In vitro circumvention of anthracycline--resistance in Ehrlich ascites tumour by anthracycline analogues.
In previously reported studies, acquired experimental resistance and cross resistance to anthracyclines are related to decreased drug accumulation and retention. The decreased accumulation seems to depend on a cellular mechanism for active drug efflux. N-Acetyl-daunorubicin (N-acetyl-DNR) has demonstrated the ability to increase drug accumulation and to overcome experimental resistance to daunorubicin (DNR) in resistant cells. In the present in vitro study 25 different anthracycline analogues were tested for their influence on [3H]DNR accumulation in resistant cells. At equimolar concentrations (5 microM) four of the analogues enhanced [3H]DNR accumulation more than 200%. Increasing the concentration of the analogues 3-20-fold, 12 of the compounds could enhance [3H]DNR accumulation above 200%. No specific structural changes separated those 12 compounds from the 13 analogues with no or minor effect. The lipid solubility of the 25 analogues was examined by measuring the partition coefficient in octanol/phosphate and pentanol/phosphate buffer (pH 7.45). A good correlation was demonstrated between increased lipid solubility of the analogues and their effect on [3H]DNR accumulation in resistant cells. Further studies demonstrated that N,N-dibenzyl-DNR was able to potentiate cytotoxicity of DNR in resistant cells. It is concluded that several anthracycline analogues are able to reverse resistance, but it is not possible from the chemical structure to predict which analogue results in enhanced [3H]DNR accumulation in resistant cells.
Friche
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Department of Medicine, Finsen Institute/Rigshospitalet, Copenhagen, Denmark.
Jensen
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PB
Roed
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Skovsgaard
T
T
Nissen
N I
NI
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D008055:Lipids; D012995:Solubility; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D008055:Lipids; C001939:N-acetyldaunomycin; D004317:Doxorubicin; D003630:Daunorubicin