Abstract Trabectedin is a tetrahydroisoquinoline molecule that was originally derived from the Caribbean marine tunicate Ectenaiscidia turbinata and is now produced by chemical synthesis. The compound is approved in the European Union and a number of other countries for use in patients with advanced soft tissue sarcomas. Zalypsis® (PM00104) is a novel synthetic tetrahydroisoquinoline structurally related to jorumycin. Both compounds have a similar A and B ring structures that bind DNA but differ in their C ring which protrudes out of DNA and is possibly relevant for the interaction with DNA binding proteins, including DNA repair proteins and transcription factors. In the present study, we characterized the in vivo antitumor activity compared to trabectedin. The antitumor activity of Zalypsis® was investigated in two murine models, M5076 reticulosarcoma and MNMCA1 fibrosarcoma, respectively metastasizing liver and lung. Zalypsis® (0.9 mg/kg) and trabectedin (0.15 mg/kg) were administered intravenously every week for three times (q7dx3). In both models Zalypsis® was very effective in inhibiting the primary tumors (T/C 18% and 20% respectively). In the case of MNMCA1, it was also effective against metastasis whereas it was inactive against liver metastasis of M5076 sarcoma. In the two experiments, trabectedin was very effective against metastasis although against M5076 sarcoma it was only marginally able to inhibit primary tumor growth (T/C 52%). In Cen3 tel sarcoma, of human origin, Zalypsis® was very effective with a T/C of 19% whereas trabectedin was essentially inactive (T/C 78%). In contrast Zalypsis® was less effective than trabectedin against HOC22 ovarian carcinoma. In summary it appears that Zalypsis® is biologically different from trabectedin when tested on in vivo tumor models, therefore its clinical development should not necessarily addressed to the same tumors that have shown sensitivity to trabectedin. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B198.