Modulation of daunorubicin intracellular accumulation in P-glycoprotein expressing MCF-7 human breast adenocarcinoma cells by thermosensitive-liposome encapsulation and hyperthermia.
Intracellular accumulation of free or thermosensitive liposome-encapsulated daunorubicin (TLED) at 37 or 43 degrees C, was evaluated using flow cytometry in chemosensitive and P-glycoprotein expressing MCF-7 human breast adenocarcinoma cells. At 37 degrees C, liposome-encapsulation significantly increased intracellular daunorubicin accumulation (IDA) in resistant cells (P=0.005) and that effect was statistically comparable to that achieved in adding 15 micromol/l verapamil to free daunorubicin (DNR). Combining TLED and verapamil further enhanced significantly (P=0.004) this effect as compared to TLED alone. However, none of these treatments restored IDA to the level achieved in sensitive cells. Hyperthermia significantly increased IDA in the sensitive cell (P<0.05), whenever free-DNR or TLED was used, but had no significant effect in the resistant cells, suggesting that P-glycoprotein could efflux the additional drug uptaken in hyperthermic conditions. In all these experiments combining the use of a modulator (verapamil or TLED) and hyperthermia, IDA was statistically comparable to that achieved with free-DNR in sensitive cells at 37 degrees C, but still remained lower than the IDA in sensitive cells at 43 degrees C (P<0.05). The results also showed that hyperthermia affected the labelling of P-glycoprotein by MRK16 monoclonal antibody.
Merlin
J L
JL
Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, Vandoeuvre-Les-Nancy, France.
Marchal
S
S
Ramacci
C
C
Notter
D
D
Vigneron
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy*; D004396:Coloring Agents; D003131:Combined Modality Therapy; D003630:Daunorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004337:Drug Carriers; D018432:Drug Resistance, Multiple; D005260:Female; D005434:Flow Cytometry; D005453:Fluorescence; D006801:Humans; D006979:Hyperthermia, Induced; D008081:Liposomes; D011419:Propidium; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004396:Coloring Agents; D004337:Drug Carriers; D008081:Liposomes; D011419:Propidium; D003630:Daunorubicin