Transient cisplatin-resistant murine fibrosarcoma cell characterized by increased metallothionein content

Abstract

Cisplatin-resistant mouse fibrosarcoma cells, SSK-R, were isolated after short and low-dose drug treatment of the sensitive SSK cells in vitro. These SSK-R sublines exhibit up to sevenfold cisplatin resistance and are characterized mainly by an increased metallothionein content. Loss of drug resistance after about 140-180 cell divisions in drug-free medium coincides with loss of metallothionein content. The glutathione level is the same in the sensitive and resistant sublines; inhibition of glutathione synthesis by buthionine sulphoximine enhances the sensitivity in both cells lines by a factor of 2.7. The resistant sublines are not cross-resistant to radiation; a radiation exposure followed immediately by cisplatin treatment results in an additive effect. The cellular cisplatin content is slightly reduced in SSK-R2 cells and it remains at this level also upon loss of drug sensitivity.

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

“…This acquired drug resistance is not associated with a decrease in radiosensitivity. The mechanisms leading to transient cisplatin resistance are similar to those described after cisplatin induced resistance (Eichholtz-Wirth et al, 1993). Both in subclones SSK-rad1 and SSK-cis2, several mechanisms may contribute to cisplatin resistance: however, the main factor correlating with the development and loss of cisplatin resistance is the cellular content of metallothioneins.…”

“…In their human ovarian cells, resistance was associated mainly with enhanced repair and increased tolerance of DNA damage; cisplatin uptake was decreased and cytotoxicity could be enhanced by verapamil, but not by inhibition of GSH with BSO. In our SSK cells, verapamil has no effect on SSK and SSK-cis2 cells (Eichholtz-Wirth, 1993), whereas BSO treatment may be used to increase cisplatin toxicity for the sensitive and resistant cells (Eichholtz-Wirth, 1993; data for SSK-rad1 cells not shown). DNA repair was not studied in our SSK cells.…”

“…SSK-cis2 cells differed from SSK-rad, cells by reduced cellular platinum content, which was also unchanged upon loss of cisplatin resistance (Eichholtz-Wirth et al, 1993).…”

“…Findings range from no effect (Wallner & Li, 1987;Eichholtz-Wirth et al, 1993;Mitchell et al, 1988) to cross-resistance (Schwartz et al, 1988;Louie et al, 1985) and even to collateral sensitivity . Lehnert et al (1989 and1990) discuss the contribution of GSH and its related enzymes to the radiation response in drug resistant human tumour cells.…”

“…We have previously described cisplatin resistance in a murine fibrosarcoma cell line (SSK-cis), induced by intermittent low dose cisplatin treatment (Eichholtz-Wirth et al, 1993). This drug resistance was transient and was characterised mainly by elevated metallothionein content.…”