Topoisomerases are essential nuclear enzymes with a
multiplicity of cellular functions involving DNA replication, RNA transcription,
mitosis, and chromosome condensation. Two classes have been identified in
mammalian cells: the class I topoisomerases, so named because such agents induce
single-strand breaks and reunions of the DNA double helix; and the class II
topoisomerases, so named because such agents induce double-strand
breakage-reunion reactions with the DNA double helix. Both enzymes catalyze the
interconversion of various topologic isomers of DNA.[2,3]
Camptothecin, an alkaloid from the tree Camptotheca acuminata (Nyssaceae), is
the parent compound of topotecan (Hycamtin), irinotecan (CPT-11, Camptosar),
9-aminocamptothecin, 9-nitrocamptothecin, and other analogs. Topotecan and
irinotecan are commercially available water-soluble derivatives of camptothecin.
The active form of the camptothecins is the closed lactone ring, which is
pH-dependent. Preclinical activity screening of camptothecin and its analogs
has been demonstrated in several models including gynecologic tumors. In
addition, irinotecan is a prodrug and needs to be metabolized for optimal
activity. A carboxylesterase catalyzes the conversion of irinotecan to its
active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin). Using a subrenal
capsule assay, irinotecan showed growth-suppressive effects of greater than 50%
in two cervical cell lines.
Camptothecin analogs also augmented the activity of cisplatin, fluorouracil
(5-FU), and etoposide in HST-1, a human squamous cell carcinoma cell line.[8-11]
This may result from inhibition of the removal of cisplatin DNA adducts.
These compounds appear to have radiosensitization properties in small-cell and
adenocarcinoma lung cancer cell lines, which has also been demonstrated in
patients. The addition of recombinant tumor necrosis factor and irinotecan
to several gynecologic cancer cell lines also demonstrated synergistic
Therapy for cervical cancer is chosen according to the clinical stage. Most
patients with early-stage disease (IA, IB1) are cured by surgery or
radiotherapy; chemotherapy has no role in this setting. For patients with
higher-stage disease (IB2 to IVA) or positive lymph nodes, chemoradiation is the
treatment of choice. Irinotecan has not been studied in combination with
radiotherapy for the treatment of cervical cancer. In animal studies, however,
the combination is synergistic.
Experimental modalities for the primary treatment of cervical cancer stages
IB to IVA include neoadjuvant chemotherapy followed by radical surgery.
Sugiyama et al tested the combination of cisplatin (60 mg/m² on day 1) and
irinotecan (60 mg/m² on days 1, 8, and 15) administered prior to surgery to 23
patients with stage IB2 to IIIB cervical cancer. The patients were
chemotherapy-naive and had a median age of 59 years. Eighty-seven percent of
patients had squamous cell histology. The overall response rate was 78%, with 3
complete remissions, 15 partial remissions, 4 stabilizations, and 1 progression
of disease. Median survival has not yet been reached.
In contrast to the first-line setting, chemotherapy is used to treat
recurrent or metastatic cervical cancer. Single-agent chemotherapy yields
survival benefits similar to that of chemotherapy combination regimens;
single-agent treatment is preferred because it is associated with fewer side
effects. Response rates to single agents vary from 15% to 30% and complete
responses are rare. Cisplatin and carboplatin (Paraplatin) are considered the
most active single drugs. Patients with renal failure or poor performance status
rarely benefit from chemotherapy. Combination chemotherapy has been tested in
numerous trials. While high response rates have been documented even in heavily
treated patients, response durations are short and survival is not improved over
that achieved with single-agent treatment. Furthermore, results from randomized
trials comparing single-agent and combination therapy demonstrated no
significant benefits for the combination.
Irinotecan is the only active agent in platinum-refractory disease. This
agent has been tested as a single agent in cervical cancer patients refractory
to platinum-based therapy in five trials (Table
1). The first phase II trial in
the United States used a schedule of 125 mg/m²/wk for 4 weeks followed by a
2-week rest. A total of 42 patients with a median age of 44 years (range: 24-59
years) were treated for a median of 2 cycles (range: 1-14 cycles). All
patients had failed previous chemotherapy. The response rate was 21% with a
median time to response of 6 weeks and a response duration of 12 weeks. The
major dose-limiting side effects were nausea and vomiting (45%), diarrhea (24%),
and myelosuppression (36%). Myelosuppression did not decrease when the
irinotecan dose was reduced, whereas gastrointestinal side effects did. The
investigators concluded that irinotecan had significant clinical activity and
warranted further investigation, although hematologic and gastrointestinal side
effects were problematic.
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