Multidrug resistance (MDR) refers to a complex phenotype that describes a number of features characterized primarily by resistance to a wide range of structurally unrelated drugs. In this paper we investigated the relationship between drug resistance and resistance to NK-mediated cytotoxicity. Studies with two independently selected multidrug-resistant cell lines indicated that increased drug resistance was associated with both an increased resistance to NK-mediated cytotoxicity and increased levels of membrane P-glycoprotein expression. This resistance to cytotoxicity appears to result partly from an alteration in the membrane structure of the target cells inasmuch as there was a reduction in effector:target cell recognition. Resistance to NK-mediated cytotoxicity should be included with the numerous pleiotropic changes associated with the multidrug resistance phenotype.
The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed Pglycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.Cultured cells and transplantable tumors selected for resistance to a single drug can often acquire cross resistance to a wide range of drugs which differ in mode of action, target, and structure (9). This phenotype, called multidrug resistance, parallels the clinical observation that patients whose malignancies recur after primary therapy are often nonresponsive to subsequent combination chemotherapy. A central role for an integral plasma membrane glycoprotein, P-glycoprotein, in mediating multidrug resistance is supported by different observations (9). (i) Independent multidrug-resistant clones selected in our laboratory and those of others consistently overexpress P-glycoprotein (5, 9-12). (ii) Increases in the level of drug resistance are matched by increases in the amount of P-glycoprotein expressed at the cell surface (9-11). (iii) Single-step revertants to wild-type levels of drug resistance show a simultaneous decrease in the level of P-glycoprotein expression to near wild-type levels (10, 11). (iv) P-glycoprotein is highly conserved, and multidrug-resistant tissue culture mutants of hamster, mouse, and human origin all display elevated levels of P-glycoprotein (9-11). (v) The location of P-glycoprotein in the plasma membrane is consistent with a functional role for this molecule in view of the results of drug uptake studies. Such studies have shown that the phenotype is a result of a reduced net intracellular accumulation of drugs (for reviews, see references 2 and 18) and that agents which act on the membrane, such as anaesthetics, nonionic detergents, and calcium channel antagonists, alter the expression of multidrug resistance (for a review, see reference 18).Despite the close correlation between P-glycoprotein overexpression and multidrug resistance, there is no direct evidence that P-glycoprotein overexpression is the causative * Corresponding author. molecule in multidrug resistance. We have isolat...
The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.
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