Establishment and characterization of an etoposide-resistant human small cell lung cancer cell line.
An etoposide-resistant subline, SBC-3/ETP, from a human small cell lung cancer cell line, SBC-3, was developed by continuous exposure to increasing concentrations of etoposide in culture. The SBC-3/ETP was 52.1-fold more resistant to etoposide than the parent cell line. The SBC-3/ETP was highly cross-resistant to teniposide, adriamycin, vinca alkaloids, 4-hydroperoxycyclophosphamide, CPT-11 and mitomycin C, and marginally cross-resistant to cisplatin, while the subline showed a collateral sensitivity to bleomycin. Topoisomerase I activity in the SBC-3/ETP was reduced to an extent of one half and topoisomerase II activity to an extent of one eighth in comparison with those of the SBC-3. Intracellular accumulation of [3H]-etoposide in the SBC-3/ETP was significantly lower in comparison to the SBC-3. An overexpression of MDR1 mRNA, and the presence of its product, P-glycoprotein, were detected in the SBC-3/ETP by Northern blotting and flowcytometry using a monoclonal antibody of the protein, MRK16. These results indicate that a decreased activity of topoisomerase II is the major factor for the development of etoposide resistance, and that an overexpression of the MDR1 gene is responsible, in part, for the development of resistance to the drug and some structurally unrelated compounds such as adriamycin and vinca alkaloids.
Takigawa
N
N
Second Department of Medicine, Okayama University Medical School, Japan.
Ohnoshi
T
T
Ueoka
H
H
Kiura
K
K
Kimura
I
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018288:Carcinoma, Small Cell / Q000473:pathology*; D004250:DNA Topoisomerases, Type II / Q000032:analysis; D004351:Drug Resistance / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D005978:Glutathione