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 2,900+ scientific posters on ePosters
  • More than 4,200+ 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

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
CRISPR-Cas9 Genome Editing Hurdle Overcome
Team re-engineers system to dramatically cut down on editing errors; improvements advance future human applications.
Thursday, December 03, 2015
Drug-Resistance Mechanism in Tumor Cells Unravelled
Targeting the RNA-binding protein that promotes resistance could lead to better cancer therapies.
Friday, October 23, 2015
Quantum Physics Meets Genetic Engineering
Researchers use engineered viruses to provide quantum-based enhancement of energy transport.
Friday, October 16, 2015
Viruses Join Fight Against Harmful Bacteria
Engineered viruses could combat human disease and improve food safety.
Friday, September 25, 2015
Targeting DNA
Protein-based sensor could detect viral infection or kill cancer cells.
Tuesday, September 22, 2015
Targeting DNA
Protein-based sensor could detect viral infection or kill cancer cells.
Tuesday, September 22, 2015
Searching Big Data Faster
Theoretical analysis could expand applications of accelerated searching in biology, other fields.
Thursday, August 27, 2015
A Metabolic Master Switch Underlying Human Obesity
Researchers find pathway that controls metabolism by prompting fat cells to store or burn fat.
Friday, August 21, 2015
Identifying a Key Growth Factor in Cell Proliferation
Researchers discover that aspartate is a limiter of cell proliferation.
Friday, July 31, 2015
Scientific News
Genetic Cause of Rare Allergy
Institute has identified a genetic mutation responsible for a rare form of inherited hives induced by vibratory urticaria.
Mitochondria Shown to Trigger Cell Ageing
An international team of scientists has for the first time shown that mitochondria, the batteries of the cells, are essential for ageing.
Cancer Cells Kill Off Healthy Neighbours
Cancer cells create space to grow by killing off surrounding healthy cells, according to UK researchers working with fruit flies.
Validating the Accuracy of CRISPR-Cas9
IBS Researchers create multiplex Digenome-seq to find errors in CRISPR-Cas9 processes.
Cancer Drug Target Visualized at Atomic Resolution
New study using cryo-electron microscopy shows how potential drugs could inhibit cancer.
Genetic Mechanism Behind Cancer-Causing Mutations
Researchers at Indiana University has identified a genetic mechanism that is likely to drive mutations that can lead to cancer.
"Gene Fusion" Drives Childhood Brain Cancers
Study co-led by Penn scientists highlights potential targets for future cancer therapies.
Enzyme Links Age-Related Inflammation, Cancer
Researchers have shown that an enzyme key to regulating gene expression -- and also an oncogene when mutated -- is critical for the expression of numerous inflammatory compounds that have been implicated in age-related increases in cancer and tissue degeneration.
How to Unlock Inaccessible Genes
An international team of biologists has discovered how specialized enzymes remodel the extremely condensed genetic material in the nucleus of cells in order to control which genes can be used.
Viral Gene Editing System Corrects Genetic Liver Disease
Penn study has implications for developing safe therapies for an array of rare diseases via new gene cut-and-paste methods.
Skyscraper Banner

Skyscraper Banner
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
2,900+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,200+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!