Chlorambucil Resistance

H6. Hall, A., Robson, C. N., Hickson, I. D., Harris, A. L., Proctor, S. J., and Cattan, A. R., Possible role of inhibition of glutathione S-transferase in the partial reversal of chlorambucil resistance by indomethacin in a Chinese hamster ovary cell line. Cancer Res. 49, 6265-6268 (1989). 

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). 

Bakka et al. (1981) were among the first to suggest a role for metals in resistance to electrophilic anticancer drugs when they noted mammalian cells made chronically resistant to Cd were cross-resistant to the toxic effects of cisplatin. In subsequent studies they found the sensitivity of Cd-resistant cells was reduced by 1.5- to 3-fold not only to cisplatin but also to chlorambucil and prednimustine (Endresen et al. 1983 Endresen and Rugstad 1987). Andrews et al. (1987) and Kelley et al. (1988) confirmed that Cd-resistant human tumor cells were cross-resistant to cisplatin. Moreover, Andrews et al. (1987) demonstrated that Cd-resistant cells did not have a decreased uptake of radiolabeled cisplatin. Webber et al. (1988) examined the sensitivity of Cd-resistant human DU-145 prostate cells to the anthra-cycline doxorubicin. A very modest (1.5-fold) resistance to doxorubicin was observed but the specificity of this resistance with respect to other antineo-plastic agents was not determined. 

Endresen L, Rugstad HE (1987) Protective function of metallothionein against certain anticancer agents. Experientia 52 595-602 Endresen L, Bakka A, Rugstad HE (1983) Increased resistance to chlorambucil in cultured cells with a high concentration of cytoplasmic metallothionein. Cancer Res 43 2918-2926... 

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