PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma.
iScience
; 25(2): 103725, 2022 Feb 18.
Article
em En
| MEDLINE
| ID: mdl-35098099
ABSTRACT
Current therapy is ineffective for relapsed and metastatic Ewing sarcoma (EwS) owing to development of drug resistance. Macromolecular prodrugs potentially lead to lower drug exposure in normal tissues and reduced toxicity. We evaluated the efficacy of PEGylated talazoparib (PEGâ¼TLZ), a PARP1 inhibitor, alone or in combination with the DNA-alkylating agent temozolomide (TMZ) in EwS and other pediatric tumors using conventional testing or single-mouse trial (SMT). A single dose of PEGâ¼TLZ (10 µmol/kg on day 0) combined with 5 daily doses of TMZ (40 mg/kg starting on day 3/4) produced minimal toxicity, and the combination achieved maintained complete response in EwS and glioblastoma models. The SMT trial with the 3-day interval between PEGâ¼TLZ and TMZ resulted in objective responses in EwS and other xenografts. Thus, PEGâ¼TLZ + TMZ demonstrated a broad range of activity in pediatric solid tumor models. Furthermore, the therapeutic window of PEGâ¼TLZ + TMZ was enhanced compared with the free-TLZ combination.
Texto completo:
1
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article