Metallothionein drug-resistant cells

Keenan C, Thompson S, Knox K, Pears C (1999) Protein kinase C-alpha is essential for Ramos-BL 6 cell survival. Cell Immunol 196 104-109 Kelley SL, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS (1988) Overex3q>res-sion of metallothionein confers resistance to anticancer drugs. Science 241 1815-1818... 

Bid H, Geczi L, Magori A, et al. Drug resistance and sensitivity of germ cell testicular tumors evaluation of clinical relevance of MDRl/Pgp, p53, and metallothionein (MT) proteins. Anticancer Res. 1998 18 3059. 

Fig. 1. Survival curves of C127 cells transduced with a bovine papilloma virus alone (O) or bovine papillomavirus containing an hMT IIA gene construct ( ). Cells were treated for 72 h with the drugs and the number of cells determined by a colorimetric assay. (From Kelley et al. 1988, Overexpression of metallothionein confers resistance to anticancer drugs. Science 241 1813-1815)...

Despite the lack of a clear understanding of the mechanism by which metallothionein engenders drug resistance, the isotypes involved, and the subcellular location of metallothionein, several investigators have begun to probe whether the successful cell culture observations can be applied to preclinical tumor models or patients. 

Lazo JS, Basu A (1991) Metallothionein expression and transient resistance to electrophilic antineoplastic drugs. Semin Cancer Biol 2 267-271 Lazo JS, Sebti SM (1989) Malignant cell resistance to bleomycin to bleoymycin-group antibiotics. In Kessel D (ed) Anticancer drug resistance. CRC, Boca Raton, pp 276-279... 

There is no evidence that 5-fluorouracil becomes unable to penetrate tumor cells. There may be an increase in P-glycoprotein, but this is not usually associated with 5-fluorouracil. There may be an induction in the drug metabolism for some antineoplastic drugs, but this does not appear to be the case for 5-fluorouracil. Increased metallothionein content has been associated with resistance in the case of cisplatin but not 5-fluorouracil. 

Metallothionein expression in certain tumour cells has been associated with resistance to anticancer drugs. Increased resistance to chlorambucil occurred in cultured cells with a high concentration of cytoplasmic metallothionein (Endresen et al. 1983). Metallothionein inhibited hydroxyl radicalgenerated DNA degradation (Abel and Ruiter 1989). Satoh et al. (1994) showed that pretreatment of tumour-bearing ICR nude mice with zinc salts increased metallothionein content, both in normal and tumour tissues, with a marked reduction in the antitumour activity of cisplatin, Ad-riamycin , and melphalan. Metallothionein null cells have increased sensitivity to anticancer drugs (Kondo et al. 1995). 

Metallothionein is also induced by a variety of nonmetals, and exposure to these agents often can cause tesistance to anticancer drugs such as cisplatin (Basu and Lazo 1991). Expression of v mos can attenuate the glucocorticoid-induced metallothionein expression and cisplatin resistance. Transcriptional activation of c-Ha-ras oncogene expression in murine NIH 3T3 cells with dexamethasone produces an increase in metallothionein content and a decrease in cisplatin accumulation (Isonishi et al. 1991). The ability of dexamethasone to affect the sensitivity of cells to electrophilic antineoplastic agents could be of some clinical interest because of its frequent usage as an antiemetic. 

---