Oral Administration of the Opium Alkaloid Noscapine (NOS) Exhibits Potent Anti-Tumor Activity Against Non-Hodgkin's Lymphomas and Myeloma Cell Lines In Vitroand In Vivoin SCID-beige Murine Xenograft Models.

Noscapine is an oral opiate alkaloid with structural similarity to colchicine that induces cell cycle arrest and apoptosis. Its mechanism of action appears similar to vincristine (VCN). In a trypan blue exclusion assay, noscapine exhibits increasing potency with increasing duration of exposure in B- and T-cell lymphomas, and myelomas (MM). For example, following 24 hours of exposure to noscapine, the OPM2 (MM), H9 (TCL) and RL (BCL) lines exhibited an IC50of approximately 10 to 15 mM. Exposure for up to 96 hours effected IC50of 30 nM, 700 nM, and 500 nM for the OPM2, H9 and RL lines respectively. Across all cell lines studied, increasing the duration of exposure by only a couple of days resulted in multiple log decreases in IC50. Combining noscapine with doxorubicin and 4-hydroxycyclophosphamide in vitroresulted in at least additive or better cytotoxicity. In vivo, both intraperitoneal and oral doses of noscapine were evaluated on a daily schedule for 14 days (200, 300, 400 and 600 mg/kg). These data demonstrated that the toxicity was much greater when administered by the i.p. route, where 60% of animals died as a result of toxicity in the 600 mg/kg i.p. cohort, while none died from toxicity when given by oral gavage. Preliminary efficacy experiments demonstrated that by day 15, animals treated with 600 and 400 mg/kg noscapine by oral gavage exhibited tumor growth delays that were 30 to 50% of the control tumor volume. Activation of caspase 3 by noscapine demonstrated a linear dose response relationship which was strongly related to duration of drug exposure. Noscapine may represent a new well tolerated oral therapy for the control of lymphoma and myeloma. Antimitotic agents with effects like VCN may be improved with higher area under of the curve of exposure, and thus are well suited for oral administration. Ongoing phase I studies are determining the MTD and DLT associated with noscapine. Phase 2 studies are warranted.