Mechanisms of multidrug resistance in human tumor cells. The roles of P-glycoprotein, DNA topoisomerase II, and other factors.

Multidrug resistance (MDR) associated with overexpression of P-glycoprotein (Pgp) is a well-described experimental phenomenon that appears to have clinical correlates. However, recent descriptions of non-P-glycoprotein forms of MDR have complicated efforts to detect and circumvent MDR in the tumors of patients. One major form of natural product MDR appears to be due to alterations in the amount of activity of DNA topoisomerase II. Compared to Pgp-MDR cells, cells expressing this form of MDR (at-MDR) do not overexpress the mdr1 gene or its product, Pgp, are unaltered in drug accumulation and retention, are unaffected by such 'modulators' of Pgp-MDR as verapamil, and express this phenotype recessively. Recently, other MDR cell lines have been described with some characteristics of Pgp-MDR (decreased drug accumulation and retention, increased drug cytotoxicity by modulators of MDR), but not others (no expression of the mdr1 gene or Pgp). Whether any non-Pgp forms of MDR occur in patients' tumors remains to be determined.