Noscapine is synergistic with vincristine and provides neuroprotection of myelin in cell culture.

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Vincristine, a vinca alkaloid, is frontline therapy for many solid tumors and acute lymphoblastic leukemia. Unfortunately, treatment for most patients is complicated by the dose-limiting side effect, neuropathy. Combination chemotherapy that reduces or eliminates the neurotoxicity without compromising the efficacy of vincristine would lead to a significant improvement in patient outcomes. We have performed preclinical studies using noscapine, an FDA-approved antitussive, in combination with vincristine. Both vincristine and noscapine are antimitotics that bind microtubules at distinct locations and appear to act by altering the dynamics of microtubule assembly, which is critical during cell division. We developed a mouse embryonic stem cell system comprised of differentiated central nervous system (CNS)-type cells including neurons, oligodendrocytes and astrocytes. Cells are grown for about two weeks under conditions that are permissive for myelination prior to drug treatment. Vincristine treatment was shown by transmission electron microscopy to cause demyelination, whereas simultaneous treatment with vincristine and noscapine preserved the myelin. Human acute lymphoblastic and acute myelogenous leukemia cell lines CCRF-CEM and HL60, respectively, were used to determine the antiproliferative effect of the drug combination. Vincristine and noscapine were both independently effective at decreasing cell proliferation with IC₅₀ concentrations of 1 nM and 7 µM, respectively. Quantitative analysis of dose-effect relationships using isobolograms and combination indices (CI) demonstrated that noscapine acts synergistically with vincristine. In conclusion, noscapine has been shown in cell culture to be a promising candidate for use in combination chemotherapy with vincristine with the goal of decreasing neurotoxicity and enhancing the antineoplastic effect.