm
J
J
Mattern
E W
EW
Pommerenke
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