Intravenous nutrition source could reduce side effects of chemotherapy

Carnegie Mellon researchers show that Intralipid can also increase the effectiveness of cancer-fighting nanodrugs.

A single dose of an FDA-approved intravenous nutrition source may be able to significantly reduce the toxicity and increase the bioavailability of platinum-based cancer drugs, according to a study by Carnegie Mellon University biologists published in Scientific Reports.

Platinum-based drugs, including cisplatin, carboplatin and oxyplatin, have been used to treat cancer for more than 35 years. While they remain among the most prescribed and most potent chemotherapy drugs, they also cause serious side effects, including kidney damage.

Many of the side effects of these drugs occur when the drug settles in healthy tissue. To deliver these drugs in a more targeted way, researchers have created nanoscale delivery systems engineered to make the drug reach and accumulate at the tumor site. However, tests of these nanodrugs show that only between one and 10 percent of the drugs are delivered to the tumor site, with the majority of the remainder being diverted to the liver and spleen.

The body’s immune system, especially the liver and spleen, has been one of the biggest stumbling blocks in developing nanoscale chemotherapy drug delivery systems,’ said Chien Ho, the alumni Professor of biological sciences at Carnegie Mellon. ‘When the drugs collect in those organs, they become less available to treat the cancer, and can also cause toxicity.’

In the past few years, Ho and his colleagues were developing cellular nanotags to help detect organ rejection, when Ho noticed that Intralipid, a fat emulsion that is FDA-approved for use as an intravenous nutrition source, reduced the amount of nanoparticles that were being cleared by the liver and spleen by about 50 percent. As a result, the nanoparticles remained in the blood stream for longer periods of time.

Ho and his colleagues decided to see if Intralipid had the same effect on platinum-based anti-cancer nanodrugs. In the newly published study, the researchers administered a single, clinical dose of Intralipid to a rat model. One hour later, they administered a dose of a platinum-based chemotherapy drug that had been incorporated into a nanoparticle.

Twenty-four hours after the drug was administered, the researchers found that pre-treatment with Intralipid reduced the accumulation of the platinum-based drug by 20.4 percent in the liver, 42.5 percent in the spleen and 31.2 percent in the kidney. Consequently, in these organs, the toxic side effects of the nanodrug decreased significantly. Furthermore, the researchers found that Intralipid pre-treatment allowed more of the drug to remain available and active in the body for longer periods of time. After five hours, availability of the drug was increased by 18.7 percent, and after 24 hours it was increased by 9.4 percent. The researchers believe that this increased availability will allow more of the drug to reach the tumor site, and could perhaps also allow clinicians to reduce the dosage needed to treat a patient.

The researchers are currently investigating the possibility of bringing this research to a clinical trial.

Lui et al. A new approach to reduce toxicities and to improve bioavailabilities of platinum-containing anti-cancer nanodrugs. Scientific Reports 2015;5:10881 doi:10.1038/srep10881 [Article]

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New computational model could design medications like chemotherapy with fewer side effects

Medications, such as chemotherapy, are often limited by their tendency to be detrimental to healthy cells as an unintended side effect. Now research in the Cell Press’s Biophysical Journal offers a new computational model that can help investigators design ways to direct drugs to their specific targets.

A major problem with many cancer drugs is the harmful effects they can have on normal cells. Similarly, treatments for a variety of other diseases can have side effects by acting on cells that are not meant to be targeted. Researchers have tried to overcome this by linking drugs to antibodies, for example by linking a chemotherapy agent to an antibody that specifically attaches to cancer cells to create a fusion protein. However, it can be difficult to do so without compromising the medication’s effectiveness because the drug has to be able to reach its targeted cell receptor at the same time as the antibody binds to its own target on the cell.

Investigators have now developed a computational model to help design the most effective way to link an antibody to a therapeutic drug to create such a fusion protein. The model takes into consideration how the length of an antibody linker will affect a drug’s ability to interact with its target and uses this information as well as other parameters to model and predict how a particular fusion protein will look geometrically, how it will act when applied to cells, and what concentration is optimal.

The importance of this finding is that it has the potential to allow us to predict the behavior of fusion proteins without having to physically make them, eliminating unsuccessful candidates for drug design using modeling and thereby saving time and effort,” explains senior author Dr. Pamela Silver, of Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering at Harvard University. Therefore, accurately modeling the behavior associated with a given design for a fusion protein could allow researchers to move away from a screening-based, guess-and-check method to one that is based on rational design. “Using modeling as a first step of validation will allow us to determine which constructs are likely to be promising and focus our efforts on the best candidates for testing,” says lead author Dr. Avi Robinson-Mosher, of the Wyss Institute.

The scientists verified their approach by creating various geometric combinations of antibody fragments and therapeutic molecules with linkers of different lengths, then successfully demonstrated that each fusion protein’s effectiveness could be predicted through their model.

This study is important because it provides a roadmap for how to design more selective, less toxic chemotherapies,” adds Dr. Leslie Loew, Director of the R. D. Berlin Center for Cell Analysis and Modeling at the University of Connecticut Health Center and Editor in Chief of Biophysical Journal. “It is especially impressive that these researchers not only developed very elegant computational models, but then went to the lab to verify the predictions with experiments.”

