Swedish scientists have created a new cancer treatment strategy
Cancer cells have lost a savior
Nadezhda Markina, Newspaper.Roo
Swedish researchers from five universities, led by specialists from the Karolinska Institute, have proposed a new cancer treatment strategy. They outlined their concept in the latest issue of the journal Nature (Gad et al., MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool). Scientists have found a protein whose suppression kills a cancerous tumor. In addition to the Karolinska Institute, the Salgrenska Academy of the University of Gothenburg, Uppsala University, Linkoping University and Stockholm University participate in the collaboration.
A protein called MTH1 works exclusively in cancer cells, helping them survive. Namely, to overcome oxidative stress, which occurs in cells with the formation of reactive oxygen species. These molecules, carrying an unpaired electron, actively react with other molecules. In particular, they attach to the nucleotides, the "bricks" that make up DNA. During cell division, the DNA molecule doubles, while the double chain is unwound, and a paired chain is built on each single chain according to the principle of complementarity from nucleotides. If oxidized nucleotides are used as a building material during the construction of this paired chain, in the future this will lead to fatal DNA breaks and cell death.
The role of the MTH1 protein is to "sanitize" – it catches oxidized nucleotides when they approach the assembly site of the DNA molecule and does not allow their inclusion in the molecule. So with its help, the cancer cell avoids the fatal destruction of DNA and death.
To kill a cancerous tumor, scientists have proposed inhibitors of the MTH1 protein, which suppress its activity and deprive cancer cells of protection.
Recently, the development of cancer treatments has been in the direction of targeted therapy aimed at specific genetic mutations that occur in cancer cells. But the cancer continues to change, and new mutations appear, for which this medicine no longer works. The resistance (resistance) of the tumor develops.
In contrast, MTH1 inhibitors act in any cancer cells, regardless of the mutations that occur in them. Therefore, scientists believe that there will be no resistance to such drugs.
This discovery was preceded by fundamental research that clarified the specific role of the MTH1 protein in cancer cells. Normal cells do not need MTH1 to work, they have a different regulatory mechanism for culling damaged nucleotides.
"The concept is based on the fact that cancer cells have an altered metabolism, which consists in blocking the access of oxidized nucleotides to DNA," explains Thomas Helday, professor at the Karolinska Institute, head of the study. – MTH1 does not allow oxidized nucleotides in DNA, thereby preventing oxidative damage to DNA. This allows cancer cells to divide and multiply unhindered. MTH1 inhibitors block its activity, and cancer cells die. The discovery of this cancer cell-specific mechanism opens up a new path to cancer treatment."
In order for the new concept to become applicable in the clinic, scientists have developed a multidisciplinary strategy for the collaboration of five Swedish universities. They created a powerful MTH1 inhibitor that selectively kills cancer cells in a tumor, and tested it on melanoma cells removed from a patient.
"When we saw that a tumor taken from one of the patients with melanoma resistant to all previously used drugs began to die, we were incredibly happy," says surgeon Roger Olofsson Budge. "This is a real breakthrough."
Nevertheless, there is a lot of work to be done before clinical trials of new drugs. Scientists hope that clinical trials will be possible in a year or two.
In a second paper published in the same issue of Nature (Huber et al., Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy), Swedish researchers in collaboration with Austrian and British colleagues showed that already known cancer drugs also inhibit MTH1. This fact was not known before.
"The fact that existing anticancer agents inhibit MTH1 confirms that our concept works," emphasizes Thomas Helday. "Now that we understand the mechanism, our task is to create more selective inhibitors."
The authors of the study, even before publication, sent the selective MTH1 inhibitors they created to several scientific centers in different countries for independent verification of their effectiveness.
Portal "Eternal youth" http://vechnayamolodost.ru03.04.2014