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.
This investigation was supported in part by funds from USPHS Grant CA-08748.
