Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms.
Br J Cancer
; 116(3): 335-343, 2017 01.
Article
em En
| MEDLINE
| ID: mdl-28072764
ABSTRACT
BACKGROUND:
Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN.METHODS:
Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines.RESULTS:
On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models.CONCLUSIONS:
Trabectedin could be good candidate for clinical studies in JMML/CMML patients.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Síndromes Mielodisplásicas
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Leucemia Mielomonocítica Crônica
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Antineoplásicos Alquilantes
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Tetra-Hidroisoquinolinas
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Dioxóis
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Leucemia Mielomonocítica Juvenil
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article