In a new study, researchers at St. Jude Children's Research Hospital have found the basis of resistance provided by anticancer drug, methotrexate in childhood acute lymphoblastic leukemia (ALL).
This first of its kind analysis of the genetic determinants of resistance to methotrexate in childhood ALL, could help researchers predict the pathway behind such resistance, thus paving the way for developing future treatments.
According to study head, Dr. William E. Evans, St. Jude hospital director and member of St. Jude Pharmaceutical Sciences, the in vitro tests of leukemia cells to explore the basis of resistance have not proved beneficial in case of methotrexate unlike other anti-leukemia drugs.
Thus for their study, the researchers analyzed the genetic profiles of 161 St. Jude patients undergoing methotrexate treatment for ALL to identify genes that governed their response to the drug. They measured the patients' response to initial methotrexate treatment and then used gene microarray analysis to measure the activity levels of 12,357 genes in the patients.
"In our analysis, we identified a large number of genes in the treated patients that differed in their expression level at a very significant level statistically. We elected to focus on the 50 most highly significant genes," said Evans.
These genes also included those involved in DNA synthesis, its components and repair of DNA. Distinct gene expression "profiles" among the groups were found after comparing the gene expression patterns of patients who responded well to methotrexate to those who responded poorly. Also, patients with profiles having a good methotrexate response had significantly better five-year, disease-free survival than those with profiles indicating a poor response.
Analyzing the predictive effects of those distinctive profiles in an independent group of 18 patients, they found that the gene expression profiles for the top 50 genes also predicted methotrexate response in those patients.
Further research of the genes identified in this study could yield clinical benefits as Evans said: "Some of these could become potential targets for developing other drugs that would make methotrexate more effective in those children who are resistant."
For example, one gene they identified as relevant to resistance produces a protein that transports the drug out of the leukemia cell
The researchers are planning to conduct further studies to search for such drug targets.
The findings of this study are reported in the recent issue of "PLoS Medicine."