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Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies.
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1970
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PathologyAntimicrobial ChemotherapyAntibiotic ResistanceDrug ResistanceMolecular PharmacologyDaunomycin-resistant Cell LinesChinese Hamster CellsAntibacterial MechanismsCytogenetic StudiesAntimicrobial ResistanceResistant SublinesDrug Resistance AnalysisBiochemistryAntimicrobial PharmacokineticsPharmacologyCell BiologyAntimicrobial SusceptibilityAntibioticsAntimicrobial PharmacodynamicsMedicineCellular ResistanceDrug Discovery
Several actinomycin D‑resistant sublines were generated in vitro from Chinese hamster cells, maintained at 0.1, 1.0, and 10.0 µg/ml AD, and displayed up to 2,500‑fold increased resistance. The resistant sublines showed cross‑resistance to multiple chemotherapeutics, with greater resistance correlating with higher molecular weight, and radioautographic and karyotype analyses indicated that resistance arises from reduced membrane permeability and stable chromosomal alterations.
Summary Several actinomycin D (AD)-resistant sublines maintained at 0.1, 1.0, and 10.0 µg/ml AD and exhibiting an increase in resistance up to 2500-fold were developed in vitro from Chinese hamster cells. Dose-response data for sensitive and resistant sublines demonstrated that AD-resistant cells were cross-resistant, in decreasing order, to mithramycin, vinblastine, vincristine, puromycin, daunomycin, demecolcine, and mitomycin C. In general, the greater the cross-resistance to an agent, the greater its molecular weight. Increase in resistance to AD of a graded series of sublines was accompanied by proportional decrease in sensitivity to vincristine and daunomycin, and several experimentally derived daunomycin-resistant cell lines also exhibited increased resistance to AD. In radioautographic experiments, it was found that degree of resistance was inversely related both to degree of nuclear labeling by AD-3H and to inhibition of uridine-5-3H incorporation by the antibiotic. Karyotype analysis revealed that chromosomal alterations, once established, were stable and apparently were not specifically related to the resistant state. These investigations support the hypothesis that the development of resistance to AD in Chinese hamster cells is due to qualitative difference in cell membrane, resulting in decreased permeability to AD and other compounds.