Comparison of in vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis® (PM00104)

This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold 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 (approximately fivefold) 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 tumors 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. What's new? Several synthetic derivatives of marine natural compounds are currently under investigation for efficiency in distinct cancer types such as soft tissue sarcomas. A leading molecule is trabectedin, a pentacyclic compound that binds the minor groove of DNA. Here, the authors performed a systematic analysis of trabectedin and its analogues, lurbinectedin and Zalypsis®. In vivo, all three drugs showed a very marked but different antitumor activity, with Zalypsis® being distinct from the other two compounds. Notably, the sensitivity observed in vivo did not correlate with the in vitro sensitivity, suggesting that in addition to direct cytotoxic effects host‐mediated effects support the promising antitumor properties of the drugs.