Zalypsis

Zalypsis(PM00104) is an alkaloid analog to certain natural marine compound. Zalyps is a potent antimyeloma agent with IC50 values from picomolar to low nanomolar ranges. IC50 value: Target: Anticaner in vitro: Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression [1]. Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells [2]. Zalypsis-DNA adducts eventually give rise to double-strand breaks, triggering S-phase accumulation and apoptotic cell death. The potent cytotoxic activity of Zalypsis was ascertained in a 24 cell line panel. The mean IC(50) value was 7nM and leukemia and stomach tumor cell lines were amongst the most sensitive [3]. in vivo: Zalypsis-induced PARP and caspase-3 cleavage were observed in the resected tumors from xenografts of both cell lines. H2AX also showed an increase in phosphorylation in MM1S and OPM-1 xenografts, suggesting the induction of DSBs in the tumors on treatment with Zalypsis [1].Zalypsis administration in four murine xenograft models of human cancer demonstrates significant tumor growth inhibition that is highest in the Hs746t gastric cancer cell line with no weight loss of treated animals [3].