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Camptothecin Radiation Sensitization: Mechanisms, Schedules, and Timing

Camptothecin Radiation Sensitization: Mechanisms, Schedules, and Timing

ABSTRACT: Based on high tumoricidal activity of the camptothecin analogs topotecan (Hycamtin), irinotecan (CPT-11[Camptosar]), and 9-aminocamptothecin (9-AC) in preclinical studies, clinical trials began testing these agents against human cancers. The cytotoxic activity of camptothecins in the clinic has been lower than predicted from the laboratory, however, and new approaches are needed. One method that holds promise is the use of the camptothecins as radiation sensitizers. The camptothecin dose, schedule, method of administration, and timing of administration, when given with irradiation, are likely to be important factors for these new S-phase radiation sensitizers. Phase I trials of the camptothecins as radiation sensitizers have begun, and multicenter phase II studies are planned by the Radiation Therapy Oncology Group (RTOG). One new approach based on preclinical observations that deserves clinical evaluation is chronomodulated camptothecin delivery with irradiation in order to widen the therapeutic window. [ONCOLOGY 12(Suppl 6):114-120, 1998]

Introduction

Recent Food and Drug Administration approval of the camptothecin
analog irinotecan (CPT-11 [Camptosar]) for the treatment of
colorectal cancer resistant to fluorouracil (5-FU)[1] has opened a
new chapter in chemotherapeutic radiation sensitization. High
interest in using this and other camptothecins (eg, topotecan
[Hycamtin], 9-aminocamptothecin) in combination with irradiation is
based in part on past successes with 5-FU, an antimetabolite, as a
radiation sensitizer.[2] Both camptothecin analogs and
antimetabolites have cytotoxic activity against S-phase cells, and
both have a defined role in the treatment of colorectal cancer, a
disease in which radiation sensitization has improved locoregional
control and overall survival.[3]

Radiation sensitization with either class of agents is dose- and
schedule-dependent,[4] and the importance of the timing of
administration of these drugs when given with fractionated
irradiation is a new factor that is gaining attention. This knowledge
combined with new laboratory data will be important in the design of
new camptothecin radiosensitizer trials.

Cytotoxic Mechanisms of Camptothecins and Irradiation

The molecular basis for the lethal effects of ionizing radiation
alone include the production of single- and double-strand breaks in
DNA.[5] Another basic observation regarding repair of x-ray- or
chemotherapeutic-induced genomic damage is the requirement for
topoisomerase I, which is widely used in DNA metabolism.[6]

In the presence of camptothecin, the camptothecin-topoisomerase I-DNA
complex becomes stabilized because the 5¢-phosphoryl terminus of
an enzyme-catalyzed DNA single-strand break is bound covalently to a
tyrosine of topoisomerase I. Irradiation can create thousands of
single-strand breaks per cell per gray, leaving these sites to 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 a factor of 800 to 1,000) than its binding rate to
undamaged supercoiled DNA.[7,8] These stabilized complexes interact
with the advancing replication fork during S-phase or during
unscheduled DNA replication after genomic stress and cause the
conversion of single-strand breaks into irreversible DNA
double-strand breaks, resulting in cell death (Figure
1
).[7,9]

Topoisomerase I may also compete with DNA repair complexes (DNA
ligases, poly-(adenosine diphosphate)-ribosyl-transferase) for the
single-strand breaks. In the presence of camptothecins, this can
result in unrepaired DNA damage that can be recognized by the p53
damage-sensing pathway, initiating and possibly amplifying the
apoptotic pathway of cell death.[7,10-12] The camptothecins have also
been found to modulate apoptosis independently of DNA synthesis in
postmitotic neurons[13] and confluent cell cultures,[10] as well as
in actively proliferating cell cultures[14] and in murine tumors in vivo.[15]

High levels of topoisomerase I are associated with a high frequency
of cleavable complex formation.[16] High topoisomerase I levels have
been detected in surgical specimens from malignant melanoma, colonic,
ovarian, esophageal, breast, stomach, and lung cancers, and in
cultures from non-Hodgkin’s lymphoma and leukemia cells.[17] One
basis for selective camptothecin toxicity in malignant cells compared
to normal tissues may relate to these enzyme levels. An additional
biological basis for selective camptothecin activity is the low pH
found in cancers that can stabilize the closed (active) lactone ring form.[17,18]

