Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms.
Br J Cancer
; 116(3): 335-343, 2017 01.
Article
en 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
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Síndromes Mielodisplásicos
/
Leucemia Mielomonocítica Crónica
/
Antineoplásicos Alquilantes
/
Tetrahidroisoquinolinas
/
Dioxoles
/
Leucemia Mielomonocítica Juvenil
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Br J Cancer
Año:
2017
Tipo del documento:
Article
País de afiliación:
Italia