Over-expression of MDR1 gene with no DNA amplification in a multiple-drug-resistant human ovarian carcinoma cell line.
Human ovarian adenocarcinoma cells IGROV1 were induced to become resistant in vitro to Vincristine (VCR) by continuous and discontinuous stepwise exposure to the drug. Both sublines exhibited similar indexes of resistance (approx. 800). The acquisition of VCR resistance was associated with changes of morphology and with cross-resistance to Adriamycin, VP16 and actinomycin D. Addition of verapamil enhanced sensitivity of resistant cells to VCR. This multi-drug-resistant (MDR) phenotype was associated with high levels of human MDR1 gene transcripts (25- to 100-fold). In contrast to other reports, no significant amplification of the locus could be observed. Reactivity with MRK16, a monoclonal antibody (MAb) directed against the MDR 170 kDa protein, was found to be related to the level of MDR1 transcription. In addition, both OV1/VCR sublines exhibited a marked loss of tumorigenicity. Besides the chromosomal markers of OV1/p, the two resistant sublines revealed a common cytogenetic rearrangement: a deletion of the short arm of one chromosome 11: del(11)(p12). We suggest that the acquisition of this marker might be associated with the non-tumorigenic phenotype of OV1/VCR-resistant sublines.
Bénard
J
J
Laboratoire de Pharmacologie Clinique et Moléculaire, Institut Gustave Roussy, Villejuif, France.
Da Silva
J
J
Teyssier
J R
JR
Riou
G
G
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002872:Chromosome Deletion; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D003609:Dactinomycin; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D014700:Verapamil