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establish robustness to the second drug will appear, for
which a third drug should be prepared. This is therefore the
method for exploring the fragility of cancer by changing the
treatments consecutively. Further exploration of the above
approach would be via the development of a method for
controlling and creating/inducing fragility artificially.
Some readers may wonder if such a convenient set of
circumstances could really happen. In fact, the phenom-
enon whereby a cancer that obtained tolerance to a certain
type of anticancer drug became fragile to other anticancer
drugs was already known in the 1970s as 'collateral
sensitivity'. Skipper et al. investigated into when a cancer
becomes tolerant to one of 30 drugs, and to which other
drugs that cancer becomes fragile [49] . Figure 24.4 shows
the tolerance to 10 anticancer drugs out of 30. This research
was not pursued, but it shows the trade-offs of robustness
and so needs to be studied anew.
Second, there are possibilities for deploying more
'ecological' approaches. When cancer cells with multiple
kinds of genetic diversity coexist, they may be in compet-
itive and symbiotic situations. There is an interesting
example in the treatment of prostate cancers. For prostate
cancer, androgen-dependent cancer cells proliferate to
grow a tumor. Blocking androgen to destroy those cells is
the main purpose of treatment. However, it is known that
after the shrinkage of tumor primarily consisting of
androgen-dependent cells, androgen-independent cancer
cells begin to proliferate. The androgen-independent cancer
cells are more malignant and harder to cure. In the situation
where the androgen-dependent cells and the androgen-
independent cells coexist, it is observed that there is
a possibility of slight reductions in androgen-independent
cancer cell clusters. In this case, it will be possible to
establish a treatment to control the proliferation and
reduction of the tumor by blocking androgen intermittently.
The actual clinical results show the effectiveness of such an
intermittent androgen control method [50
52] . Aihara and
his team at the University of Tokyo conducted mathemat-
ical analyses of these dynamics to derive an optimum
treatment strategy [53] . This is a method of controlling the
ecology of cancer cell clusters having diversity. Through
the further generalization of this method and the systematic
use of multiple treatments, the method of controlling the
ecology of cancer will become an important approach in
the future.
Third, approaches that avoid increases in robustness are
another possibility. Since genetic heterogeneity is
enhanced, at least in part, by somatic recombination,
selectively inducing cell cycle arrest in tumor cells can
effectively control the robustness. There is a theoretical
possibility that such subtle control can be achieved by
careful combination of multiple drugs that specifically
perturb biochemical interactions. A computational study
indicates that removal or attenuation of specific feedback
loops involved in the cell cycle reduces robustness of the
cell cycle against changes in rate constants [54] .The
challenge is to find appropriate combinations of drugs that
can effectively induce cell cycle arrest only in tumor cells,
but not in other cells. While this approach uses a combi-
nation of multiple drugs, the hope is to find a set of drugs
that can be administered at minimum dosage and toxicity.
This approach results in dormancy of tumors. Cancer
dormancy has already been proposed [55,56] and several
reports indicate that induced dormancy has been observed
in the mouse [57,58] . However, these studies report cases
where tumor cell proliferation is offset by increases in
apoptosis. Since heterogeneity may increase by cell
proliferation, this type of dormancy, which can be called
'pseudo dormancy,' does not prevent an increase of
heterogeneity, hence robustness is not controlled. Genuine
dormancy needs to induce cell cycle arrest as selectively as
possible.
e
Drugs that cancer cells show sensitivity
1
23456789 0
1
Collateral Sensitive
1. Ara-C
2. Hydroxyurea
3. Guanazole
4. Pyridine-2-CATS
5. Amethopter in
6. 6-MP
7. 6-Thioguanine
8. 8-Azaguanine
9. 6-Metyhyl MPR
10. 5-FU
2
3
4
5
6
Cross Resistant
Therapeutic Potentiation
7
8
9
10
Excerpt from Skipper, et al.,
Cancer Chemotherapy Reports
Part 1 Vol. 56, No. 4, 1972
FIGURE 24.4 Collateral sensitivity.
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