In vitro radiosensitisation by trabectedin in human cancer cell lines.
OBJECTIVE
To examine the potential radiosensitising properties of trabectedin (ET-743, Yondelis).


METHODS
In vitro chemosensitivity was assessed in four tumour cell lines (DU145, HeLa, HT29, HOP62) by the crystal violet method. IC10s and IC50s were established for 1-h, 24-h and 7-day (continuous) exposure times. Radiosensitisation was evaluated by conventional colony assay. BrdUrd DNA-labelling and flow cytometry were used to analyse cell cycle kinetics. The rate of apoptotic induction was assed by annexyn-V labelling.


RESULTS
Mean IC50s were 18.8 nM (10.5 - 30), 2.5 nM (1.5 - 5) and 0.25 nM (0.2-0.8) for 1 h, 24 h and continuous exposure times, respectively. HT29 and HOP62 were the most sensitive cells lines to trabectedin. Radiosensitisation was observed in DU145 and HeLa cells with a dose enhancement factor (DEF) of 1.92 and 1.77 at IC50 dose level, respectively. Trabectedin induced early S phase arrest in all cell lines studied.


CONCLUSIONS
Trabectedin, at pharmacologically appropriated concentrations, harbours a significant in vitro radiosensitising effect and induces cell cycle changes and apoptosis in several human cancer cell lines. Further studies to define the clinical potential of the combination of trabectedin and radiotherapy are needed.
Romero
Jesús
J
Department of Radiation Oncology, Hospital Universitario Puerta de Hierro, Madrid, Spain. jromero.hpth@salud.madrid.org
Zapata
Irma
I
Córdoba
Sofía
S
Jimeno
José María
JM
López-Martín
José Antonio
JA
Tercero
Juan Carlos
JC
De La Torre
Alejandro
A
Vargas
Juan Antonio
JA
Molerón
Rafael
R
Sánchez-Prieto
Ricardo
R
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D004149:Dioxoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D005434:Flow Cytometry; D019073:HT29 Cells / Q000187:drug effects / Q000528:radiation effects; D006367:HeLa Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077606:Trabectedin; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D011838:Radiation-Sensitizing Agents; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin