Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks

Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bortezomib and dexamethasone

“…In this work, we have evaluated the combination of bortezomib and dexamethasone with zalypsis, a novel DNA-damaging agent derived from marine organisms, for which an anti-MM effect has been demonstrated in preclinical settings 5 and in an early-phase clinical trial. 6 The ZaBDe combination was effective in different preclinical models and patient samples; the most significant results being the differences in terms of tumor growth control and survival in the two xenograft models evaluated.…”

“…5 In this study, ZaBDe increased DNA fragmentation, as suggested by the comet assay ( Figure 4A). Triple combination as well as dexamethasone in monotherapy and all the doubles, induced H2AX phosphorylation, a marker of DNA double-strand breaks (DSBs) (Fig.…”

“…The follow-up of this xenograft model has been described elsewhere. 5 The same strain of mice was used to generate the disseminated MM xenograft model by tail vein injection of 3 x 10 6 MM.1S-luc cells. Tumor development was monitored by non-invasive bioluminescence imaging (BLI) with a Xenogen IVIS 50 system (Caliper Life Sciences, Hopkinton, MA, USA).…”

“…5 When tumors became palpable, mice were randomized to receive different treatments. The control group received the vehicle of zalypsis, which was a dilution containing sucrose, potassium dihydrogen phosphate, phosphoric acid and sterile water for injection.…”

“…Interestingly, this activity is present in cells with a functional, as well as a mutated, p53. 5 Moreover, in a recent phase I/II dose-escalation clinical trial carried out in previously refractory MM patients, zalypsis showed a predictable, manageable and reversible toxicity profile with some long-lasting disease stabilization, particularly when dexamethasone was added. 6 Some responses (1 PR and 5 MR) were observed D espite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment.…”