The diagnosis of brain glioblastoma is dismal prognosis. Most patients die within five years. Currently, a team led by researchers at Massachusetts General Hospital found that adding hydroxyurea to the current chemotherapy protocol significantly increases the survival of glioblastoma (a study carried out in animal models).
Team report published in the Journal of Neuro-Oncology.
"Thanks to the screening of drugs aimed at the re-use, we have demonstrated that the FDA approved hydroxycarbamide (hydroxyurea) interacts well with temozolomide in glioblastoma cells," - says Bajos Tannus. "The combination resulted in a significant increase in survival in different mouse models, some of which 40-60% of the animals got rid of tumors."
The addition of temozolomide (TMZ) to surgical and radiation treatment the best solution for the treatment of glioblastoma in the past 20 years. It led to a survival increase of up to two years from 11 to 27 percent. But 90 percent of patients receiving this combination die within five years. The cause of death was tumors resistant to temozolomide which acts by inhibiting protein synthesis in cancer cells.
Much of this resistance depends on the action of an enzyme called of MGMT, which restores the DNA change caused by temozolomide. Regardless of whether the methylated MGMT-promoter - modification of the DNA that suppresses the expression of the gene - it is possible to predict whether the tumor is glioblastoma respond to temozolomide. Changes in methylation status, which activates MGMT, may stand for the initial resistance temozolomide tumors studied but other resistance mechanisms.
In search of ways to overcome the TMZ team, led by the MGH, through a strategy of screening drugs that are already approved to treat several types of cancer, to determine whether they can improve the results of treatment of glioblastoma. Tannus explains that the development of new drugs - is a long, complex and costly process which fails due to unexpected side effects in patients. But much is known about the pharmacology, mechanism of action and the potential toxicity of existing drugs. "The advantage of teaching old drugs new tricks" is that, in comparison with conventional medicines discovery, clinical use could be much faster to go to the clinic, "- he says.
Group conducted screening libraries of anticancer drug 21 - new targeted agents and conventional chemotherapies - 18 against cultured glioblastoma cell lines, including stem cells from newly diagnosed or recurrent tumors which were susceptible and resistant to TMZ treatment. Several agents have improved response to TMZ resistant crops only hydroxyurea (hydroxycarbamide) sensitized cell lines - including those that are resistant to TMZ treatment.
With these promising results the team investigated this combination in several models of glioblastoma mice, including tumors with different status of MGMT. Although only one drug has only a moderate effect on tumor growth and survival, the combination of hydroxyurea and TMZ significantly improved. Half the animals receiving the combination treatment remained without tumor at the end of the study, and patients with certain tumor subtype were cured 60 percent.
"The fact that the combination of hydroxyurea and TMZ is effective in models and animal cells and not selective for a specific type of tumor, is interesting because it suggests that the combination is effective for patients with glioblastoma, not only with an inactive MGMT», - says Tannus. "Hydroxycarbamide used for decades for the treatment of conditions such as sickle cell anemia and some types of cancer, however, this approach the clinic should be simple. We are preparing to test this combination in the clinical trial phase 1, which we hope to start soon. "