Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

How to Minimize the Side Effects of Cancer Treatment

Published: Monday, April 08, 2013
Last Updated: Monday, April 08, 2013
Bookmark and Share
Measuring enzyme levels in patients may reveal healthy cells’ ability to survive chemotherapy.

New research from MIT may allow scientists to develop a test that can predict the severity of side effects of some common chemotherapy agents in individual patients, allowing doctors to tailor treatments to minimize the damage.

The study focused on powerful cancer drugs known as alkylating agents, which damage DNA by attaching molecules containing carbon atoms to it. Found in tobacco smoke and in byproducts of fuel combustion, these compounds can actually cause cancer. However, because they can kill tumor cells, very reactive alkylating agents are also used to treat cancer.

The new paper, which appears in the April 4 issue of the journal PLoS Genetics, reveals that the amount of cellular damage that alkylating agents produce in healthy tissues can depend on how much of a certain DNA-repair enzyme is present in those cells. Levels of this enzyme, known as Aag, vary widely among different tissues within an individual, and among different individuals.

Leona Samson, a member of MIT’s Center for Environmental Health Sciences and the David H. Koch Institute for Integrative Cancer Research, is the senior author of the paper. She has previously shown that when alkylating agents damage DNA, the Aag enzyme is called into action as part of a DNA-repair process known as base excision repair. Aag cuts out the DNA base that is damaged, and other enzymes cleave the DNA sugar-phosphate backbone, trim the DNA ends and then fill in the empty spot with new DNA.

In this work, the researchers studied mice engineered to produce varying levels of Aag over a 10- to 15-fold range. This is similar to the natural range found in the human population.

The mice with increased levels of Aag resembled normal mice in their lifespan and likelihood of developing cancer, says Jennifer Calvo, a research scientist in Samson’s lab and lead author of the paper. However, “we found drastic differences when we started challenging them with these alkylating agents,” she says.

Mice with excessive or even normal levels of the Aag enzyme showed much greater levels of cell death in certain tissues after being treated with alkylating agents.

“It’s counterintuitive that extra DNA-repair capacity, or even the normal level, is bad for you,” says Samson, who is a professor of biological engineering and biology at MIT. “It seems that you can have too much of a good thing.”

A fine balance

It appears that too much Aag can upset the balance in the base excision repair pathway, the researchers say. This pathway involves several steps, some of which produce intermediates that can be extremely toxic to the cell if they do not promptly move to the next step. The researchers theorize that when Aag is too active, these toxic intermediates build up and destroy the cell.

Certain organs appear more vulnerable to this Aag-mediated tissue damage — in particular, the retina, pancreas, cerebellum and bone marrow — and the tissue damage is specific to certain types of cells within those tissues. Samson says all of the cells are likely experiencing similar DNA damage, but for some reason they don’t all respond the same way.

“It’s a very cell-specific phenomenon,” she says. “We haven’t completely gotten to the bottom of what it is that makes some cells behave in a certain way when they make zero or extra of a certain enzyme.”

That kind of specificity has not been seen before, notes Samuel Wilson, a principal investigator at the National Institute of Environmental Health Sciences. “It points to a different dynamic for base-lesion repair in different tissues,” says Wilson, who was not involved in the research. “That fundamental question of why there are tissue-specific differences would be very interesting to follow up on.”

The researchers found that an enzyme called Parp1 also plays an important role in Aag-related tissue damage. Parp1 helps to promote the  repair of single-stranded breaks in DNA; such breaks are readily produced after Aag cuts out a damaged base. When Parp1 recognizes such a break, it starts to coat itself with chains of molecules called PolyADP-ribose, which then helps to recruit some of the additional proteins needed to continue the repair process.

When there is too much Aag, Parp1 becomes overactive and begins to deplete the cell’s stores of NAD and ATP, which are critical for energy transfer in cells. Without enough NAD and ATP, the cell goes into an energetic crisis and dies.

Measuring levels of Aag, Parp1 and other enzymes before chemotherapy could be useful for doctors, not only to minimize side effects but also to maximize drugs’ effects on cancer cells, Samson says.

