CONCEPTS INTRODUCED

1. Microtubules
2. Clinical Studies: Phases


Microtubules are a kind of cell skeleton
and make up the organs of movement.
This spindle formation is necessary
process for a cell to divide into two.
when cell division is about to take place
microtubules depolymerise back to
tubulin and repolymerise to form the
spindle of cell division
as



Microtubule and its role during cell division
Role of microtubule in cancer c


Sackett & Sept. Proteinprotein interactions: Making
drug design second nature
Nature Chemistry 1, 596 - 597 (2009)
doi:10.1038/nchem.427
The structure of a microtubule is shown
on the left and a pair of tubulin
heterodimers are shown in longitudinal
contact on the right. Colchicine and
Taxol can bind to every -tubulin (only two
sites are shown here). Colchicine binds
to the unpolymerized dimer in the
intradimer contact region, whereas Taxol
binds to the polymerized dimer, but in the
lateral contact site. The binding site for
both the natural peptides and the
designed peptides in the paper of Sironi
and co-workers, is in the interdimer site
involved in longitudinal dimer contact.
Why target microtubules?


The cell cycle
microtubule-targeted antimitotic drugs
1. microtubule destabilizing agents,
inhibits microtubule
polymerization at high concentrations
and includes a number of compounds
such as the
Vinca alkaloids (vinblastine, vincristine,
vinorelbine, vindesine, and vinflunine),
cryptophycins,
halichondrins, dolastatins, estramustine,
2-methoxyestradiol, colchicine, and
combretastatins (62,63,154) that are
used clinically or are under clinical
investigation for
treatment of cancer.
2. microtubule stabilizing agents., These
agents stimulate microtubule
polymerization and include paclitaxel
(Taxol; the
first identified in this class), docetaxel
(TaxotereR Sanofi-Aventi), the
epothilones, discodermolide,
the eleutherobins, sarcodictyins,
laulimalide, rhazinalam, and certain
steroids
and polyisoprenyl benzophenones
(62,161).
Molecular Cell Biology. 4th edition
Lodish H, Berk A, Zipursky SL, et al.
New York: W. H. Freeman; 2000.

http://www.ncbi.nlm.nih.gov/books/NBK215
37/
Microtubule dynamics during mitosis
In both interphase and mitotic cells,
most microtubules radiate from the
microtubule-organizing centers (MTOCs), with
the () ends of the microtubules closest to
the MTOC and the (+) ends extending
outward. A typical interphase cell has long
microtubules; during mitotic prophase the
microtubule-nucleating activity of the already
replicated MTOCs (centrosomes in animal
cells) increases, generating a larger number of
shorter, more dynamic microtubules. In late
prophase, some of the microtubules interact
with kinetochores, causing the microtubules to
be partially stabilized. In
the metaphase mitotic apparatus, astral
microtubules elongate and shorten.
Epothilones


as
1. Patupilone
2. Ixabepilone
3. BMS-310705
4. KOS-862
5. ZK-EPO