Qualitatively different mechanisms of resistance to doxorubicin, both involving altered glutathione pools, in two myeloid cell lines in vitro.
Subclones of the two well-characterized myeloid cell lines HL-60 and KG1a were selected for doxorubicin resistance by systematic exposure to increased concentrations of the drug in vitro. Both subclones demonstrated a threefold increased resistance to the drug as evident from cell growth in liquid culture and clonogenicity in a semisolid matrix. Both resistant subclones displayed a similar degree of reduced total and nuclear doxorubicin levels. The HL-60 and the KG1a cells differed qualitatively and quantitatively with respect to glutathione (GSH) levels during culture, with markedly elevated concentrations in the resistant HL-60 subclone during 1 week of culture. Total GSH pools in resistant and sensitive KG1a cells were similar, but maximum GSH levels were reached earlier in the resistant KG1a clones than in the parental cells. Northern blot analysis suggests that resistance was accompanied by increased mdr1 expression in the KG1a but not in the HL-60 cells, whereas alterations in the glutathione S-transferase P1-1 and topoisomerase II message was evident in the latter. The results demonstrate the complex, multifactorial mechanisms behind the in vitro induction of even moderate resistance in anthracyclines.
Dajani
L K
LK
Department of Clinical Pharmacology, Norwegian Radium Hospital, Montebello, Oslo, Norway.
Warren
D J
DJ
Andersen
A
A
Strømhaug
A
A
Slørdal
L
L
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle; D004317:Doxorubicin / Q000032:analysis / Q000494:pharmacology*; D004351:Drug Resistance; D005978:Glutathione / Q000378:metabolism*; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005978:Glutathione