Navigation Links
Cancer therapy -- Nanokey opens tumors to attack
Date:11/14/2012

There are plenty of effective anticancer agents around. The problem is that, very often, they cannot gain access to all the cells in solid tumors. A new gene delivery vehicle may provide a way of making tracks to the heart of the target.

Many types of tumor form a compact mass, like the phalanx formation of Greek antiquity. And although many drugs are known to be toxic to cancer cells, they are often unable to percolate into the inner recesses of the tumor. Upon intravenous administration, for instance, cytotoxic drugs may only be able to penetrate the outermost layers of a solid tumor. A team led by LMU pharmacologist Dr Manfred Ogris has now developed a new type of gene delivery vehicle, which is designed to open up a route through the vascular network that supplies the tumor so that drugs can reach their target.

Large tumors need a local blood supply for continued growth, and are capable of inducing the formation of new vessels. The resulting vasculature is more permeable than normal vessels, which should facilitate the delivery of cytotoxins. However, the lymphatic system does not work optimally in tumors, and back-pressure associated with the build-up of lymph limits the diffusion of drugs. As it happens, the cytokine Tumor Necrosis Factor α (TNFα), which can kill tumor cells directly, is able to increase blood vessel permeability as part of its pro-inflammatory function.

Shielding the organism from the drug

TNFα is already being used in combination with chemotherapeutic agents for the treatment of muscle tumors in arms and legs, but in this case, the local vasculature must be cut off surgically. "Unfortunately, therapeutically effective amounts of TNFα cannot be administered systemically, because this would lead to activation of, and damage to, all the vessels in the organism," says Ogris. "For this reason, it is not possible to use this approach on tumors in internal organs or against dispersed metastases."

A new strategy employing gene therapy could provide a solution to this problem. The idea is to deliver the gene for TNFα directly and specifically to the tumor cells. If this worked, the tumor cells themselves could produce and secrete the cytokine, ensuring that its local concentration becomes sufficiently high to permeabilize the blood vessels only in the immediate vicinity of the tumor. "We first designed a version of the TNFα gene that allows for the production of large amounts of the protein," Dr. Baowei Su, first author on the study, explains.

Shielding the drug from the organism

In collaboration with researchers at the Technische Universitt Mnchen and the Helmholtz Center Munich, the LMU team constructed a form of the gene which, in contrast to the normal version, is unlikely to induce non-specific inflammation. The plasmid was then incorporated into special nanoparticles, which not only protect the DNA from inactivation during its journey through the bloodstream, but also allow it to be targeted to the tumor. Experiments carried out on cell cultures confirmed that tumor cells treated with these particles synthesize large amounts of TNFα.

Treatment with the loaded nanoparticles alone, however, had only a moderate effect on tumor cells, but when they were administered in combination with the DNA-intercalating drug doxorubicin, the impact on tumor cell growth was markedly enhanced. Under the trade name Doxil, doxorubicin, which inhibits DNA replication, is available in a liposome-encapsulated form. Incorporating the drug into liposomes of 100 nm in diameter reduces side-effects and increases its half-life in the circulation, making it more effective than unencapsulated formulations.

No evidence for drug resistance

When mice with neuroblastoma, or mice that had received a xenograft of a human liver tumor, were first exposed to nanoparticles carrying the TNFα gene and subsequently treated with Doxil the researchers observed, in real time, that the drug became concentrated in the tumor tissue. Indeed, in some cases, the combination was sufficient to bring tumor growth to a standstill, even in animals that had already undergone three cycles of treatment. This finding suggests that drug resistance, which often limits the efficacy of chemotherapy, does not develop in this context.

In addition to eliminating the primary tumor, a successful therapy must be able to kill metastatic tumors in other tissues. When the researchers looked at mice with neuroblastoma, or mice carrying implanted human colon tumors that had metastasized to the liver, they found that the new treatment strategy also significantly reduced the growth of metastases. "TNFα might also be useful in combination with other agents and other treatment regimens," says Ogris. "We now plan to optimize our gene delivery system, and hope that we can soon begin to plan preclinical tests of the new approach." (suwe)


'/>"/>

Contact: Kathrin Bilgeri
kathrin.bilgeri@lmu.de
49-892-189-6938
Ludwig-Maximilians-Universitt Mnchen
Source:Eurekalert

Related medicine news :

1. Study Suggests Vaccine May Help Kids With Brain Cancer
2. New Stool Test Might Aid in Early Detection of Colon Cancer
3. Study reveals how cancer drug causes diabetic-like state
4. How a cancer drug leads to diabetes
5. You Survived Cancer: Now Pay Attention to Your Overall Health
6. New drug prevents spread of human prostate cancer cells
7. Eliminating the good cholesterol receptor may fight breast cancer
8. Taller, Heavier Women May Face Higher Ovarian Cancer Risk
9. Experimental Chemo Combo for Colon Cancer Disappoints
10. Veggies Like Broccoli, Cabbage May Help Fight Breast Cancer: Study
11. Targeted therapeutics for colon cancer to be presented at AACR meeting
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/25/2016)... ... June 25, 2016 , ... "With 30 hand-drawn hand gesture animations, FCPX users ... - CEO of Pixel Film Studios. , ProHand Cartoon’s package transforms over 1,300 ... Pro X . Simply select a ProHand generator and drag it above media or ...
(Date:6/25/2016)... Montreal, Canada (PRWEB) , ... June 25, 2016 , ... ... the pursuit of success. In terms of the latter, setting the bar too high ... low, risk more than just slow progress toward their goal. , Research from ...
(Date:6/24/2016)... Texas (PRWEB) , ... June 24, 2016 , ... ... International Conference and Scientific Sessions in Dallas that it will receive two significant ... of the grants came as PHA marked its 25th anniversary by recognizing patients, ...
(Date:6/24/2016)... Plano, TX (PRWEB) , ... June 24, 2016 , ... ... taking part in Genome magazine’s Code Talker Award, an essay contest in which patients ... for an award to be presented at the 2016 National Society of Genetic Counselors ...
(Date:6/24/2016)... ... June 24, 2016 , ... National recruitment firm ... sciences executive with extensive sequencing and genomics experience, as Vice President of North American ... Hill will be responsible for leading the sales team in the commercialization of the ...
Breaking Medicine News(10 mins):
(Date:6/26/2016)... -- VMS Rehab Systems, Inc. ( www.vmsrehabsystemsinc.com ) reported today ... to build a strong and stable market for trading ... the OTC Markets-pink current trading platform. Explains ... seeing an anomaly in market trading activities that may ... Company, but shareholders and market players as well. I ...
(Date:6/24/2016)... Mass. , June 24, 2016   ... Spaulding Rehabilitation Network,s Dean Center for Tick ... Physical Medicine and Rehabilitation, MIT Hacking Medicine, University ... for Innovation, today announced the five finalists of ... for Lyme disease.  More than 100 scientists, clinicians, ...
(Date:6/24/2016)... SAN CLEMENTE, Calif. , June 24, 2016 /PRNewswire/ ... pulmonary function testing company, is now able to perform sophisticated lung ... ndd Medical Technologies , Inc. Patients are ... labs.  Thanks to ndd,s EasyOne PRO ® , ARL patients like ... any needed testing done in the comfort of her own home. ...
Breaking Medicine Technology: