Scientists Establish Database of Genes Associated With Cancer Drug Resistance
Scientists at the National Cancer Institute (NCI), a part of the
National Institutes of Health, have created a database of information
about a group of genes associated with multidrug resistance in cancerous
tumors. The research, published in the August 22, 2004, issue of
Cancer Cell*, details the gene expression of a 48-member family
of proteins called ABC transporters. The NCI scientists identified
associations between expression of individual ABC transporters in
cancer cells and resistance to specific drugs.
Though ABC transporters are primarily associated with drug resistance,
the researchers report an association between some of these proteins
and an increase in effectiveness of some cancer drugs. Their database
should serve as a starting point for research into novel therapies
designed to either evade or exploit the action of ABC transporters.
ABC transport proteins are embedded in the cell membrane and regulate
traffic of many molecules, including hormones, lipids, and drugs,
in and out of the cell. Because they transport toxic materials out
of cells, many of these 48 proteins confer resistance to cancer
drugs in humans. The study’s lead authors were Jean-Philippe
Annereau, Ph.D., and Gergely Szakács, M.D., Ph.D., both visiting
fellows at NCI’s Center for Cancer Research (CCR). Szakács
said, “Multidrug resistance is a major barrier to effective
cancer chemotherapy, and even low levels of resistance can have
a significant impact on the efficacy of chemotherapy.”
Though these proteins have major implications for the treatment
of cancer, previous studies had characterized only 17 of them using
much less sensitive techniques. Szakács and Annereau studied
the ABC transporters in a group of cancer cell lines called the
NCI-60 cells, which includes leukemias, melanomas, and ovarian,
breast, prostate, lung, renal, and colon cancers.
They used the real-time polymerase chain reaction to detect and
quantify the expression of ABC transporter genes as messenger RNA
in these cells. With help from collaborators in the laboratory of
John Weinstein, M.D., Ph.D., also in CCR, the researchers found
statistical correlations between tests of the cell lines’
sensitivity to cancer drugs and these cells’ expression of
ABC transporters. Further tests, such as measuring changes in cell
growth to evaluate the cells’ response to the drugs, supported
the statistical correlations.
Analysis of 68,592 ABC gene and drug relationships yielded 131 strongly
inverse-correlated pairs that is, in these 131 cases, cells’
ABC gene expression was strongly correlated with decreased sensitivity
to the drug. Michael Gottesman, M.D., one of the paper’s senior
authors and chief of the Laboratory of Cell Biology in CCR, said,
“These results indicate that some of the ABC transporters
whose function remains unknown can influence the response of cells
to cancer treatment.”
Gottesman, Szakács, and colleagues hope this data will be
used to find commonalities in compounds transported by MDR1, one
of the ABC proteins most strongly associated with multidrug resistance.
With this information, they could begin developing a drug to undermine
MDR1’s ability to transport drugs out of the cell.
Expression of some ABC transporters, most notably MDR1, caused
an increase in cancer cells’ sensitivity to some drugs. This
increase was unexpected, as MDR1 is perhaps the best-known multidrug
resistance protein. The researchers advocate further research in
order to discover even more compounds that interact in this way
with MDR1 and other ABC transporters. For more information about
cancer, please go to http://cancer.gov.
* Szakács G and Gottesman MM. "Predicting drug sensitivity and resistance: Profiling ABC transporter genes in cancer cells." Cancer Cell. 22 August 2004.