Establishment of an etoposide-resistant human epithelial tumour cell line in vitro: characterization of patterns of cross-resistance and drug sensitivities.

A human tumour cell line resistant to etoposide ( VP16 -213) has been produced by fractionated X-irradiation exposure in vitro. Characterization of this line, derived from an epithelioid carcinoma of the tongue, revealed no significant differences in terms of several cytological and kinetic parameters compared with the parent line. Patterns of cross-resistance and drug sensitivities were determined by colony formation in soft agar after 24 h drug exposures. Three patterns of response were observed with the VP16 -213-resistant cells showing: marked cross-resistance to vincristine and teniposide , collateral sensitivity to 5- fluorouracil , hydroxyurea and cis-platinum, and comparable responses to the parent line for adriamycin, bleomycin, dibromodulcitol and methotrexate. This is the first demonstration that specific drug resistance can be induced by prior exposure to X-irradiation in vitro. This cell line appears to show a unique lack of cross-resistance between adriamycin and vincristine or etoposide. Preliminary investigations into possible mechanisms of etoposide resistance demonstrated similar DNA sedimentation profiles after etoposide exposure in both tumour cell lines, implying no differential effects of this drug on DNA of resistant cells. These data raise the possibility that the expression and mechanism of resistance may differ, depending on the manner in which drug resistance is induced.