A team of specialists at the University Hospital of Navarra have revealed the existence of genetic variants that have greater resistance to a specific treatment and a greater toxicity of the pharmaceutical drug in some child patients affected by osteosarcoma. The team investigated the mechanisms of the illness in order to obtain a personalised therapeutic treatment in the future.
In concrete, the research focused on the analysis of the side effects due to the administration of methotrexate in a hundred of such patients. This medication was chosen because, to treat infant osteosarcoma, high levels of dosage are administered – in terms of grammes – being a multiplication by a thousand of the methotrexate dosage given in other, frequently-occurring cancer diseases, such as leukaemia. Such high dosage can cause very important toxic effects, and thus the need to know the genetic mechanisms bearing on the resistance to treatment and the tolerance to the pharmaceutical drug, explained Doctor Ana Patiño, main research author of the article to be published in the scientific journal, The Journal of Pediatrics, the second with the greatest world impact in its speciality.
Notable amongst the team participating in the study is the biologist/biochemist Doctor Marta Zalacain, who suffered an osteosarcoma when she was 11 years old, and for which she was treated and cured at the University Hospital by a team led by Dr Sierrasesúmaga, the group with which she is currently working on the mechanisms of this illness.
Large group of patients
The work was drawn up for a group of 100 patients, one of the largest in the world, given the scant incidence of the illness (estimated annually at one person per million inhabitants). To give an idea of the importance of the group studied by Doctor Sierrasesúmaga, Director of the Department of Paediatrics at the University Hospital of Navarra and specialist in infant cancer, it can be pointed out that, in all of Spain, 45 child patients suffering from osteosarcoma are detected on average each year there. Thus, the hundred patients under study is a very large number and, moreover, it is a particularly exceptional study in that it provides access to its genetic material, to the tumour material and to all the complete clinical data of the hundred patients studied.
70% survival rate at the University Hospital
The survival prognosis of infant patients with osteosarcoma at the University Hospital of Navarra, including the metastasic ones, is about 70%, compared to the 60-65% average at other international centres of reference in the treatment of this oncological illness. As a consequence of this high survival rate, added Doctor Patiño, the concern is also with the quality of life of survivors. The goal of the research work is focusing on finding therapeutic tools that minimise the toxic effects of treatment and maximise the therapeutic effects.
Observing the genetic variants of the genes involved in the methotrexate metabolism, they have shown that some of these variants are associated with different toxicity of the pharmaceutical drug and, accordingly, obtain better or worse therapeutic effects, stated the specialist. In concrete, the research team studied genetic variants of children in which the tumours prove themselves to be intrinsically resistant to the medical treatment. These are the patients for whom it is necessary to administer high levels of methotrexate in order to obtain a good response.
To obtain these data, the researchers were able to work closely with the Department of Pharmacology at the University Hospital of Navarra, where the kinetics of the drug in the blood was analysed for each of the patients in the study. In this way, explained Ms Patiño, they monitored the children to see if they had eliminated the amount of drug left over after the required therapeutic effect had taken effect, given that, otherwise, significant toxicity could be caused.
As a result of the research, the specialists have identified the genetic variant responsible for this greater methotrexate toxicity affecting certain children with osteosarcoma. Although, for the moment, the genotype has not yet changed the treatment of the illness, the aim is to gradually intensify this type of genetic study through analysis the results of which can be readily obtained - in a matter of 90 minutes. In this way, what is involved is the location of new genes and thus being able to adjust the dosage of the various pharmaceutical drugs that we administer, in order to maximise the therapeutic results and minimise the toxicity in each one of the patients treated, concluded the researcher.
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