Biology Reference
In-Depth Information
However, this criterion poses a problem for drug design,
because the current efficacy index by which antitumor
drugs are measured is based on tumor mass reduction.
Drugs that induce dormancy will not satisfy this efficacy
criterion. Whether such an approach can be taken may
depend on a perception change in practitioners, drug
industries, and regulatory authorities.
distribution with a double logarithm, the appearance
frequency is plotted on the vertical axis and the number of
interactions on the horizontal axis. With a single logarithm,
the number of interactions is plotted on the vertical axis
and the appearance frequency or the order on the horizontal
axis in most cases. Because of the shape of this single
logarithmic graph,
it
is sometimes called the long-tail
distribution.
This long-tail distribution is well known in the world of
internet business. This is because the long-tail distribution
has become the theoretical background of the profit struc-
ture of online shops. It started from the study of the sales of
Amazon.com
by a team from the MIT business school
[68]
.
Amazon.com
sells more than 2.5 million topics online, and
the sales amount and ranking of each topic form the long-
tail distribution. This means a few bestsellers and a great
many bad sellers form the long-tail distribution. It turns out
that half of the total sales came from the topics with sales
ranking No.1 to about No. 40 000. However, the other half
(estimations differs in the range of 57
LONG-TAIL DRUG
One of the points clarified in the discussions so far is that the
living body is a robust and evolving system, that its control
cannot be effective if an effort is made to simply identify
one factor and suppress it, and that it may rather bring about
undesirable side effects. Actually, it has been reported that
the genes involved in the initiation and maintenance of
cancers are quite often the hubs of networks
[65,66]
. The
fact that the causative gene of a cancer is mostly found in the
hub of a network means that, when the causative gene is set
as a target of a drug, there is an inherent risk of severe side
effects. Statistical studies indicate that the average number
of interactions involving targeted molecules of anticancer
drugs is significantly higher than those of non-cancer drugs
[67]
. This difference seems to reflect the degree of side
effects between anticancer drugs and other drugs. In order to
avoid the side effects, it is necessary to adapt the strategy to
avoid perturbing major hubs in molecular interaction
networks. In view of the above, cancer treatment requires
strategic and logical approaches.
When we look at the distribution of the number of
interactions that each molecule has, it seems to exhibit
a power law distribution. That is, the distribution indicates
that only a few proteins have a large number of interacting
partners, while a majority of proteins interact with only
small numbers of other molecules. The distribution
becomes a straight declining line on a double logarithmic
chart, while on a single logarithmic chart (vertical axis:
logarithm), it becomes a curved line with a very long tail in
the direction to the right (
Figure 24.5
). To show the
30%, depending on
studies) resulted from poorer sellers at No. 40 000 or lower.
In other words, even the bad sellers have a big impact
on total sales. It means that a concentration on bestsellers
may miss the business opportunity available in the thin but
long tail.
What does this imply for the interactions within cells
that show the same distribution pattern statistically? Is it
not possible to generate the effects similar to those by the
drugs that suppress very important genes and proteins by
applying weak suppression widely to the genes and proteins
that do not seem to be so important? This leads to the
conjecture that an effective synergy can be obtained by
targeting multiple non-hub genes and proteins and inter-
vening in them weakly rather than strongly. Let's call it
a 'Long-tail Drug'. If it goes well, treatments can be
provided without great disturbances to the hub molecules,
hence with fewer side effects.
Researches that aim to create effective drugs by dis-
turbing multiple target molecules with multiple chemical
e
FIGURE 24.5
Long-tail distribution.
