Biology Reference
In-Depth Information
(30 mg/m
2
/day) combined with cyclophosphamide
(250 mg/m
2
/day) on days 1
Although 53% of patients presented with positive
responses, over half of the patients displayed hemato-
logical toxicity and one out of every ten patients
displayed infections that required hospitalization. Flu-
darabine has been combined with mitozantrone and
dexamethasone in a dose-escalation study for the treat-
ment of non-Hodgkin's lymphoma.
199
The doses used
in this preliminary study consisted of 25 mg/m
2
fludar-
abine for 3 days, 10 mg/m
2
mitozantrone on day 1, and
20 mg dexamethasone for 5 days. Although patients
with recurrent or refractory low-grade non-Hodgkin's
lymphoma showed an overall response rate of 94%,
immunosuppression was described as a significant
complication.
200
3 every 28 days. The over-
all response rate was slightly higher in patients receiving
the combination of fludarabine and cyclophosphamide
(94%) compared to fludarabine monotherapy (83%). In
addition, the median progression-free survival was
over twice as long in patients treated with fludarabine
alone versus the combination of fludarabine and cyclo-
phosphamide (compare 20 vs. 48 months, respectively).
Despite this, combination therapy caused significantly
more thrombocytopenia and leukocytopenia than flu-
darabine monotherapy although the number of severe
infections did not increase.
Results from the long-term UK LRF CLL4 trial are
perhaps the most impressive.
195
In this study, 777 previ-
ously untreated patients with CLL were randomly
assigned to three arms testing fludarabine alone
(25 mg/m
2
fludarabine for 5 days), chlorambucil alone
(10 mg/m
2
chlorambucil for 7 days), and combination
of fludarabine and cyclophosphamide (25 mg/m
2
fludarabine and 250 mg/m
2
cyclophosphamide for 3
days). The overall and complete response rates were
significantly better when fludarabine was combined
with cyclophosphamide (94% and 38%, respectively)
compared to fludarabine monotherapy (80% and 15%,
respectively), which were better than chlorambucil
alone (72% and 7%, respectively). Progression free
survival at 5 years was significantly better with fludara-
bine and cyclophosphamide (36%) compared with flu-
darabine (10%) or chlorambucil (10%) alone. Despite
these promising results, there was no significant differ-
ence in overall survival in patients given fludarabine
and cyclophosphamide compared to patients treated
with fludarabine or chlorambucil alone. In addition,
patients treated with fludarabine alone or fludarabine
and cyclophosphamide suffered more neutropenia
than patients undergoing chlorambucil monotherapy.
However, patients receiving fludarabine and cyclophos-
phamide presented with less autoimmune hemolytic
anemia (5%) than patients treated with fludarabine
(11%) or chlorambucil (12%) alone.
The combination of fludarabine and cisplatin also
displays synergistic effects, most likely due to inhibition
of the repair of DNA crosslinks.
196,197
Initial evaluations
of 100 mg/m
2
cisplatin over 4 days combined with
30mg/m
2
fludarabine followed with high doses (1 g/m
2
)
of cytarabine on days 3 and 4 generated a response
rate of 35% in 17 patients with fludarabine-refractory
CLL. However, this regimen was toxic due to signifi-
cant hematological toxicity and renal impairment.
198
Combinations of fludarabine with agents that induce
DSBs have also been evaluated. In a dose-finding study
of fludarabine plus doxorubicin in previously treated
patients with CLL, the MTD was 30 mg/m
2
fludarabine
daily for 4 days with 50 mg/m
2
doxorubicin on day 1.
e
Other Purine Nucleoside Analogs
2-Chlorodeoxyadenosine (2-CdA) is a deoxyadeno-
sine analog that is resistant to deamination by adenosine
deaminase and commonly used in the treatment of indo-
lent lymphoid malignancies, most notably hairy-cell
leukemia.
201,202
The pharmacokinetic profile of 2-CdA
is very similar to that of fludarabine,
203
the key excep-
tion being the need for dephosphorylation to gain
cellular entry. In rapidly dividing cells, the triphosphate
of 2-chlorodeoxyadenosine (2-CdATP) inhibits DNA
synthesis, and this is the primary mechanism for its anti-
cancer activity.
204,205
2-CdATP can also be incorporated
into DNA during nucleotide excision repair in which
its chain termination capabilities cause the progressive
accumulation of SSBs that eventually initiate apoptosis
via pathways that are p53-dependent or p53-indepen-
dent.
206,207
In addition, 2-CdA can also inhibit DNA
replication indirectly through its inhibitory action on
RnR
208
which causes a subsequent reduction of the
dNTPs pool required for DNA synthesis. Finally,
2-CdATP can function as a mimic of dATP to activate
caspase-3 and induce the activation of apoptosis.
209
Clofarabine is another deoxyadenosine analog that
shows promising anticancer activities against hemoto-
logical disorders and certain solid malignancies
including non-small-cell lung, colon, ovarian, prostate,
and breast cancer.
210,211
The pharmacokinetic profile of
clofarabine is similar to that of fludarabine. However,
the major exception is that the rate-limiting step for
forming clofarabine triphosphate is the conversion of
clofarabine monophosphate to clofarabine diphosphate
by a purine nucleotide monophosphate kinase.
212
In
2004, clofarabine received accelerated approval from
the FDA for treating pediatric patients with relapsed
or refractory ALL.
213
A phase I study with pediatric
patients concluded that the maximum tolerated dose is
52 mg/m
2
once daily administrated over a 2-hour
interval for five days repeated for various cycles every
2
6 weeks.
214
Promising results from this study lead
e