“Aag is just one of many enzymes that you’d probably want to know the level of, and in the end make some kind of matrix to determine what the therapeutic window would be,” she says. “We’re trying to develop ways of measuring the activity of a whole battery of different DNA repair pathways in one mega-assay.”


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,500+ scientific posters on ePosters
  • More than 5,000+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Linking RNA Structure and Function
Biologists have deciphered a lncRNA structure and used the information to investigate its cellular protein interactions.
Friday, September 09, 2016
Protecting Privacy in Genomic Databases
System helps ensure databases used in medical research will not leak patients’ personal information.
Wednesday, August 10, 2016
Triple-Action Therapy Patch Shows Promise
Patch that delivers drug, gene, and light-based therapy to tumor sites shows promising results in mice.
Wednesday, July 27, 2016
New Device can Study Electric Field Cancer Therapy
Microfluidic device allows study of electric field cancer therapy through low-intensity fields, preventing malignant cells spreading.
Friday, July 08, 2016
Illuminating Hidden Gene Regulators
New super-resolution technique visualizes important role of short-lived enzyme clusters.
Friday, May 27, 2016
A Programming Language for Living Cells
New language lets researchers design novel biological circuits.
Monday, April 04, 2016
Cancer Cells Remodel Environments Before Spreading
Researchers at MIT have found that the cancer cells remodel their environment to make it easier to reach nearby blood vessels.
Wednesday, March 16, 2016
Paving the Way for Metastasis
Cancer cells remodel their environment to make it easier to reach nearby blood vessels.
Tuesday, March 15, 2016
A New Way to Discover DNA Modifications
Researchers systematically find molecules that help regulate and protect DNA.
Wednesday, March 02, 2016
Mapping Regulatory Elements
Systematically searching DNA for regulatory elements indicates limits of previous thinking
Wednesday, February 03, 2016
Curing Disease by Repairing Faulty Genes
New delivery method boosts efficiency of CRISPR genome-editing system.
Wednesday, February 03, 2016
Supply Chain
Chemists discover how a single enzyme maintains a cell’s pool of DNA building blocks.
Wednesday, January 13, 2016
How Cancer Cells Spread
Study offers new targets for drugs that may prevent cancer from spreading.
Thursday, December 17, 2015
Scaling Up Synthetic-Biology Innovation
MIT professor’s startup makes synthesizing genes many times more cost effective.
Monday, December 14, 2015
Delivering microRNAs for Cancer Treatment
Scientists exploit gene therapy to shrink tumors in mice with an aggressive form of breast cancer.
Wednesday, December 09, 2015
Scientific News
Scientists Find Lethal Vulnerability in Treatment-Resistant Lung Cancer
The study describes how the drug Selinexor killed lung cancer cells and shrank tumors in mice when used against cancers driven by the aggressive and difficult-to-treat KRAS cancer gene.
Faecal Bacteria Linked to Body Fat
Researchers at King’s College London have found a new link between the diversity of bacteria in human poo – known as the human faecal microbiome - and levels of abdominal body fat.
How Baby’s Genes Influence Birth Weight And Later Life Disease
The large-scale study could help to target new ways of preventing and treating these diseases.
Genes Underlying Dogs’ Social Ability Revealed
The social ability of dogs is affected by genes that also seem to influence human behaviour, according to a new study from Linköping University in Sweden.
ReadCoor Launched to Commercialize 3D Sequencing Tech
ReadCoor will leverage the Wyss Institute’s method for simultaneously sequencing and mapping RNAs within cells and tissues to advance development of diagnostics.
NCI Collaborates with Multiple Myeloma Research Foundation
NCI collaborates with MMRF to incorporate genomic and clinical data into NCI Genomic Data Commons database.
Modified Yeast Shows Plant Response to Key Hormone
Researchers have developed a toolkit based on modified yeast to determine plant responses to auxin.
Epigenetic Clock Predicts Life Expectancy
New research finds 5 percent of population ages faster, faces shorter lifespan.
Blood Pressure Drug May Boost Effectiveness of Lung Cancer Treatment
Researchers at Imperial College London have suggested that the blood pressure drug may make a type of lung cancer treatment more effective.
Regulatory RNA Essential to DNA Damage Response
Researchers discover a tumour suppressor is stabilized by an RNA molecule, which helps cells respond to DNA damage.
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!