Navigation Links
St. Jude gene study reveals basis of anticancer drug resistance in childhood leukemia
Date:4/15/2008

The first analysis of the genetic determinants of resistance to the anti-cancer drug methotrexate in childhood acute lymphoblastic leukemia (ALL) could offer a pathway to predicting such resistance and treatments to overcome it, according to a St. Jude Childrens Research Hospital study.

Besides its use in ALL, methotrexate is widely used to treat other cancers and some autoimmune diseases. However, until the new study there was no valid test for analyzing the genetic basis of resistance. Such genetic analysis is important in childhood ALL because, although 80 percent of children with the disease can be cured, determining the basis of drug resistance in the other 20 percent would help increase the cure rate.

The researchers, led by Dr. William E. Evans, St. Jude hospital director and member of St. Jude Pharmaceutical Sciences, reported their findings in the April 2008 issue of PLoS Medicine.

Researchers have successfully used laboratory studies of leukemia cells to explore the basis of resistance in other anti-leukemia drugs. However, according to Evans, such in vitro tests have not worked with methotrexate. The researchers analyzed the genetic profiles of St. Jude patients undergoing methotrexate treatment for ALL to identify genes that governed their response to the drug.

In their study of 161 ALL patients, they measured the response to initial methotrexate treatment and then used gene microarray analysis to measure the activity levels of 12,357 genes in the patients. In microarray analysis, researchers apply genetic material from the patients leukemia cells to small gene chips on which samples of thousands of genes are arrayed. Researchers can analyze the reactions on the gene chip to each gene to measure the level of expression for those genes in the patient samples.

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, Evans said. We elected to focus on the 50 most highly significant genes.

Among the genes were those involved in DNA synthesis, its components and repair of DNA. The identity of some of these genes was not surprising because the drug kills leukemia cells by interfering with their ability to replicate their DNA.

When the researchers compared the gene expression patterns of patients who responded well to methotrexate to those who responded poorly, they found distinct gene expression profiles among the groups. In further analysis to validate their findings, they found that the profiles predicted methotrexate response in an independent group of patients: Patients with gene expression profiles indicating a good methotrexate response had significantly better five-year, disease-free survival than those with profiles indicating a poor response.

To confirm their findings, the researchers also analyzed 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 exploration of the genes identified in this study could yield clinical benefits. Some of these could become potential targets for developing other drugs that would make methotrexate more effective in those children who are resistant, Evans said.

For example, one gene they identified as relevant to resistance produces a protein that transports the drug out of the leukemia cell. It might be possible to give a drug along with methotrexate that blocks this transporter, which would make methotrexate more effective without having to give another cytotoxic drug, Evans said.

In further studies, the researchers plan to search for such drug targets. They will also search for subtle genetic differences among patients in the response-related genes in search of inherited genetic differences that might explain gene expression and methotrexate response. Finally, the researchers will explore whether patients who respond poorly to methotrexate have specific gene deletions or other genetic alterations in their leukemia cells that cause such poor response.

The findings broadly confirm the value of such sweeping surveys of gene expression in understanding response to anti-cancer drugs.

Studies such as these add another piece of evidence that this genome-wide approach is very insightful and helpful and informative, Evans said. If you simply look for the genes that you think might be important, you are likely to miss a number of genes that are.


'/>"/>

Contact: Carrie Strehlau
media@stjude.org
901-495-2295
St. Jude Children's Research Hospital
Source:Eurekalert

Related medicine news :

1. Penn study finds pro-death proteins required to regulate healthy immune function
2. New study shows promise in reducing surgical risks associated with surgical bleeding
3. Study, meta-analysis examine factors associated with death from heatstroke
4. Study suggests loss of 2 types of neurons -- not just 1 -- triggers Parkinsons symptoms
5. Study says COPD testing is not measuring up
6. Preclinical study suggests organ-transplant drug may aid in lupus fight
7. Ability to cope with stress can increase good cholesterol in older white men, study finds
8. High alcohol consumption increases stroke risk, Tulane study says
9. Mailman School of Public Health study examines link between racial discrimination and substance use
10. Pitt study finds inequality in tobacco advertising
11. Stanford study highlights cost-effective method of lowering heart disease risks
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/3/2016)... ON (PRWEB) , ... May 03, 2016 , ... ... recognized as one of Canada’s top Information and Communication Technology (ICT) companies in ... Canadian and Multinational ICT companies operating in Canada, as ranked by revenue. ...
(Date:5/3/2016)... CA (PRWEB) , ... May 03, 2016 , ... ... a special type of surgical procedure that can be used to diagnose and treat ... instruments can be inserted. These instruments include a special lighting system and lens that ...
(Date:5/3/2016)... ... May 03, 2016 , ... ... connectivity solutions, today announced the new SecureAccess feature for its CelestixEdge solution. ... SecureAccess release will enable organizations to get the DirectAccess user experience on ...
(Date:5/3/2016)... ... ... LunchSkins is changing the future of ocean plastic pollution by launching ... baggies. The mission-driven bags give back to global leaders in the fight to end ... is all about reducing global plastic waste and we’ve teamed up with some powerful ...
(Date:5/3/2016)... (PRWEB) , ... May 03, ... ... Carnival Cruise Lines premiered the state-of-the-art Carnival Vista – the line’s largest ... ship, The Cruise Web has created an infographic spotlighting the Carnival ...
Breaking Medicine News(10 mins):
(Date:5/3/2016)... May 3, 2016  While you may be familiar with watching a film or TV show ... as ultra-high-definition or 8MP in the Medical Industry.  Ampronix  is a renowned authorized reseller of ... Photo - http://photos.prnewswire.com/prnh/20160502/362730 ... ... ...
(Date:5/3/2016)... DUBLIN , May 3, 2016 ... to pay $55 million to a woman who says ... State court awarded Gloria Ristesund $5 million ...      (Logo: http://photos.prnewswire.com/prnh/20160330/349511LOGO ) , ... of accusations against the company. In February, the same ...
(Date:5/3/2016)... May 3, 2016 Intec Pharma ... clinical-stage biopharmaceutical company, today announced the appointment of ... Affairs. "Ms. Strauss-Levy has 15 years of ... established an outstanding track record, having supported the advancement ... approval processes in the United States ...
Breaking Medicine Technology: