Featured Research

from universities, journals, and other organizations

Basis Of Anticancer Drug Resistance In Childhood Leukemia Revealed

Date:
April 18, 2008
Source:
St. Jude Children's Research Hospital
Summary:
The first analysis of the genetic determinants of resistance to the anti-cancer drug methotrexate in childhood acute lymphoblastic leukemia could offer a pathway to predicting such resistance and treatments to overcome it, according to a St. Jude Children's Research Hospital study.

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 Children's 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.

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."

Journal reference: Sorich MJ, Pottier N, Pei D, Yang W, Kager L, et al. (2008) In vivoresponse to methotrexate forecastsoutcome of acute lymphoblasticleukemia and has a distinct geneexpression profile. PLoS Med 5(4): e83.

Other authors include Deqing Pei, Wenjian Yang, Cheng Cheng, Ching-Hon Pui, Mary Relling, John Panetta and Meyling Cheok (St. Jude); Michael J. Sorich (University of South Australia); Nicolas Pottier (Pole Recherche, France); Leo Kager (St. Anna Children's Hospital, Austria); and Gabriele Stocco (University of Trieste, Italy).

This work was supported by National Institutes of Health grants, a Cancer Center Support Grant, a FM Kirby Clinical Research Professorship from the American Cancer Society and ALSAC.


Story Source:

The above story is based on materials provided by St. Jude Children's Research Hospital. Note: Materials may be edited for content and length.


Cite This Page:

St. Jude Children's Research Hospital. "Basis Of Anticancer Drug Resistance In Childhood Leukemia Revealed." ScienceDaily. ScienceDaily, 18 April 2008. <www.sciencedaily.com/releases/2008/04/080414221554.htm>.
St. Jude Children's Research Hospital. (2008, April 18). Basis Of Anticancer Drug Resistance In Childhood Leukemia Revealed. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2008/04/080414221554.htm
St. Jude Children's Research Hospital. "Basis Of Anticancer Drug Resistance In Childhood Leukemia Revealed." ScienceDaily. www.sciencedaily.com/releases/2008/04/080414221554.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
Powered by NewsLook.com
$23.6 Billion Awarded To Widow In Smoking Lawsuit

$23.6 Billion Awarded To Widow In Smoking Lawsuit

Newsy (July 20, 2014) Cynthia Robinson claims R.J. Reynolds Tobacco Company hid the health and addiction risks of its products, leading to the death of her husband in 1996. Video provided by Newsy
Powered by NewsLook.com
Tooth Plaque Provides Insight Into Diets Of Ancient People

Tooth Plaque Provides Insight Into Diets Of Ancient People

Newsy (July 19, 2014) Research on plaque from ancient teeth shows that our prehistoric ancestor's had a detailed understanding of plants long before developing agriculture. Video provided by Newsy
Powered by NewsLook.com
Contaminated Water Kills 3 Babies in South African Town

Contaminated Water Kills 3 Babies in South African Town

AFP (July 18, 2014) Contaminated water in South Africa's northwestern town of Bloemhof kills three babies and hospitalises over 500 people. The incident highlights growing fears over water safety in South Africa. Duration: 02:22 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins