Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026986 (
myelodysplastic syndrome
)
14,926
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Myelodysplastic syndromes
and acute myeloid leukemia with
TP53
mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1
Met
(APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in
TP53
-mutated
myelodysplastic syndromes
(
MDS
)/acute myeloid leukemia (AML) cell lines and in
TP53
-mutated primary cells from
MDS
/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy
in vivo
Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that
TP53
-mutated
MDS
/AML may be better targeted by the addition of APR-246 to conventional treatments.
...
PMID:Synergistic effects of PRIMA-1
Met
(APR-246) and 5-azacitidine in
TP53
-mutated myelodysplastic syndromes and acute myeloid leukemia. 3148 57
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