Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2005-04-12
2005-04-12
Wang, Shengjun (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S172000, C514S175000, C514S182000
Reexamination Certificate
active
06878699
ABSTRACT:
In accordance with the present invention, there have been identified extracts from a tropical plant that initiate paclitaxel-like microtubule bundling. Bioassay-directed purification yields the steroid taccalonolide A. Taccalonolide, like paclitaxel, initiates the formation of abnormal interphaes and mitotic microtubules. Cells treated with taccalonolide exhibit thick bundles of microtubules that appear to nucleate independent of the microtubule organizing center. Abnormal mitotic spindles consisting of multi-polar spindles are initiated by taccalonolide and resemble abnormal mitotic spindles found in the presence of paclitaxel. Like paclitaxel, taccalonolide causes the breakdown of the nucleus into micronuclei. Taccalonolide causes G2/M arrest, Bc1-2 phosphorylation and initiates an apoptotic cascade that includes the activation of caspase 3. Taccalonolide is an effective inhibitor of proliferation against both SK-OV-3 and MDA-MB-435 cell with IC50values of 2.3 μM and 2.1 μM respectively. In contrast to paclitaxel, taccalonolide is effective against the multidrug resistant SKVLB-1 cellline and thus appears to be a poor substrate for P-glycoprotein-mediated transport. Although taccalonolide is almost equipotent with paclitaxel in its effects on cellular microtubules, it is much less potent than paclitaxel in its ability to initiate the polymerization of purified tubulin and microtubule protein. Taccalonolide A is the first microtubule stabilizing agent to be discovered from a plant since identification of the mechanism of action of paclitaxel and it is the first natural product steroid identified to have these cellular effects.
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Hemscheidt Thomas K.
Mooberry Susan L.
Foley & Lardner LLP
Reiter Stephen E.
University of Hawai'i
Wang Shengjun
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