Compositions and methods for treating cancer and inflammatory disease using noscapine and noscapine analogues conjugated to targeting molecules.
Noscapine is a plant-derived alkaloid with a long-history of human use as an anti-cough agent. Noscapine is non-toxic even in large experimental doses (1-2 gm a day), and is orally available (its plasma concentration peaks at 2.5 to 3 hours after oral ingestion, and is non-detectable after 5.5 hours in plasma). Noscapine, and various noscapine analogs, are known to exhibit tubulin-binding properties, without substantially altering tubulin polymerization, and have been shown in the clinic to be useful anti-cancer agent and Noscapine is currently in phase I clinical trial for the treatment of multiple myeloma.
The present inventors sought a novel, targeted approach aimed at preventing and treating recurrence of aggressive tumors, for example, ovary, breast, prostate, and brain tumors. We can target noscapine in high concentrations to the tumor cells without reducing its anti-cancer activity, and hence prevent, treat and achieve prolonged disease-free survival in preclinical models. Targetin, a conjugate of Noscapine and a targeting molecule, shows enhanced antitumor efficacy relative to noscapine. Because both components are non-toxic separately, and the conjugate additionally appears to be non-toxic, it is believed that treatment of various cancer types which over-express a receptor for the targeting agent can extend the disease-free survival of cancer patients without compromising their quality of life.
In contrast to other microtubule interacting agents such as Paclitaxel, Nocodazole, and Vinblastine, Noscapine modifies microtubule dynamics without affecting total tubulin polymer mass in reconstituted systems and without altering the steady-state monomer/polymer equilibrium of microtubule assembly in cells. In addition, noscapine does not appear to cause the toxic side effects associated with other microtubule targeting agents such as alopecia, diarrhea, nausea, and peripheral neuropathy. Because noscapine interaction with tubulin is different than those of paclitaxel and vincas, it can be used to increase the clinical efficacy of these drugs at lower less toxic doses.