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Iwao Ojima, Ph.D.
Distinguished Professor and Chairman, Department
of Chemistry.
Funding through the National General Medical Sciences.
Figure 1. Illustration of a taxoid-MAb
immunoconjugate (taxoid is represented by yellow "warhead"),
wherein four taxoid molecules are attached to one antibody.
The immunoconjugate specifically binds to EGFR on tumor surface
and internalized to the cancer cell via endocytosis, and the
taxoid is released only in the cytosol of the cancer cells so
that it does not affect normal cells. |
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The research in my laboratory focuses on the chemistry and chemical biology
of antitumor agents that block the cell division cycle of cancer cells
by stabilizing microtubules. A well-known drug in this class of compounds
is Taxol®. Taxol® (paclitaxel), a naturally occurring diterpenoid isolated
from the bark of the Pacific yew tree (Taxus brevifolia), is currently
considered one of the most important drugs in cancer chemotherapy, which
has been extensively used against ovarian, breast, AIDS related Kaposi's
sarcoma, lung, head and neck, prostate, and cervial cancers. Paclitaxel
binds to the ß-subunit of the tubulin heterodimer, and accelerate the
polymerization of tubulin and stabilizes the resultant microtubules, thereby
inhibiting their depolymerization. The stabilization of microtubules results
in the arrest of the cell division cycle mainly at the G2/M stage, leading
to apoptosis of the cancer cells through cell signaling cascade.
Although paclitaxel possesses potent antitumor activity, it has been
shown that treatment with this drug often encounters undesired side effects
as well as various drug-resistance. Therefore, it is important to develop
new taxoid anticancer agents with fewer side effects, superior pharmacological
properties, and improved activity against various classes of tumors, especially
against drug-resistant human cancers. Our research program has discovered
and developed "second generation taxoids", which are substantially more
potent than paclitaxel against a variety of cancer cells and tumors, in
particular against drug-resistant cancers that are expressing multi-drug
resistance (MDR) caused by the overexpression of P-glycoprotein. We have
also succeeded in developing the first hightly efficient orally active
taxoid antitumor agent, which is in human clinical trials at present.
This line of research, aiming at developing advanced second generation
and third generation taxoid antitumor agents, is actively underway. It
is well known that general weakness of cytotoxic chemotherapeutic agents
is the fact that these drugs cannot distinguish cancer cells from normal
cells. This unfortunate feature constitutes major basis for a variety
of undesirable side effects associated with these drugs for cancer chemotherapy.
However, this basic weakness can be overcome by tumor-activated prodrug
"TAP" strategy with the use of appropriate antibodies that recognize particular
tumor surface antigens as specific vehicle for highly cytotoxic anticancer
drugs.
We are exploring novel immunoconjugates of the second generation taxoids
with monoclonal antibodies (MAb) that recognize antigens specific to certain
tumor surfaces such as epidermal growth factor receptor (EGFR). Our taxoid-MAb
conjugates (Fig. 1) have exhibited remarkable antitumor activity in animal
models, resulting in complete inhibition of tumor growth in all treated
animals for the duration of experiments. Moreover, the immunoconjugates
were totally non-toxic to animals at the effective doses, showing no weight
loss. Based on the extremely promising result, we are currently developing
immunoconjugates suitable for human clinical use.
The students in my research program will be introduced to a variety of
chemical syntheses, synthetic methodology, spectroscopic analyses including,
NMR, IR, UV, and Mass spectrometry, analysis and purification using HPLC
and GC, computer molecular modeling, structure-activity relationships,
etc. The students will be involved in a drug discovery and/or a structure-activity
relationship study wherein they can learn rational drug design, mechanism
of action of a drug, molecular targets in cancer chemotherapy, and actual
syntheses of anticancer agents and related compounds as well as characterization
of their structures using modern analytical techniques. The students will
also experience very interdisciplinary nature of this type of research,
which includes many collaborations with experts in molecular pharmacology,
cell biology, computational biology, experimental therapeutics, and oncology.
Contact Information
email: iojima@notes.cc.sunysb.edu
url: http://ojima10.chem.sunysb.edu/~ojimaweb/ojima/ojima.html
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