Generation and characterization of a low-degree drug-resistant human tumor cell line.
A 2780 human ovarian cancer cells, obtained from an untreated patient, have been exposed to a relatively low, clinically maintainable dose (10 nmol/l) of the anthracycline doxorubicin (DX) to derive a low-degree (5-fold) drug-resistant subline (A2780-DX1). Compared to parental cells, these DX-resistant cells have increased size (+60% of cell volume) and contain a greater number of cytoplasmic vacuoles as determined by electron microscopy. When exposed to several other antiproliferative drugs, A2780-DX1 cells were highly cross-resistant (greater than 10-fold) to epirubicin, mafosfamide and cisplatin and slightly cross-resistant (2- to 3-fold) to navelbine and bleomycin, while they retained the original sensitivity to vinblastine, Ara-C and fluorouracil. Gel electrophoresis of cytoplasmic membrane proteins showed differences between the pattern of parental A2780 sensitive and A2780-DX1 cells as far as low-molecular-weight proteins (less than 45 kD) are concerned, while no clear overexpression of P-glycoprotein (P-170) could be detected. Membrane modifications yielding a decrease of both DX uptake and retention, increased content of intracellular glutathione (+32%) and reduced DNA double-strand breaks seem to be involved in the resulting multidrug-resistant phenotype of A2780-DX1 cells.
Mazzoni
A
A
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italia.
Trave
F
F
Russo
P
P
Nicolin
A
A
Rustum
Y M
YM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004249:DNA Damage; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005978:Glutathione / Q000032:analysis; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
D000970:Antineoplastic Agents; D004317:Doxorubicin; D005978:Glutathione