Radiation-induced transient cisplatin resistance in murine fibrosarcoma cells associated with elevated metallothionein content

Abstract

Cisplatin resistant mouse fibrosarcoma cells were isolated after fractionated irradiation in the absence of any drug treatment. Several sublines have been established; clone SSK-rad1 was used for further studies. 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 reduced CdCl2 sensitivity, indicating enhanced metallothionein content; loss of cisplatin resistance occurs after 10 to 25 generations and correlates with rising CdCl2 toxicity. Increase of MT is demonstrated directly by 109Cd binding to the MT containing region after FPLC. Both sublines differ in GSH level, which is increased only in SSK-rad1 cells, and in cellular platinum content, which is reduced in SSK-cis2 cells compared to the parental SSK cell line. These factors may contribute to cisplatin resistance but are not the main cause responsible for the transient nature of the drug resistance observed. Our results indicate that transient cisplatin resistance in SSK cells can be induced not only by the drug itself but also by gamma-irradiation and is based on the same mechanism of increased cellular MT content.