Biology Reference
In-Depth Information
compounds have already started. CombinatoRX, a Boston-
based drug development venture, has been exploring
a drug that can generate useful synergy by combining two
out of 1200 kinds of drugs
[68]
. As a result, it found some
interesting combinations. For example, there is data that, if
chlorpromazine (commercial name Contmin), a psycho-
tropic drug, and pentamizin (commercial name: Benam-
bax), an antibiotic substance of Pneumonia carinii
therapeutic agent, are given at the same time, the cytostatic
effect increases and an effect similar to or stronger than
that of paclitaxel (commercial name Taxol) used as an
anticancer drug can be obtained according to the experi-
ments of cultured cells. It is the important experimental
data to indicate that unexpected synergy is obtained by
multiple drugs, but no methodology has been established
that can estimate 'what kinds of effects can be obtained
when which molecules are set as targets.' At present,
screening to examine possible combinations one after
another is mainly done. This approach will be practical
for selecting the combination of two chemical substances
and a few targets from the molecules whose mechanisms
are known to some extent, but it will not be realistic
for identifying high-order and effective combination
efficiently.
A group of Hungarian researchers, using the metabo-
lism model of budding yeasts and bacteria, calculated how
much the metabolic rate decreases when the largest hub is
eliminated. Then they computed how many interactions are
necessary to realize a similarly decreased metabolic rate
using the method of reducing the number of interactions by
half
[69,70]
. As a result, it was found that 10
candidate proteins between the target cells and the off-
target cells will become a workable option.
OPEN PHARMA
The generation of synergy effect from the parallel use of
multiple drugs indicates the possibility of producing new
effects through the combination of off-patent drugs. For
example, given that a certain chemical substance was
developed and patented, the effect similar to that of new
chemical substance may be realized by the combination of
off-patent chemical substances. In this case, the value of
patented chemical substance may be significantly reduced.
When a combination of off-patent chemical substances is
packaged as a drug, clinical trials need to be done with the
package, which will cost almost the same amount of money
as a normal new drug. If the simple prescription of multiple
drugs will do, it could be a less costly solution. For
example, Toxol cost about 40 000JPY per 100 mg in Japan,
Contmin and Benambax cost about 3000JPY in total. If the
prescription of these drugs generates a certain effect, the
drug cost decreases dramatically.
At the same time, to discover the effects of the
combinations of drugs it is necessary to tackle enormous
numbers of combinations. The screening of the combina-
tions of only two drugs cost a lot, and so the screening of
the combinations of three or more drugs is too much for one
company. Disclosing the combination information and
searching for new combinations in open collaboration will
be effective. At the same time, the combination of off-
patent chemical substances should be aggressively exam-
ined. That is to say, it is the opening of medicine
manufacturing processes to the public. In this paradigm,
part of the pharmaceutical industry changes from
a manufacturing industry to a service industry. That is, the
companies will provide the public with the information on
the combination of drugs and their usage instead of
developing new drugs. The same thing has already
happened in the computer industry. IBM used to sell patent-
protected computers, but it has become a solution provider
to support positively open sources now (but their main-
frame is doing well). Similar things may happen to the
pharmaceutical industry.
This indicates a very interesting possibility. If the
combinations of inexpensive drugs produce effects similar
to those of expensive ones, they will contribute to the
substantial decrease in drug cost in medical expenses, and
at the same time they will be able to respond to the
substantial needs for the drugs that can be used for the
people who cannot afford to use these expensive drugs
economically.
When this technology advances further, it will become
possible to design drugs optimized to individual genetic
and
50 interac-
tions need to be suppressed. Theoretically this shows the
possibility of having a big impact on the cells with the use
of the combination of weak interactions.
These results imply that the approach of intervening in
multiple targets with the use of network structures and
multiple chemical substances, when applied to the devel-
opment of new drugs and the study of combination therapy
using existing drugs, becomes an important option. The
ultimate goal is a long-tail drug combination that generates
the synergy of weak interactions with the simultaneous use
of very many substances. The procedure is to avoid as much
as possible the important targets
e
and
try to get the synergy effect on many targets that are not
thought to be important but which exist abundantly in the
long tail of the distribution of the number of interactions of
proteins and genes
[64]
.
Since there are enormous numbers of possibilities in the
selection of target molecules and in the combinations of
drugs in this case, it is necessary to establish technology to
efficiently select effective combinations with the fewest
side effects. The author considers that the approach of
measuring the differences of robustness against the altered
expression of candidate genes and the altered activity of
e
the so-called hubs
e
epigenetic
characteristics
by
replacing
some
