Biology Reference
In-Depth Information
safe regimen that offers the potential for curative resec-
tion and improvement in overall survival in patients
with pancreatic cancer.
both cytostatic and cytotoxic effects that reduce tumor
growth. Radiosensitization with nucleoside analogs
including gemcitabine and fludarabine has improved
clinical outcome for patients with solid malig-
nancies.
264
e
266
The rationale for combining nucleoside
analogs with ionizing radiation lies in the ability of the
corresponding nucleoside triphosphates to inhibit poly-
merases involved in DNA synthesis and repair. Since
these agents can inhibit DNA repair, they can increase
the amount of residual DNA and chromosome damage
after irradiation to induce apoptosis. As inhibitors of
DNA synthesis, they specifically target S-phase cell pop-
ulations to overcome tumor repopulation that can occur
during fractionated irradiation therapies. Finally, nucle-
oside analogs can also inhibit DNA synthesis and DNA
repair by depleting nucleotide pools.
Potential Mechanisms for Synergistic Activity
Several preclinical studies have been performed to
address the ability of gemcitabine to synergize with
cisplatin/oxaliplatin.
253,254,259,260
A study performed by
Jensen
et al.
used the ovarian cancer cell line, A2780, as
a model to evaluate the synergistic activity of combining
gemcitabine and cisplatin compared with using either
agent alone.
259
These authors demonstrated that the
combination of gemcitabine and cisplatin causes an
increase in the retention of platinum-DNA adducts
compared to treatment with cisplatin alone, and that
this increase resulted from decreased DNA repair. The
authors argued that inhibition of specific exonucleases
such as excision repair cross-complementation group 1
(ERCC1) is instrumental in the ability of gemcitabine
to inhibit the repair of the platinum-adducts. However,
other models for the synergistic effects have been
proposed. One intriguing model is based on the ability
of gemcitabine to inhibit specialized DNA polymerases
that are involved in by-passing platinum-adducts.
260
For example, cells derived from XP-V patients that are
deficient in the specialized polymerase pol
h
are more
sensitive to ara-C, gemcitabine, or cisplatin single-agent
treatments than normal human fibroblast cells that
possess pol
h
. More importantly, pol
h
deficient cells
are ~10-fold more sensitive to the combined treatment
of gemcitabine and cisplatin. The results of cellular
and biochemical studies suggest that the higher sensi-
tivity of the pol
h
-deficient cells results from their
inability to complete DNA replication beyond unre-
paired cisplatin-adducts. The fact that pol
h
plays an
important role in defining sensitivity of a cell to DNA
damaging agents has important implications for devel-
oping new therapeutic agents, and this aspect is dis-
cussed in more detail later.
COMPLICATIONS ASSOCIATED WITH
THE CLINICAL USE OF NUCLEOSIDE
ANALOGS
While nucleoside analogs are important in the treat-
ment of cancer, their utility is often limited by dose-
limiting toxicity that arises due to their non-selective
nature. Non-selective killing occurs since a number of
the body's normal cells also are rapidly dividing and
are thus killed more frequently by compounds that alter
DNA replication. Common side effects that occur with
chemotherapeutic agents that target DNA synthesis
include anemia, leukopenia, thrombocytopenia, and
gastrointestinal symptoms such as nausea, vomiting,
and diarrhea.
267
Of these, the most serious side effects
are those associated with immunosuppression. Treat-
ment with purine nucleoside analogs generally causes
a decrease in the CD4
ratio for an extensive
period of time that often exceeds 24 months.
268
As
a result, the development of opportunistic infections
are frequent events and infections with fatal outcome
have been reported.
269,270
As a result, patients receiving
nucleoside analogs are sometimes co-adminsitered anti-
biotics as prophylactic measures against opportunistic
infections. Treatment with purine nucleoside analogs is
also associated with bone marrow suppression with pro-
longed thrombocytopenia, neutropenia, and anemia. In
one randomized study, strong myelosuppression was
observed with 2-CdA treatment that resulted in a high
incidence of neutropenia (23%) in patients treated with
this nucleoside analog when compared to treatment
with chlorambucil and prednisone (11%).
271
Infections
or fever of unknown origin were also more frequent
after treatment with 2-CdA compared to chlorambucil.
The study by Rai
et al.
reported a higher incidence of
neutropenia and infections after treatment with fludara-
bine compared to treatment with chlorambucil.
187
Other
þ
/CD8
þ
NUCLEOSIDE ANALOGS AS
RADIOSENSITIZERS
Ionizing radiation is used in nearly 50% of all cancer
patients as it shows effectiveness against many malig-
nancies, including brain, cervix, breast, and colon
cancers that are in many cases inaccessible to surgery
or refractory to standard chemotherapeutic agents.
261
At the molecular level, ionizing radiation destroys
cancer cells by creating radicals that ultimately damage
genomic DNA.
262
Although several forms of DNA
damage are produced, DSBs are the most lethal.
263
The
inability of a cancer cell to effectively repair DSBs causes
