Comparison of in vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis® (PM00104). Issue 9 (25th May 2013)

• Record Type: Journal Article
• Authors: Romano, Michela; Frapolli, Roberta; Zangarini, Monique; Bello, Ezia; Porcu, Luca; Galmarini, Carlos M.; García‐Fernández, Luis F.; Cuevas, Carmen; Allavena, Paola; Erba, Eugenio; D'Incalci, Maurizio
• Is Part Of: International journal of cancer. Volume 133:Issue 9(2013:Nov. 01)
• Page Start: 2024
• Page End: 2033
• Publication Date: 2013-05-25
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28213
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>This study: (<italic>i</italic>) investigated the <italic>in vitro</italic> cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (<italic>ii</italic>) evaluated their <italic>in vivo</italic> 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 <italic>in vivo</italic> 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 <italic>in vitro</italic> cytotoxic potency and the <italic>in vivo</italic> antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host‐mediated effects are involved in the <italic>in vivo</italic> pharmacological effects.</p> </abstract>