Cancer Chemotherapy, Theoretical Foundations of
173
1
Cancer Therapy
Cancer remains largely a clinically unmet
disease. Statistics tell us that cancer affects
one person in three, and in the Western
world, it is the cause of about a quarter of all
mortality. Worldwide, cancer is the second
largest cause of death, and the World
Health Organization estimates that by
2020, there will be 20 million new cancer
patients each year. Cancer is not a single
disease, as there are over 200 different
typesofdiseasesthatfallintothiscategory.
However, four cancers dominate, namely,
lung, breast, colon, and prostate, which
account for over half of all new cases.
Most current cancer therapies employ
one of three approaches, namely, surgery,
radiotherapy, or chemotherapy. Surgery
and
radiotherapy
are
frequently
used
to treat localized primary tumors, but
have limited application in disseminated
disease in which the tumor is not localized,
usually as a result of metastasis. Needless
to say, disseminated disease is the cause
of most cancer deaths. Current cancer
chemotherapy is dominated by treatments
that use cytotoxic agents or hormone-based
therapy, for example, in breast and prostate
cancer (Table 1).
Tab. 1
Examples of conventional cancer
chemotherapeutic agents.
Drug
Category
Methotrexate
Antimetabolite
Taxol
Spindle modulator
Cyclophosphamide
Alkylating agent
Cisplatin
Platinum-DNA
complexes
Doxorubicin
DNA intercalat-
ing/topoisomerase
inhibitor
Furthermore, while advances have been
made in all three approaches to treat-
ment,
the
impact
on
mortality
rates
has been modest. As an example, lung
cancer,
the
leading
cause
of
cancer
death worldwide, has a ±ve-year survival
rate of only 5%, which hardly differs
from the survival that prevailed 30 years
ago
(www.cancerresearchuk.org).
How-
ever, there are some notable improve-
ments. Cures are achievable in certain
childhood leukemias and testicular cancer,
although of the six most common can-
cers, only breast cancer has a survival rate
greater than 50%. Overall, conventional
chemotherapy is relatively ineffective in
many cancers.
This situation reflects the mechanism
of action of most current cancer therapy
regimes, which are dominated by cyto-
toxic chemotherapies (Table 1). In general,
these chemotherapies target mechanisms
employed by most dividing cells, rather
than speci±c genetic abnormalities associ-
ated with tumor cells. Because of this, their
normal healthy counterparts are affected
almost as severely as the tumor cells, lead-
ing to the highly debilitating side effects
seen with many therapies, such as myelo-
suppression, hair loss, and gastrointestinal
toxicity. This problem, combined with the
poor quality of life and diminishing effec-
tiveness in the patient (usually because of
the emergence of drug resistance), means
that many late stage cancer treatments pro-
vide minimal survival advantage.
2
The New Era of Mechanism-based Drug
Design
Because of the limited therapeutic value
of many current treatments, major ef-
forts are being applied toward identi-
fying new cancer therapies that target
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