PM01183 / Zalypsis / Yondelis . Comparison of in vitro and in vivo biological effects of Trabectedin, Lurbinectedin ( PM01183 ) and Zalypsis® (PM00104). .

International Journal of Cancer .


Keywords:

Trabectedin , lurbinectedin . Zalypsis®; DNA damage and repair mechanisms;control of cell cycle progression;animal models of cancers; cellular response to anticancer drugs; novel marine antitumor agents


Abstract

This study: i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared to trabectedin in cell lines deficient in specific mechanisms of repair, ii) evaluated their in vivo antitumor activity against a series of murine tumours and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumour lines were very similar. Nucleotide Excision Repair (NER) deficient cells were ~4-fold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in Non-Homologous End Joining (NHEJ), MRN complex and Translesion Synthesis (TLS) were slightly more sensitive to the three compounds (~ 5-fold) while cells deficient in Homologous Recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumours and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects.

© 2013 Wiley Periodicals, Inc.