Robinson-Mosher et al. Designing cell targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding. Biophys J. 2014;107(10):2456–2466 DOI: http://dx.doi.org/10.1016/j.bpj.2014.10.007 [Abstract]

The Side Effects of Chemotherapy on the Body

Chemotherapy drugs are powerful enough to kill rapidly growing cancer cells, but they also can harm perfectly healthy cells, causing side effects throughout the body.

Cancer cells divide more quickly than healthy cells, and chemotherapy drugs effectively target those cells. Unfortunately, fast-growing cells that are healthy can be damaged too. There are many different chemotherapy drugs with the potential for many different side effects. These effects vary from person to person and from treatment to treatment.

Factors that play a role in side effects include other ongoing treatments, previous health issues, age, and lifestyle. Some patients experience few side effects while others feel quite ill. Although most side effects clear up shortly after treatment ends, some may continue well after chemotherapy has ended, and some may never go away.

Chemotherapy drugs are most likely to affect cells in the digestive tract, hair follicles, bone marrow, mouth, and reproductive system. However, cells in any part of the body may be damaged.

– See more at: http://www.healthline.com/health/cancer/effects-on-body#sthash.ZbSMeewY.dpuf

Metal implants may cut chemotherapy side effects

Cancer patients could one day experience fewer side effects from chemotherapy following a discovery that opens the door for more targeted treatments.

Researchers have identified a possible way of treating tumours that would see doctors place harmless metal implants at the cancer site.The discovery could make treatment more targeted than existing therapies, avoiding unwanted side effects, such as hair loss, tiredness and nausea. These occur when chemotherapy drugs carried in the blood kill healthy cells as well as cancer cells. The scientists found that they could alter the chemical composition of commonly used chemotherapy drugs so that they only become active when they come into contact with a metal called palladium.

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Scientists have developed modified chemotherapy drugs that are designed to remain inactive until they come into contact with a palladium implant located at the tumor site. The hope is that this approach could help reduce side effects associated with treatment by minimizing damage to the rest of the body.
Credit: Asier Unciti-Broceta

Researchers hope that by implanting small devices coated with palladium into patients’ tumours, the drugs would become activated only where they are needed, causing minimal damage to the rest of the body. The scientists reported their discovery today in the journal Nature Communications but the approach will first need to be tested in animals before it can be studied in patients.

The research was led by scientists from the Edinburgh Cancer Research UK Centre at the MRC Institute of Genetics and Molecular Medicine, the University of Edinburgh.

Dr Asier Unciti-Broceta, who led the study, said: “It will be several years before we’re able to start treating patients but we’re hopeful that this approach will lead to better tolerated cancer therapies in the future.”

Weiss et al., (2014). Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat. Comm., 5:3277 doi:10.1038/ncomms4277 [Article]

Grape seed promise in fight against bowel cancer

University of Adelaide research has shown for the first time that grape seed can aid the effectiveness of chemotherapy in killing colon cancer cells as well as reducing the chemotherapy’s side effects.

Published in the prestigious journal PLOS ONE, the researchers say that combining grape seed extracts with chemotherapy has potential as a new approach for bowel cancer treatment – to both reduce intestinal damage commonly caused by cancer chemotherapy and to enhance its effect.

Lead author Dr Amy Cheah says there is a growing body of evidence about the antioxidant health benefits of grape seed tannins or polyphenols as anti-inflammatory agents and, more recently, for their anti-cancer properties.

This is the first study showing that grape seed can enhance the potency of one of the major chemotherapy drugs in its action against colon cancer cells,” says Dr Cheah, researcher in the School of Agriculture, Food and Wine.

Our research also showed that in laboratory studies grape seed taken orally significantly reduced inflammation and tissue damage caused by chemotherapy in the small intestine, and had no harmful effects on non-cancerous cells. Unlike chemotherapy, grape seed appears to selectively act on cancer cells and leave healthy cells almost unaffected.”

The researchers used commercially available grape seed extract, a by-product of winemaking. Tannins extracted from the grape seed were freeze-dried and powdered. The extract was tested in laboratory studies using colon cancer cells grown in culture.

The research showed grape seed extract:

    • showed no side effects on the healthy intestine at concentrations of up to 1000mg/kg;
    • significantly decreased intestinal damage compared to the chemotherapy control;
    • decreased chemotherapy-induced inflammation by up to 55%
    • increased growth-inhibitory effects of chemotherapy on colon cancer cells in culture by 26%

Our experimental studies have shown that grape seed extract reduced chemotherapy-induced inflammation and damage and helped protect healthy cells in the gastrointestinal tract,” says Dr Cheah. “While this effect is very promising, we were initially concerned that grape seed could reduce the effectiveness of the chemotherapy.”

In contrast, we found that grape seed extract not only aided the ability of chemotherapy to kill cancer cells, but was also more potent than the chemotherapy we tested at one concentration.”

Co-author and project leader Professor Gordon Howarth says: “Grape seed is showing great potential as an anti-inflammatory treatment for a range of bowel diseases and now as a possible anti-cancer treatment. These first anti-cancer results are from cell culture and the next step will be to investigate more widely.”

Fellow co-author and joint lead researcher Dr Sue Bastian, Senior Lecturer in Oenology, says: “These findings could be a boost to the wine grape industry as it value adds to what is essentially a by-product of the winemaking process.

Cheah et al., (2014). Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; Concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells. PLOS One, DOI: 10.1371/journal.pone.0085184 [Article]