MULTIDRUG RESISTANCE PROTEIN: P-GLYCOPROTEIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 245

to establish. Some tumors express Pgp before chemotherapy treatment (e.g., colorec-
tal and renal cancers), while in others, expression increases after exposure to MDR
drugs (e.g., leukemias, lymphomas, myeloma, and breast and ovarian carcinomas).
In general, patients with Pgp-positive tumors respond less well to chemotherapy
and have a poorer outlook and long-term survival. There is strong evidence linking
Pgp expression with poor response to chemotherapy in acute myelogenous leukemia
(AML). 196 , 197
Studies to validate the role of MDR reversal in the treatment of various malig-
nancies are under way; there have been some partial successes, and many failures.
However, there is still no consensus on the useful of MDR modulators in treating hu-
man cancers, and the controversy is likely to continue. 198 , 199 Four contributing factors
make the results of many clinical trials with modulators uninterpretable. First, there
is a need to establish whether a patient's tumor contains Pgp and whether the level
is clinically significant. Second, many modulator clinical trials have used first- and
second-generation compounds that are poorly effective at the clinically achievable
dose. This limitation will hopefully be overcome by new, more potent and specific
third-generation Pgp modulators. A third factor is that modulators affect the disposi-
tion of other drugs, either by decreasing drug elimination via Pgp or by inhibiting drug
metabolism via cytochrome P450. Cancer patients treated with both chemotherapy
drugs and a modulator are thus exposed to higher levels of anticancer drug, which
confounds interpretation of the results. In some trials, the dose of anticancer drug
was lowered to avoid toxicity and allow direct comparison of results from the two
study arms. Finally, tumors have multiple, often redundant mechanisms of cellular
resistance to drugs. 200 Not only do tumor cells have other defense mechanisms at
their disposal, they can also express other multidrug efflux pumps. Thus, the potential
contribution of Pgp to drug resistance in a tumor is very difficult to assess. Modula-
tion of Pgp in tumors is likely to be accompanied by altered Pgp function in normal
tissues. 201 However, in some trials, tumor regression was obtained without apparent
increases in normal tissue toxicity. There have been suggestions that MDR modu-
lation may delay the emergence of clinical drug resistance. Thus, administration of
modulators in the earlier stages of cancer may prevent drug resistance.
10.16. REGULATION OF P-GLYCOPROTEIN EXPRESSION
Cells adapt to the presence of toxic xenobiotics in their environment by up-regulation
of drug efflux pumps, such as Pgp, which provides them with a long-term survival
advantage. The MDR1 gene is activated, and a stable MDR phenotype induced, after
short-term exposure of cells to a variety of environmental insults. This response is
of fundamental importance in the case of emergence of MDR in tumor cells exposed
to anticancer drugs. MDR1 expression may be up-regulated by two mechanisms: an
increase in the amount of MDR1 message by transcriptional regulation, and stabiliza-
tion of the mRNA. A considerable amount is now known about the transcriptional
regulation of ABC proteins, including the MDR1 gene. 202-204 Transcription of a par-
ticular gene is determined by various response elements present within the promoter