RADIATION-INDUCED TRANSIENT CISPLATIN RESISTANCE IN MURINE FIBROSARCOMA CELLS ASSOCIATED WITH ELEVATED METALLOTHIONEIN CONTENT

Cisplatin resistant mouse fibrosarcoma cells were isolated after fract ionated irradiation in the absence of any drug treatment. Several subl ines have been established; clone SSK-rad1 was used for further studie s. These cells exhibit unchanged radiosensitivity and are compared to cisplatin resistant sublines, SSK-cis2, previously induced by low dose cisplatin exposure. Both resistant sublines are characterised by redu ced CdCl2 sensitivity, indicating enhanced metallothionein content; lo ss of cisplatin resistance occurs after 10 to 25 generations and corre lates with rising CdCl2 toxicity. Increase of MT is demonstrated direc tly by Cd-109 binding to the MT containing region after FPLC. Both sub lines differ in GSH level, which is increased only in SSK-rad1 cells, and in cellular platinum content, which is reduced in SSK-cis2 cells c ompared to the parental SSK cell line. These factors may contribute to cisplatin resistance but are not the main cause responsible for the t ransient nature of the drug resistance observed. Our results indicate that transient cisplatin resistance in SSK cells can be induced not on ly by the drug itself but also by gamma-irradiation and is based on th e same mechanism of increased cellular MT content.