VOL.: 76 (2000) (p. 177)
Etoposide
CAS No.:
Chem. Abstr. Name: (5R,5aR,8aR,9S)-9-{[4,6-O-(1R)-Ethylidene-b-D-
glucopyranosyl]oxy}-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)furo-
[3¢,4¢:6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one
Etoposide phosphate
CAS No.:
Chem. Abstr. Name: (5R,5aR,8aR,9S)-5-[3,5-Dimethoxy-4-(phosphonooxy)phenyl]-9-{[4,6-O-(1R)-
ethylidene-
b-D-glucopyranosyl]oxy}-5,8,8a,9-tetrahydrofuro[3¢,4¢:6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one
Etoposide is a semi-synthetic podophyllotoxin derivative that has been used in cancer treatment since the early 1970s. This DNA topoisomerase II inhibitor is one of the most widely used and effective cytotoxic drugs in combination therapy, particularly in the treatment of lymphoma, small-cell lung cancer, testicular cancer, childhood malignancies and, to a lesser extent, a number of other cancers.
5.2 Human carcinogenicity data
One cohort study of patients with Langerhans cell histiocytosis and several cohort studies of patients with germ-cell tumours or lung cancer treated with etoposide-containing chemotherapy showed increased risks for acute myeloid leukaemia.
In the patients with Langerhans cell histiocytosis, a strongly increased risk for acute myeloid leukaemia of the promyelocytic type was found after treatment with etoposide alone; however, the possibility could not be ruled out that such patients have an inherently increased risk for acute promyelocytic leukaemia.
In several cohort studies of germ-cell tumours in men, treatment with etoposide, cisplatin and bleomycin was associated with an increased risk for acute myeloid leukaemia. On the basis of the combined data from six studies, the relative risk for acute myeloid leukaemia was 40 times greater than that of the general population; substantially higher relative risks have been found with high cumulative doses of etoposide. Although the other two agents (cisplatin and bleomycin) in etoposide-containing chemotherapy regimens for germ-cell tumours may have contributed to the positive association seen in the cohort studies, use of these agents in a similar regimen without etoposide has not been associated with acute myeloid leukaemia. As the background risk for acute myeloid leukaemia is low, the absolute risk for this disease in men treated for germ-cell tumours with etoposide-containing regimens is low. A strongly increased risk for acute myeloid leukaemia was also found in one cohort study of lung cancer patients treated with etoposide, cisplatin and vindesine. The possibility cannot be excluded that etoposide exerts its effects only in the presence of other cytotoxic agents.
Several other cohort studies reported strongly increased risks for acute myeloid leukaemia following treatment of various primary malignancies with etoposide-containing regimens that also included alkylating agents, or etoposide-containing regimens in combination with teniposide. In these studies, the possibility cannot be excluded that the excess leukaemia risk was partly or wholly due to the other agents.
5.3 Animal carcinogenicity data
Etoposide was tested in one experiment in wild-type and heterozygous neurofibromatosis type 1 gene (Nf1) knock-out mice. No increase in the incidence of leukaemia was observed.
5.4 Other relevant data
In humans, etoposide is eliminated biphasically, with an elimination half-time of 3–9 h. The pharmacokinetics of this compound is linear up to 3.5 mg/m2 (typical single dose, 100 mg/m2). Its bioavailability is around 50%, but this decreases with oral doses of > 200 mg. Etoposide is about 95% protein-bound in plasma. About 50% of an intravenous dose of etoposide is recovered in urine; up to 17% is excreted as a glucuronide metabolite and less than 2% as a catechol metabolite. Preliminary studies suggest that the remainder of the dose is excreted in the faeces. The catechol metabolite has also been detected in plasma at concentrations around 2.5% that of etoposide.
