Figure 20.12 Dose response of the effects of an anti-Fas antibody on apoptosis (cell survival) in sensitive and doxorubicin (S and Dox40 respectively) in cell culture. (Adapted from Landowski et al., 1997, with permission of the authors and publisher.)

This finding further establishes and relates apoptosis resistance as a mechanism of drug resistance to the alterations in glutathione metabolism that are similarly related to drug resistance.

Glutathione and Related Enzymes in Multidrug Resistance

As noted in Chapter 8, glutathione and the enzyme glutathione peroxidase play important roles in the inhibition of active oxygen radical-induced alterations in cellular metabolism. These reactions appear to play a similar role in the metabolism and resistance to some chemotherapeutic agents (Morrow and Cowan, 1990). But perhaps more important in drug resistance is the family of glutathione S-transferases. These are phase II (Chapter 3) enzymes involved in the conjugation of a variety of substrates, many of which include drugs used in the chemotherapy of cancer or their metabolites. A listing of these is seen in Table 20.9, adapted from the review by O'Brien and Tew (1996). A variety of human neoplasms exhibit altered levels of glutathione-metaboliz-ing enzymes, as can be noted from Table 20.10.

Table 20.8 Evaluation of the Frequency of bcl-2 Overexpression in Different Cancers




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