Camptothecin is an alkaloid
obtained from the Camptotheca acuminata tree. The original clinical preparation,
camptothecin sodium, was evaluated in clinical trials in the late 1960s and
early 1970s, but was abandoned due to severe and unpredictable hemorrhagic
cystitis.[1-3] A semisynthetic derivative of camptothecin is irinotecan (CPT-11,
Camptosar), with higher water solubility, greater in vitro and in vivo activity,
and milder and more predictable toxicity than camptothecin.[4-6]
Camptothecin and its derivative, irinotecan, are potent inhibitors of
topoisomerase I, an enzyme normally active during DNA replication. Topoisomerase
I induces transient breaks in a single strand of DNA, which release the
torsional strain caused by synthesis of a new strand of DNA or RNA around a
double helix. The campthothecins target this topoisomerase I-DNA complex,
stabilize it, and inhibit the reannealing of the parent DNA. When an advancing
replication fork collides with the camptothecin-topoisomerase I-DNA complex,
double-stranded DNA breaks occur that lead to cell death.[7,8]
Irinotecan has been evaluated using several schedules and dosages, the most
frequent being weekly for 4 weeks with 1- or 2-week treatment breaks.
Alternatively, in Europe, where the drug has also been developed primarily for
the treatment of colorectal cancer, single doses of 350 mg/m² have been given
every 3 weeks with response rates ranging from 14% to 18%, depending on the
extent of previous therapy.[9,10] The every-21-days irinotecan schedule is more
attractive for the treatment of lymphoma because it will be easier to combine
with other myelosuppressive drugs that are active in lymphoma, which are also
usually given every 21 days, and can be supported by hematopoietic growth
factors to minimize or prevent neutropenia.
Based on these considerations, we decided to investigate the clinical
activity of irinotecan administered at 300 mg/m² every 21 days in patients
with relapsed or refractory non-Hodgkin’s lymphoma (NHL).
Patients were eligible for study entry if they had histologically confirmed
relapsed or refractory NHL. Relapsed disease indicates recurrence after a
complete or partial response to the initial regimen. Refractory disease
indicates less than a partial response or progression during the initial
regimen. Eligible patients had bidimensionally measurable disease, a Zubrod
performance status ≤ 2, normal serum creatinine and bilirubin levels, serum
transaminase levels £ 4 times the upper normal limit, absolute granulocyte
count ³ 1,500/µL, and platelet count ³
100,000/µL. Patients with central
nervous system involvement or human immunodeficiency virus infection, or who had
been treated with three or more previous regimens or with transplantation of
stem cells or bone marrow, were ineligible. The study was approved by the
Investigational Review Board and the National Cancer Institute for activation to
the Cancer Community Oncology Program. All patients signed informed consent.
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and daily treatment with camptothecin (NSC-100880): Correlation with preclinical
studies. Cancer Chemother Rep 56:515-521, 1972.
2. Moertel CG, Schutt AJ, Reitemeier RJ, et al: Phase II study of
camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer.
Cancer Chemother Rep 56:95-101, 1972.
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derivatives. Proc Jpn Cancer Assoc 281, 1981.
5. Yokokura T, Furuta T, Sawada S: Antitumor activity of newly synthesized,
lactone ring-closed and water-soluble camptothecin derivative in mice. Proc Jpn
Cancer Assoc 261, 1984.
6. Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of
7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxy-camptothecin, a novel
water-soluble derivative of camptothecin, against murine tumors. Cancer Res
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intracellular target of the anticancer drug camptothecin. Cancer Res
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protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem
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irinotecan during a phase II clinical trial in colorectal cancer. Pharmacology
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opportunities. Semin Oncol 23:42-50, 1996.
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Clinical efficacy and safety profile. Semin Oncol 23:34-41, 1996.
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Rep 71:1079-1085, 1987.
13. Rodriguez MA, Cabanillas FC, Velasquez W, et al: Results of a salvage
treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin
Oncol 13:1734-1741, 1995.