The object of this thesis is the acute promyelocytic leukemia (APL) and the use of the arsenic trioxide (ATO) for its treatment. The acute promyelocytic leukemia was identified for the first time at the end of the 1950s and it’s characterized by a chromosomal translocation of the retinoic acid receptor-alpha (RAR-α) gene on chromosome 17 with the promyelocytic leukemia gene (PML) on chromosome 15. The patients develop an abnormal accumulation of promyelocytices in the bone marrow and they have different symptoms like hemorrhage, anemia and petechiae. It can be indiscriminately contracted by men and women at any age. The acute promyelocytic leukemia can be detected with different analytical techniques such as the review of the peripheral blood smear, the reverse transcriptase-PCR, the analysis of metaphase chromosomes or the hybridization fluorescence. The therapeutic model used to defeat the APL represents an innovation of the history of medicine because this cancer can be cured without using chemotherapeutic agents, but just with specific drugs, even in combination with other molecules. In fact, it has been demonstrated that the arsenic trioxide-based therapy, even in association with tretinoin (ATRA), has an optimal efficacy. ATO determines the degradation of the gene PML/RAR-α promoting the differentiation, the induction of apoptosis, the accumulation of reactive oxygen species and the removal of the leukemic stem cells. Even if the treatment has a high efficacy, some patients don’t respond well to it because they don’t achieve complete remission in the first months of the therapy or because they have a relapse. In these conditions it can be made a cell transplantation that is successful for a significant part of patients. It must be noted that the cell transplantation must be associated with the maintenance of the therapy with ATO.
L’oggetto di studio di questo elaborato è la leucemia promielocitica acuta e, nello specifico, la cura della stessa tramite l’utilizzo dell’ossido arsenioso. La leucemia promielocitica acuta, identificata per la prima volta verso la fine degli anni cinquanta del secolo scorso come sottotipo di leucemia mieloide acuta, è caratterizzata da una traslocazione tra il cromosoma 15 ed il cromosoma 17, t(15;17)(q22;q21), che porta alla fusione del gene PML con il recettore dell’acido retinoico RAR-α. I pazienti affetti da questa patologia presentano un accumulo anormale di promielociti a livello del midollo osseo e diversi sintomi quali, ad esempio, gravi emorragie, anemia e petecchie. Colpisce indistintamente uomini e donne di qualunque età. Questo sottotipo di leucemia viene diagnosticato tramite differenti tecniche analitiche quali, ad esempio, l’osservazione morfologica dello striscio di sangue periferico, la reverse transcriptase PCR, l’analisi della metafase dei cromosomi o l’ibridazione fluorescente. Il modello terapico adottato per eradicare la leucemia promielocitica acuta rappresenta un’innovazione nella storia della medicina in quanto, da un’iniziale condizione in cui si sfruttava l’azione generica delle antracicline, si è giunti ad una situazione tale per cui questa neoplasia, nella stragrande maggioranza dei casi, può essere curata con farmaci mirati eventualmente in combinazione. È stato infatti dimostrato che una terapia a base di triossido arsenioso (ATO), in associazione o meno con la tretinoina (ATRA), ha un’efficacia ottimale. ATO determina la degradazione del gene PML/RAR-α promuovendo la differenziazione, l’induzione di apoptosi, l’accumulo di specie reattive dell’ossigeno e l’eliminazione delle cellule staminali leucemiche. Pur avendo un’efficacia elevata, alcuni pazienti non rispondono bene al trattamento perché non hanno raggiunto una completa remissione nei primi mesi di terapia o perché sviluppano successivamente una ricaduta. In tali condizioni si può effettuare un trapianto cellulare che ha successo in una significativa parte dei pazienti. Da notare che il trapianto va associato al mantenimento della terapia con ATO.
L'uso dell'ossido arsenioso nella cura della leucemia promielocitica acuta
LIMONTA, STEFANO
2014/2015
Abstract
The object of this thesis is the acute promyelocytic leukemia (APL) and the use of the arsenic trioxide (ATO) for its treatment. The acute promyelocytic leukemia was identified for the first time at the end of the 1950s and it’s characterized by a chromosomal translocation of the retinoic acid receptor-alpha (RAR-α) gene on chromosome 17 with the promyelocytic leukemia gene (PML) on chromosome 15. The patients develop an abnormal accumulation of promyelocytices in the bone marrow and they have different symptoms like hemorrhage, anemia and petechiae. It can be indiscriminately contracted by men and women at any age. The acute promyelocytic leukemia can be detected with different analytical techniques such as the review of the peripheral blood smear, the reverse transcriptase-PCR, the analysis of metaphase chromosomes or the hybridization fluorescence. The therapeutic model used to defeat the APL represents an innovation of the history of medicine because this cancer can be cured without using chemotherapeutic agents, but just with specific drugs, even in combination with other molecules. In fact, it has been demonstrated that the arsenic trioxide-based therapy, even in association with tretinoin (ATRA), has an optimal efficacy. ATO determines the degradation of the gene PML/RAR-α promoting the differentiation, the induction of apoptosis, the accumulation of reactive oxygen species and the removal of the leukemic stem cells. Even if the treatment has a high efficacy, some patients don’t respond well to it because they don’t achieve complete remission in the first months of the therapy or because they have a relapse. In these conditions it can be made a cell transplantation that is successful for a significant part of patients. It must be noted that the cell transplantation must be associated with the maintenance of the therapy with ATO.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/19218