Extreme sensitivity to Yondelis (Trabectedin, ET-743) in low passaged sarcoma cell lines correlates with mutated p53.
Yondelis (Trabectedin, ET-743) is a marine anticancer agent currently in Phase II/III development in patients with advanced pretreated soft tissue sarcoma. In the present study, we generated a panel of low passaged tumor cell lines from samples explanted from chemonaive sarcoma patients with different tumor types. We assessed in vitro sensitivity/resistance to Trabectedin and doxorubicin in a panel of sarcoma cell lines and examined the correlation between molecular alterations in DNA repair genes and sensitivity to Trabectedin. We treated cell lines with Trabectedin and doxorubicin in both 96-h and clonogenic assays. In both assays, well-defined groups of resistant and sensitive cell lines were observed. Resistance to Trabectedin did not correlate with resistance to doxorubicin, indicating that the two drugs may have different mechanisms of resistance. p53 mutations and deletions correlated with extreme sensitivity (IC50 < 1 nM) to Trabectedin (P < 0.01). In a pair of isogenic cell lines differing only in the presence or absence of wild-type p53, the absence of p53 rendered cells threefold more sensitive to Trabectedin.
Moneo
Victoria
V
Experimental Therapeutics Programme, Madrid, Spain.
Serelde
Beatriz G
BG
Fominaya
Jesús
J
Leal
Juan F M
JF
Blanco-Aparicio
Carmen
C
Romero
Lourdes
L
Sánchez-Beato
Margarita
M
Cigudosa
Juan C
JC
Tercero
Juan C
JC
Piris
Miguel A
MA
Jimeno
Jose
J
Carnero
Amancio
A
D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology* / Q000633:toxicity; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007621:Karyotyping; D009154:Mutation / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012680:Sensitivity and Specificity; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000633:toxicity; D000077606:Trabectedin; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004149:Dioxoles; D034741:RNA, Small Interfering; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D000077606:Trabectedin