Biology Reference
In-Depth Information
enzymes such as hMLH1.
240
Epigenetic silencing,
whether it be genome-wide or gene-specific, provides
another potentially cytotoxic mechanism. Indeed,
5-aza-2'-deoxycytidine (Decitabine) is another pyrimi-
dine analog that is a near perfect mimetic of 2-deoxy-
cytidine as only the C5 carbon is replaced with nitrogen
(
Figure 5.10
). This simple substitution does not hinder
incorporation into DNA. However, the introduction of
nitrogen prevents the ability of nucleobase to be modi-
fied by DNA methyltransferases. Preventing DNA
methylation leads to hypomethylation of certain gene
promoters which then influences transcription rather
than replication.
241
For example, many sporadic colon
cancers show hypermethylation of the hMLH1 gene
promoter which correlates with lower expression of
gene product, hMLH1, an essential DNA repair
protein.
242
Reduced levels of this repair enzyme play
important roles in the development of carcinogenesis
in addition to drug-resistance to various chemothera-
peutic agents such as temozolomide that damage
DNA. Upon treatment with 5-aza-2'-deoxycytidine,
these cells regain expression of the hMLH1 protein
which then sensitizes cells to the cytotoxic effects of
certain chemotherapeutic agents. Although 5-aza-2'-
deoxycytidine is sometimes used clinically, it possesses
a relatively narrow therapeutic window as it affects
the methylation patterns of normal and cancer cells.
243
transaminases, fever, myalgia, flu-like symptoms, and
extremity edema. Nausea, vomiting, fatigue, and head-
ache are typically mild and are not dose-dependent.
Clinical and Biochemical Studies
of Gemcitabine Combined with DNA
Damaging Agents
As discussed previously with fludarabine, the chain
termination capabilities of gemcitabine coupled with
its effects on deoxynucleotide metabolism predict that
it could also be used in combination with DNA
damaging agents to produce synergistic cytotoxic
effects. Indeed, gemcitabine has most frequently been
combined with platinum drugs such as cisplatin and
oxaliplatin.
250
e
254
This combination has been demon-
strated to generate synergistic cell-killing activity
against several human cancer cell lines.
250,251
The basis
for combining gemcitabine with platinum agents is
based primarily on clinical evidence of drug tolerance
rather than on basic science principles. In particular, it
is clear that gemcitabine is a relatively well-tolerated
drug as it generates moderate side effects such as mild
myelosuppression, asthenia, and nausea/vomiting.
255
In contrast, treatment with oxaliplatin causes more
serious complications such as cumulative peripheral
neurotoxicity and potential nephrotoxicity.
256
As such,
the goal is to employ gemcitabine as a sensitizing agent
to lower the acute and cumulative doses of platinum-
based DNA damaging agents and thus avoid the more
serious side effects. Today, the combination of gemcita-
bine and oxaliplatin (Gemox) is widely used against
various solid tumors.
257
For example, the results of
a phase II trial using the Gemox neoadjuvant chemo-
therapy for patients with locally advanced, nonmeta-
static pancreatic cancer were published with
encouraging results.
258
This neoadjuvant chemothera-
peutic regimen consisted of gemcitabine (900 mg/m
2
)
and oxaliplatin (60 mg/m
2
) given as an intravenous
infusion once a week at day 1 of each treatment cycle.
Patients received between 6 and 9 cycles of this regimen.
Patients with sufficient tumor regression subsequently
underwent pancreatic resection and were followed post-
operatively to assess long-term survival. Of a total of 33
eligible patients treated, 18 patients had unresectable
disease at inclusion, and 15 patients had borderline
resectable pancreatic cancer. Eventually, 13 of the 33
patients (39%) had a curative resection after neoadju-
vant therapy. The median overall survival of patients
who underwent tumor resection was 22 months
compared with 12 months for patients that did not
undergo resection. In addition, the median recurrence-
free survival rate after resection was 10 months. Collec-
tively, this clinical trial demonstrated that neoadjuvant
gemcitabine plus oxaliplatin is a well tolerated and
Clinical Utility of Gemcitabine
as a Monotherapeutic Agent
The efficacy of gemcitabine in inhibiting cancer cell
growth has been documented in numerous studies
using both hematological and adherent cancer cell
lines.
244
In addition, gemcitabine shows remarkable effi-
cacy against a variety of human tumor xenografts in
nude mice models,
245
thereby validating the
in vivo
effi-
cacy of this anti-neoplastic agent. As a result of these
extensive preclinical studies, gemcitabine is currently
used as a single agent to treat patients with various
leukemias and lymphomas as well as metastatic pancre-
atic cancer
246
and is also used in combination regimens
against non-small-cell lung cancer, bladder cancer,
ovarian cancer, and breast cancer.
247,248
As a single agent, dFdC has been most extensively
evaluated using doses ranging from 800 to 1250 mg/m
2
administered as a 30-min infusion on days 1, 8, and
15 of a 28-day cycle.
249
With this dosage and dosing
schedule, the most frequently occurring toxicities asso-
ciated with dFdC are hematological in which neutro-
penia occurs more frequently than thrombocytopenia.
Fortunately, hematological toxicity is cumulative and
can be easily managed by dose elimination, dose
reduction, or by delays in dosing. Other reversible
forms of toxicity include transient increases in hepatic
