Abstract A174: Comparison of the antitumor activity of Trabectedin, Lurbinectedin, Zalypsis and PM00128 in a panel of human cells deficient in transcription/NER repair factors.

Trabectedin, Lurbinectedin, Zalypsis and PM00128 are marine-derived anticancer drugs. All these compounds contain a common pentacyclic skeleton which is responsible for the binding to the DNA minor groove. They differ in the additional chemical moiety attached to the pentacyclic skeleton that protrudes from the minor groove of the DNA. Trabectedin, Lurbinectedin and Zalypsis present a tetrahydroisoquinole, a tetrahydro β-carboline and a trifluorocinnamic groups, respectively, while PM00128 lacks such additional moiety. It is believed that the chemical structure of these groups could mediate compound specific interactions with proteins involved in different cellular functions, such as transcription or DNA repair. To gain insight into how the presence of those different chemical moieties could contribute to the specific activity of the compounds, we tested their cytotoxicity profiles against a panel of 24 fibroblast cell lines derived from patients with genetic diseases caused by mutations in the transcription/NER factors CSA, CSB, XPC, XPA, XPE, XPD and XPG. Four out of seven fibroblast cells lines carrying truncations in the XPG endonuclease gene were more resistant to Trabectedin than normal fibroblasts, with RI values ranging from 3.4 to 6.7. It was also observed that the cell line GM15754 was particularly resistant to both Trabectedin and Lurbinectedin, showing a RI of 41.0. This cell line presents a missense mutation (R112H) in the XPD helicase gene. The results indicated that the proper functionality of XPG and XPD factors in transcription and/or DNA repair may be important for the antiproliferative action of these compounds. Interestingly, no significant differences in the sensitivity of these cell lines were observed wih Zalypsis and PM00128. The sensitivity profiles obtained with standard DNA binders (cisplatin and mitomycin C) were completely opposed to those of Trabectedin and Lurbinectedin. These results indicate that i) the four compounds behave in a different way to other commonly used DNA binders such as cisplatin and mitomycin C and ii) the chemical groups attached to the common DNA binding scaffold in these compounds seem to be important for their specific biological activities against tumor cells. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A174. Citation Format: Victoria Moneo, Patricia Martinez, Beatriz de Castro, Sofia Cascajares, Sonia Avila, Luis F. Garcia-Fernandez, Carlos M. Galmarini. Comparison of the antitumor activity of Trabectedin, Lurbinectedin, Zalypsis and PM00128 in a panel of human cells deficient in transcription/NER repair factors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A174.