Nuclear transport as an ultimate step of multidrug resistance.
Adriamycin (ADM) incorporation into nuclei of whole multidrug resistant (MDR) CEM cells is lower than into sensitive ones (S), that is mostly thought to be the consequence of a decrease of drug related to the activity of the multidrug resistance plasma membrane protein P 170. Isolated nuclei of the lymphoblastic tumor cell line CEM, which structures were controlled by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and confocal microscopy, where incubated with 10(-6) mole/l of ADM. Incorporation into DNA was quantified by spectrofluorimetry. It was lower and slower into MDR nuclei than into S ones. Different modulators of active transport influence drug transfer into S nuclei and had no effect in MDR nuclei. The nuclear transfer into S nuclei appeared divided into two components: one was decreased by WGA, increased by cytosolic factors and an other part was purely passive in an identical intensity to MDR nuclei. Resistance of MDR nuclei seemed indebt to a defect, in these cells, of factors that mediate and/or activate nuclear transport of drug.
Bobichon
H
H
EA 2063, IFR 53 Biomolécules, UFR Pharmacie, Reims, France. héléne.bobichon@univ-reims.fr
Cailleret
L
L
Ploton
D
D
Belhoussine
R
R
Jardillier
J C
JC
D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001692:Biological Transport; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D017348:Microscopy, Electron, Scanning Transmission; D009685:Nuclear Envelope / Q000378:metabolism; D013194:Staining and Labeling; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004317:Doxorubicin