STUDIES OF MULTIDRUG RESISTANCE IN MAMMALIAN CELLS

Project Details

Description

The development of resistance to chemotherapeutic agents is observed in the
clinic, and has been studied extensively in tissue culture cells. One
unusual phenotype is that of multidrug resistance, in which cells that are
challenged with any one of a variety of cytotoxic drugs develop resistance
not only to the selective agent but also cross-resistance to other,
seemingly unrelated, compounds. This multidrug-resistant (mdr) phenotype
is associated with the overproduction of membrane glycoproteins, including
p-glycoprotein, and in some cases with the overproduction of cytosolic
proteins as well. The phenotype is complex, therefore, and the genetic
basis for resistance and cross-resistance is obscured by the fact that the
differential amplification of multiple genes (which we call MDRA genes)
mediates the overproduction of the glycoproteins, whereas other coamplified
genes mediate the expression of at least one cytosolic protein and probably
other proteins as well. While the ultimate cause of multidrug resistance
is the lowered intracellular concentration of drug, the role of any of the
amplified gene products in the mechanism of resistance or cross-resistance
in model tissue culture systems and in human tumors refractory to
chemotherapy, remains obscure. With the use of recombinant DNA technology,
DNA transfection techniques, and nuclear runoff transcription assays, we
propose to define the role of the MDRA gene products in the establishment
of the mdr phenotype, and to identify other genes whose products may also
be involved in its expression. Additionally, when amplified, the
expression of MDRA genes can far exceed their gene copy number, suggesting
that overexpression is not mediated by amplification alone. We will,
therefore, determine the molecular basis for this enhanced expression for
it may indicate a mechanism for overexpression in the absence of
amplification. Finally, we propose to measure the levels of expression of
MDRA genes in a large number of human tumor cell lines and normal cell
lines, and tumors and normal tissues in an effort to determine the extent
to which these genes are expressed in human cells and whether their
overexpression can be shown to be associated with the resistance that many
patients display to a wide variety of chemotherapeutic agents.
StatusFinished
Effective start/end date6/1/875/31/99

Funding

  • National Institutes of Health: $187,462.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $219,797.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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