Technology reveals gene-drug interactions
change patients' responses to cancer drugs and other medications.
By identifying genetic factors affecting patients drug responses,
customisable treatment plans may become a distinct reality.
Differences in a person's genes can change a drug that is a lifesaver for some patients into a toxin for others. The technique could influence whether a medication provides little benefit or is a remarkably effective treatment.
In a study published in the August 10 Proceedings of the National Academy of Sciences, investigators found potential connections between two chemotherapy drugs and two regions of human DNA that contain approximately 100 genes each.
Scientists exposed cells to varying doses of two chemotherapy drugs, 5-fluorouracil and docetaxel. The cells were non-cancerous, but chemotherapy can kill both cancerous and non-cancerous cells. Chemotherapy is given as a treatment for cancer because cancer cells are generally more sensitive to its effects, but many factors, including the genetics of the cells' non-cancerous precursors, can influence that sensitivity.
Howard McLeod, senior investigator of the study said: "This isn't the answer to everything in terms of finding these links, but it's an important breakthrough."
"This approach is very likely to allow us to find links between pharmaceuticals and genes that we never would have been able to anticipate."
Scientists used a robotic screening system to look for cell lines with increased sensitivity to the drugs, demonstrated by higher numbers of cell deaths in response to low drug doses. The robot also highlighted cell lines with high resistance to drugs where few or no cells were killed.
The initial test of the new approach found connections between increased sensitivity to the drugs and areas on chromosomes 5 and 9.
McLeod commented: "That part of chromosome 9 turned up in an earlier search we conducted for these genes. We're definitely going to be looking for a gene that affects sensitivity in this region."
The scientists compared and contrasted the genetics of a cell line with altered sensitivity to cell lines from other family members and from multiple generations of the same family.
Children get a random mixture of genes from both parents, so both genetic markers and changes in sensitivity are sometimes passed from parent to child and sometimes aren't. When a particular genetic marker is consistently passed from parent to child at the same time as a change in sensitivity, that tells scientists they need to look near the marker for a gene that changes sensitivity.
In the future, patients whose cells are particularly sensitive to chemotherapy may be able to be treated with relatively low doses, reducing side effects. Patients whose cells are particularly resistant may need special or added medications to assure a good outcome.
The researchers, from the University of Washington, have applied this new screening technique to six more cancer drugs, but they've just begun to find ways to use the new approach. Despite the advances, the study is still in its infancy.
James W. Watters, lead author of the study was quick to point out: "This is not a cancer research technique, it's a drug research technique"
"We want to find ways to look at new endpoints. For example, how thoroughly does a drug hit its target of interest, or how much can it slow growth or other cellular processes? Then we'll be able to look at genetic effects on medications for a range of disorders."
