The camptothecin analog irinotecan (CPT-11, Camptosar) was
recently approved for the treatment of fluorouracil (5-FU)-resistant colorectal
cancer, opening a new chapter in chemotherapeutic radiation sensitization.
The combination of CPT-11 with irradiation can build onto the successful
radiation sensitization trials with 5-FU. Both 5-FU and irinotecan have
cytotoxic activity against S-phase cells; they have a defined role in the
treatment of colorectal cancer;[3-5] and they are radiation sensitizers (Table
1). Radiation sensitization with these agents is dose- and
schedule-dependent,[6,7] based on data from preclinical models and clinical
trials. New laboratory data on the camptothecins suggest that the timing of
administration may allow for dose escalation and may be an additional important
factor in the design of irinotecan radiosensitizer trials.
The molecular basis for the lethal effects of ionizing radiation
alone include the production of single- and double-strand breaks in DNA.
Repair of x-ray and/or chemotherapy-induced genomic damage can require
topoisomerase I, which is widely utilized in DNA metabolism. In the presence
of camptothecin, camptothecin/topoisomerase I/DNA complexes become stabilized
because the 5'-phosphoryl terminus of an enzyme-catalyzed DNA single-strand
break is bound covalently to a tyrosine of topoisomerase I. Irradiation creates
many single-strand breaks and these sites can be attacked by topoisomerase I in
the presence of camptothecin. The rate of topoisomerase I binding to nicked DNA
is also more rapid (increased by factor of 800 to 1,000) than its binding to
undamaged supercoiled DNA.[11,12] Stabilized complexes interact with the
advancing replication fork during S phase or during unscheduled DNA replication
after genomic stress. The result of the presence of camptothecin is the
conversion of single-strand breaks into irreversible DNA double-strand breaks,
resulting in cell death.[11-13] Unrepaired DNA damage can be recognized by the
p53 damage-sensing pathway, initiating and possibly amplifying the apoptotic
pathway of cell death.[14,15]
Camptothecins can also modulate apoptosis independent of DNA
synthesis in postmitotic neurons and confluence-arrested cell cultures,
as well as in actively proliferating cell cultures and in murine tumors in
vivo. High levels of topoisomerase I are associated with a high frequency of
cleavable complex formation, and high topoisomerase I levels have been
detected in surgical specimens from colonic, ovarian, esophageal, breast,
stomach, and lung cancers, malignant melanoma, and in cultures from non-Hodgkin’s
lymphoma and leukemia cells.
One basis for selective camptothecin toxicity in malignant cells
as compared with normal tissues may be related to these enzyme levels. An
additional biological basis for selective camptothecin activity may be related
to the low pH found in cancers, which stabilizes the closed (active) lactone
ring. Another effect of the camptothecin/topoisomerase I/DNA cleavable
complexes is on the repair of potentially lethal damage in the DNA of
Combined camptothecin and irradiation effects appear to be
determined by position in the cell cycle. Camptothecins are considered S-phase
agents because selective cytotoxicity is observed in the S phase[20,21,23] with
relative sparing of G1-, G2-, and M-phase cells following pulse exposure to
camptothecin. Elimination by aphidocolin of the camptothecin cytotoxicity
and radiation sensitization is consistent with its S-phase effects.
Additional contributions to radiation sensitization may be related to
synchronizing effects of irradiation that preferentially kill G2-M cells,
leaving S-phase cells intact and subject to attack by camptothecin
Dose, Schedule, and Time of Day
In our laboratory we have examined the use of irradiation with
the camptothecin analog 9-aminocamptothecin (9AC), delivered in different doses,
schedules, and at different times of the day.[7,8] We determined an optimal dose
and timing of irradiation with 9AC in vivo using the MCa-4 mouse mammary
carcinoma. For example, 9AC given with daily fractionated irradiation
resulted in dose modification factors of 2.4 (95% confidence interval [CI] = 2.0
to 3.1) and 3.7 (95% CI = 3.1 to 4.6) in animals treated with 0.5 and 2 mg/kg
9AC twice a week for 2 weeks, respectively.
In experiments in which the total dose was kept constant at 4
mg/kg, 9AC was more effective when given either twice or four times a week
compared with once a week (dose modification factors of 2.8 [95% CI = 2.2 to
3.9], 2.6 [95% CI = 2.0 to 3.6], and 1.7 [95% CI = 1.3 to 2.4], respectively).
The dose modification with single-dose irradiation and 9AC is markedly reduced
(dose modification factor = 1.11). These results indicate that, in this murine
tumor, fractionation of both the radiosensitizer dose and irradiation produces
greater effect compared with large single doses used less frequently. Combined
camptothecin and irradiation can also severely affect the small intestine; we
have shown in the animal model that this is related to dose-dependent loss of
the mucosal layer of the small intestinal villi.
We also examined the acute toxicity of 9AC administered to
rodents at different times over a 24-hour period. Several phase I and II trials
using chronoregulated chemotherapy have shown that drug toxicity depends on the
time of day of administration, which provides strong support for a relationship
between trough values of gastrointestinal epithelial cell DNA synthesis rates
and reduced toxicity to anti-S-phase chemotherapeutic agents.[26-28]
Based on the hypothesis that chronomodulated delivery could be
done at a time when the systemic dose would be better tolerated, we showed that
the 9AC dose could be escalated by approximately 30% when administered at the
time it could be best tolerated. Others have also shown that irinotecan is
less toxic (less total body weight loss and acute mortality) during the animal’s
resting phase when proliferation in the gastrointestinal tract is low.[29,30]
These data underscore the need for a clinical trial of camptothecin as a
radiosensitizer with chronomodulated administration in order to ameliorate acute
Chemoradiation is based on cytotoxic cooperation between
systemic chemotherapy and fractionated irradiation. The superiority of
fractionated irradiation has long been evident because it spares late effects.
When fractionated irradiation is combined with S-phase-specific agents, a form
of "accelerated treatment" is produced whereby the dose-limiting
toxicities are not only late morbidity of irradiation (eg, fibrosis and
necrosis), but also enhanced acute toxicity expressed in the rapidly
proliferating cell compartments. The pattern of dose application used in
camptothecin radiation sensitization trials could thus play a significant role
in success or failure.
Irinotecan is a semisynthetic derivative of camptothecin that
has shown a wide range of antineoplastic activity in vitro and in vivo.
Treatment schedules with irinotecan alone have varied: in the United States, 125
to 150 mg/m2 once a week for 4 weeks followed by a 2-week drug-free interval; in
Europe, 350 mg/m2 once every 3 weeks; or in Japan, 100 mg/m2/wk or 150
every 2 weeks. Other intermittent treatment schedules using cytokine support
for neutropenia, or intensive loperamide for moderate to severe diarrhea, have
also been reported. These irinotecan regimens in patients with colorectal
cancer have resulted in median response durations ranging from 5.6 to 10.6
months, disease stabilization in 30% to 71%, and response rates of 26% to
32% in previously untreated patients.[34,35] Lower response rates have been
reported for 5-FU-refractory patients (7% to 21%). Diarrhea, nausea, and
vomiting are common toxicities; other side effects include asthenia, abdominal
pain, leukopenia, and neutropenia.
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