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Figure 20.8 Diagram of drug schedule and cell killing in mice inoculated with the L-1210 leukemia. At day 0 the animal is inoculated with 105 cells. The subsequent four conditions (A, B, C, and D) represent the growth curves of the cells under several different drug regimens as described in the text. (After Skipper, 1965, with permission of the author and publisher.)

Figure 20.8 Diagram of drug schedule and cell killing in mice inoculated with the L-1210 leukemia. At day 0 the animal is inoculated with 105 cells. The subsequent four conditions (A, B, C, and D) represent the growth curves of the cells under several different drug regimens as described in the text. (After Skipper, 1965, with permission of the author and publisher.)

transmembrane regions as well as two large intracytoplasmic components. A diagram of its appearance and possible mechanism of action is seen in Figure 20.11. In the figure a cationic drug, such as doxorubicin, is shown entering the plasma membrane and subsequently a "pore" of the P-glycoprotein either within the membrane or from the cytoplasm. Such transport back to the outside of the cell requires energy, as noted in the figure (Gottesman, 1993). The P-glycoprotein occurs in normal tissues, especially those involved in major physiological transport mechanisms such as the liver, intestine, kidney, and brain (Schinkel, 1997). In these tissues, especially in the gut, the presumed function is to remove potentially deleterious exogenous materials from the cell rapidly. In neoplasms, expression of high levels of the P-glycoprotein usually is associated with a poor prognosis with a variety of different neoplasms (cf. Bellamy, 1996; Dicato et al., 1997).

The P-glycoprotein is one member of a large superfamily of similar transport protein complexes termed the ABCsuperfamily (Bellamy, 1996). Several transport proteins involving non-P-glycoprotein-mediated multidrug resistance have also been described (cf. Bellamy, 1996; Ya-

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