Derivation and characterisation of a mouse tumour cell line with acquired resistance to cyclosporin A.

Cyclosporin A (CsA) is an effective modifier of multidrug resistance. We have studied (a) the possibility that cells grown in increasing concentrations of CsA acquire cellular resistance to the agent and, (b) whether such cells have a multidrug resistant phenotype. Sublines of the EMT6 mouse tumour cell line were developed which were able to grow in 75 and 200 micrograms/ml of CsA, respectively. The resistant sublines grew slowly in the presence of CsA but reverted to control growth rates, whilst maintaining resistance, when the drug was removed. P-glycoprotein (Pgp) was not detectable in the resistant sublines by immunocytochemistry. The CsA-resistant cells were not cross-resistant to doxorubicin or vincristine but showed a clear degree of cross-resistance to the calcium transport blocker, verapamil. Cellular accumulation of both [3H]CsA and [3H]daunorubicin was significantly increased in the EMT6/CsA200R subline compared with the parent line. In the EMT6 parent line, which expresses very low levels of Pgp, 10-30-fold sensitisation to doxorubicin may be achieved using 0.1-5 microgram/ml of CsA. Similar sensitisation by CsA was also seen in the CsA-resistant sublines.