Drug database aids cancer research
multidrug resistance in cancerous tumours has been created which
identifies transport protein expression and drug resistance in
cancer cells.
The database will serve as a starting point for research into novel therapies designed either to evade or exploit the action of these transporters eventually increasing the effectiveness of some cancer drugs.
Scientists from the National Cancer Institute (NCI) created the database of information which detailed the gene expression of a 48-member family of proteins called ABC transporters and their resistance to specific drugs.
While the ABC transporters are mainly associated with drug resistance, the team also discovered an association between some of these proteins and an increase in effectiveness of some cancer drugs.
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.
The team discovered expression of MDR1 caused an increase in cancer cells' sensitivity to some drugs. This increase was unexpected, as MDR1 is best known as a multidrug resistance protein.
ABC transport proteins make an ideal target for drugs as they are embedded in the cell membrane and regulate molecule traffic, including hormones, lipids, and drugs in and out of the cells, many of these 48 proteins confer resistance to cancer drugs in humans.
Gergely Szakács, one of the study's lead authors 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."
While ABC proteins have implications for cancer treatment, previous studies have only identified 17 of them using much less sensitive techniques. The NCI team studied the ABC transporters in a group of cancer cell lines called the NCI-60 cells, which includes leukaemias, melonomas, and ovarian, breast, prostate, lung, renal, and colon cancers.
Real-time polymerase chain reaction was used to detect and quantify the expression of ABC transporter genes as messenger RNA in these cells. Results proved a statistical correlation between tests of the cell lines sensitivity to cancer drugs and these cells expression of ABC transporters.
Analysis of 68,592 ABC gene and drug relationships yielded 131 cases in which cells' ABC gene expression was strongly correlated with decreased sensitivity to the drug. Further tests, such as measuring changes in cell growth to evaluate the cells' response to the drugs, supported the statistical correlations.
According to Michael Gottesman, one of the paper's senior authors: "These results indicate some ABC transporters, whose function remains unknown, can influence the response of cells to cancer treatment."
This data will be used to find commonalities in compounds transported by MDR1. With this information, development of a drug to undermine MDR1's ability to transport drugs out of the cell can begin.