In addition, DNA-topoisomerase I-camptothecin cleavable complexes
affect the repair of potentially lethal damage in plateau phase cells (Figure
1
).[7] In contrast, in log phase cells, lethality caused by
camptothecin and irradiation also appears to be determined by effects
on the cell cycle; ie, there appears to be differential phase
specificity of cell killing by drug and irradiation. The
camptothecins are considered to be S-phase agents since selective
cytotoxicity is observed in S-phase,[14,16,18,19] while G1-,
G2-, and M-phase cells are relatively spared following
pulse exposure to camptothecin.[19] Elimination by aphidocolin of
camptothecin-induced cytotoxicity and radiation sensitization is
consistent with these S-phase-selective effects.[20]

An additional contribution to radiation sensitization by combination
treatment may be the synchronizing effect of irradiation itself that
preferentially kills G2- through M-cells, thus leaving
S-phase cells intact and subject to attack by camptothecin.[14,19]

Clinical Studies

The clinical basis for chemoradiation is cytotoxic cooperation
between systemic chemotherapy and irradiation when chemotherapeutic
drugs are given concurrently with fractionated irradiation. Clinical
research has established the superiority of fractionated irradiation,
which spares late toxic effects. When S-phase-specific agents are
administered with conventional irradiation (eg, 2 Gy/d), this regimen
becomes a form of accelerated treatment.[21] With such regimens, the
dose-limiting toxicity may consist not only of the late morbidity of
irradiation (eg, fibrosis and necrosis) but also enhanced acute
toxicity expressed in the rapidly proliferating cell compartments.
Thus, the pattern of dose application used in camptothecin radiation
sensitization studies will likely play a role in their success or failure.

Topotecan

Topotecan is a water-soluble topoisomerase I inhibitor with cytotoxic
activity in a variety of preclinical models. Topotecan exhibits
schedule-dependency in vivo and has high cytotoxic activity with
frequently repeated (daily) dosing schedules.[22,23]

In murine systems, there is evidence that reducing the dose intensity
(by prolonging the drug administration schedule using a small amount
with each treatment) provides a therapeutic advantage because of
reduced host toxicity and equal or superior tumor responses. In
clinical studies, the short plasma half-life of topotecan also
suggests that prolonged drug exposure by infusion could be
effective.[24] In a phase I trial, an escalating low-dose topotecan
infusion was found to have an increased therapeutic ratio when
compared to an intermittent dosing schedule.[24] Neutropenia is
usually the dose-limiting toxicity of topotecan.

Phase II studies have shown that topotecan alone has cytotoxic
activity in lung cancer with intermittent (daily × 5 every 21
days) dosing schedules,[25] as well as in lung cancer patients with
topoisomerase II-refractory disease.[26] In advanced head and neck
cancer patients, topotecan is well-tolerated and has single-agent
activity similar to that of cisplatin (Platinol), 5-FU, and methotrexate.[27]

Decreased production or mutation of topoisomerase I can cause
resistance to the cytotoxic effects of topotecan and other
camptothecins. Active efflux of the camptothecins by
P-glycoprotein-mediated transport may also contribute to resistance.[28]

Radiation Sensitization--Topotecan has demonstrated
radiation-sensitizing properties in log and plateau phase cell
cultures[29,30] and in murine fibrosarcomas in vivo.[31,32] Clinical
trials have begun in patients with non-small-cell lung cancer and in
patients with central nervous system tumors.

Clinical evidence of radiation sensitization with topotecan has been
demonstrated in a dose-escalation trial in patients with locally
advanced, inoperable non-small-cell lung cancer.[33]. In this trial,
12 patients received 60 Gy (2 Gy/d) of radiation plus topotecan
delivered by bolus injection on days 1 through 5 and on days 22
through 26, beginning on the same day as irradiation. The initial
dose level of topotecan was 0.5 mg/m²; dose levels of 0.75 and
1.0 mg/m² were also tested. Doses higher than 0.5 mg/m²
were associated with relatively high acute hematologic and
gastrointestinal toxicity.

Of the 12 patients, 5 survived (2 without evident disease) and 7 died
of their cancer. Severe late pulmonary toxicity was not reported, but
pneumonitis was noted.

The Radiation Therapy Oncology Group (RTOG) is evaluating topotecan
plus cranial irradiation in patients with glioblastoma multiforme.
The Children’s Cancer Group (CCG) is also evaluating this
combination in children with pontine gliomas. In both of these
trials, topotecan is given daily as a 30-minute infusion 30 to 120
minutes before irradiation.

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