R

Figure 20.11 Proposed mechanism of action of P-glycoprotein as a "hydrophobic vacuum cleaner." As noted in the model, the multidrug transporter may remove drugs directly from the plasma membrane or from the cytoplasm through a single transport channel, as illustrated. (After Gottesman, 1993, with permission of the author and publisher.)

Figure 20.11 Proposed mechanism of action of P-glycoprotein as a "hydrophobic vacuum cleaner." As noted in the model, the multidrug transporter may remove drugs directly from the plasma membrane or from the cytoplasm through a single transport channel, as illustrated. (After Gottesman, 1993, with permission of the author and publisher.)

curs predominantly in the liver. While it is possible that some other chemotherapeutic agents requiring phase I metabolic activation may do so at very reduced rates in neoplastic cells, thus leading to drug resistance, it appears that the changes in the phase I enzymes, especially those involved in glutathione metabolism, are probably the most important in this potential mechanism of drug resistance (cf. Graham et al., 1991; cf. Iyer and Ratain, 1998).

DNA Repair Mechanisms and Cellular Resistance to Chemotherapeutics

As noted in Chapter 3, the cell contains a variety of mechanisms responsible for the repair of damaged DNA. Closely related to this fact is also the finding that a large number of neoplasms exhibit mutations in genes whose products are involved in the recovery of cells from DNA damage, such as the p53 gene. In examining the various types of DNA repair noted in Table 3.4, there is ample evidence that the O6-alkylguanine-DNA alkyltransferase (AGAT) enzyme, when expressed at high levels, enhances the resistance of a cell, normal or neoplastic, to alkylating agents that produce O6-alkylguanine. Transgenic mice expressing increased levels of AGAT

Table 20.7 Gene Amplification Induced by Chemotherapeutic Drugs

Drug

Gene (fold amplification)

Reference

Difluoromethylornithine

Ornithine decarboxylase (?)

Leinonen et al., 1987

Hydroxyurea

Ribonucleotide reductase (6-20)

Srinivasan et al., 1987

Methotrexate

Dihydrofolate reductase (100-1000)

Schimke, 1984

Nitrogen mustards

Glutathione S-transferase (4-8)

Lewis et al., 1988

0 0

Post a comment