A team from the National Cancer Research Centre (CNIO), directed by Marcos Malumbres, has discovered how a drug used to treat various types of cancer, called etoposide, could increase efficiency and specificity, combined with other compounds, that interfere with the division cell.
The study, published in the journal Cell Reports, has been conducted in collaboration with the groups of Oscar Fernandez-Capetillo and Javier Muñoz, from the CNIO, and the team of Hiroyuki Yamano, from the Cancer Institute at the University of London, as reported by the CNIO, in a statement.
The Etoposide is a compound obtainable from variants of the mandrake plant and it blocks a necessary protein for repairing the DNA, while the cells are divided by themselves; it is the enzyme “topoisomerase 2” (TOP2). It increases the damage to the genetic material and cell death.
Much of the cancer research efforts are directed toward searching combinations of existing drugs, many of them introduced in clinical practice, allowing greater overall survival and improved quality of life for patients with cancer.
In the case of etoposide is widely used to treat lung cancer, testicular, leukemia or brain tumors.
As Malumbres has indicated: "Etoposide affects tumor cells, which are the most divided and need TOP2 to repair their DNA, but also healthy cells. This lack of specificity leads to alterations in healthy tissues, that result in secondary disorders and toxicity to the organism”.
The researchers suggest that "Now, the challenge is to improve the therapeutic window of the drug, so that the effective dose range gain without an increase in toxicity and side effects associated with treatment”.
To date, data on the molecular pathways that govern topoisomerase levels in cells were very scarce and little illuminating.
Now, the research of the Malumbres´team, Manuel Eguren, has linked, for the first time, in animal models of mouse and human cells, TOP2 with the protein Cdh1, aregulatory of the cell division, so that a decrease in the activity of Cdh1, increases the levels of TOP2 in cells.
This work identifies the formula increase theTOP2 levels in the cells. The research team proposes a new effective treatment modality in tumors: the combination of inhibitors of Cdh1 --between which is a substance called proTAME-- with etoposide. "ProTAME, which is in preclinical studies to inhibit tumor cell division, could increase the effectiveness of etoposide in cancer cells, those that are most divided themselves and thus have a greater reliance on TOP2, to maintain DNA integrity”, say the researchers.
This drug combination could maximize the antitumor effect of etoposide and mean dose reduction and decreased toxicity. Moreover, previous studies indicate that Cdh1 inactive in some patients due to various oncogenic mutations. "Our data suggest that stratification of patients based on the status of Cdh1 in the tumor may improve the effect of etoposide in the treatment of these patients”.
The next step, for the Malumbres´team, is to study this new cocktail of drugs in patient samples and investigate the tumors in which this new therapeutic strategy could be more efficient.
The project was funded by the Ministry of Science and Innovation, the European Union and the Community of Madrid.
Well, I hope that the researchers, in Spain and in the rest of the world, can end this tough disease, named Cancer. God help them.
Till soon, kind regards,
Luis.
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