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 currently in phase I clinical trials for the treatment of
- Noscapine conjugate (Targetin) retains the parent compound microtubule
binding and resulting microtubule dynamics attenuating activities.
- Since activated macrophages also over express receptors for Targetin, it
can be used for the treatment of inflammatory disease.
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.
- Targetin has been synthesized in the laboratory using a four-step process
starting with Noscapine.
- In vitro and preliminary in vivo data indicate Targetin
more effective in controlling cancer cell growth as compared to parent