Biphasic elimination is seen in a number of animal species. In rhesus monkeys, 60% of a radiolabelled dose of etoposide was excreted in urine and 30% in faeces. Glucuronide metabolites have been reported in the urine of rabbits and rats. Oxidation of etoposide to quinone species and a catechol metabolite have been reported in cell systems, occurring either by peroxidase oxidation or cytochrome P450-mediated demethylation involving CYP3A4. These oxidation products have cytotoxic activity, but it is unclear how much they contribute to the activity of etoposide.
The major dose-limiting toxic effect of etoposide in humans is myelosuppression, manifest principally as leukopenia. Other toxic effects include nausea and vomiting, mucositis and alopecia. Cases of hypotension were reported in early trials in which short infusions were given, but this effect is rarely seen with infusions of longer than 30 min. Hypersensitivity reactions have been reported but are seen much less frequently than with teniposide. Cardiotoxicity and cutaneous toxicity have been reported but are rare.
Myelosuppression was the main toxic effect of intravenously administered etoposide in a number of the animal species studied. Other effects included changes in the lung in rats and renal and hepatic toxicity, electrocardiographic changes, decreased testis weight and disorders of spermatogenesis in rats and dogs. After intrapleural and intraperitoneal administration to mice and rats, delayed chronic pleuritis and peritonitis, with liver and spleen inflammation, were reported. Teratogenic effects especially on the central nervous system have been observed.
Etoposide does not bind to DNA by forming covalent bonds or through intercalation. The drug is orders of magnitude more toxic in mammalian than in microbial cells. The effects in mammals arise primarily because etoposide is a poison of DNA topoisomerase II enzymes. Etoposide also induces both aneuploidy and polyploidy. It enhances gene amplification and affects gene expression through hypermethylation of DNA. Treatment of cells with etoposide leads to an accumulation of protein-masked double-stranded DNA breaks and, with time, a variety of chromosomal aberrations. The predominant mutagenic effects detected involve the deletion and/or interchange of large DNA segments, especially balanced translocations. In vitro, etoposide and its catechol and quinone metabolites enhanced DNA topoisomerase II-mediated DNA strand breaks within the MLL gene which is implicated in leukaemia.
Etoposide-containing regimens have been associated with the development, after a short latency, of leukaemia which is characterized by chromosomal translocations. The translocations that are observed are the same as those found in de-novo cases of acute leukaemia; however, while translocations of the MLL gene at chromosome band 11q23 occur in only about 5% of cases of leukaemia in adults and are seen primarily in de-novo leukaemia in infants and young children, translocations of chromosome band 11q23 comprise the majority of the aberrations that follow leukaemias associated with administration of DNA topoisomerase II inhibitors. The translocations are considered to be primary events in leukaemogenesis. Etoposide is often used in combination chemotherapy with alkylating agents, which are themselves associated with leukaemia with specific chromosomal aberrations after a longer latency. These chromosomal aberrations are unbalanced chromosomal losses and deletions, especially monosomy 7, 7q and 5q deletions. Since the primary aberrations associated with alkylating agents are distinct from the balanced translocations with which DNA topoisomerase II inhibitors are associated, balanced translocations are specific events of epipodophyllotoxins that can be distinguished even when DNA topoisomerase II inhibitors are used in combination chemotherapy.
5.5 Evaluation
There is limited evidence in humans for the carcinogenicity of etoposide.
There is sufficient evidence in humans for the carcinogenicity of etoposide given in combination with cisplatin and bleomycin.
There is inadequate evidence in experimental animals for the carcinogenicity of etoposide.
Overall evaluation
Etoposide is probably carcinogenic to humans (Group 2A).
In reaching this conclusion, the Working Group noted that etoposide causes distinctive cytogenetic lesions in leukaemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukaemias contrasts with that of leukaemia induced by alkylating agents. Potent protein-masked DNA breakage and clastogenic effects occur in human cells in vitro and in animal cells in vivo.
Etoposide in combination with cisplatin and bleomycin is carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.
Synonyms
Etoposide
Etoposide phosphate
See Also:
Toxicological Abbreviations