VOL.: 76 (2000) (p. 259)
CAS No.:
Chem. Abstr. Name: (5R,5aR,8aR,9S)-5,8,8a,9-Tetrahydro-5-(4-hydroxy-3,5-
dimethoxyphenyl)-9-{[4,6-O-[(R)-2-thienylmethylene]-b-D-glucopyranosyl]oxy}-furo[3˘,4˘:6,7]naphtho-
[2,3-d]-1,3-dioxol-6(5aH)-one
5.1 Exposure data
Teniposide is a semi-synthetic podophyllotoxin derivative that has been used in cancer treatment since the late 1970s. This DNA topoisomerase II inhibitor has been used in combination with other chemotherapeutic agents in the treatment of adult and childhood leukaemia, brain tumours in adults and neuroblastoma in children and, to a lesser extent, a number of other cancers.
5.2 Human carcinogenicity data
One large, well-conducted cohort study of acute lymphoblastic leukaemia in the USA and one case–control study of childhood cancer in United Kingdom found strong positive associations between the incidence of acute myeloid leukaemia and treatment with teniposide. A dose–response relationship was found in the case–control study. In both studies, teniposide was administered with other cytotoxic drugs. Although some of the other agents may have contributed to the positive association seen in the cohort study, use of these agents has not been associated with acute myeloid leukaemia in other large studies of childhood cancer. In the case–control study, the use of other potentially leukaemogenic agents was adjusted for in the analysis; however, the possibility cannot be excluded that interaction occurred between teniposide and those agents. It is unlikely that the large excess risk for acute myeloid leukaemia can be explained fully by misclassification or phenotypic change of the initial haematological malignancy.
Other cohort studies have also reported strongly increased risks for acute myeloid leukaemia after treatment of various primary malignancies with teniposide-containing regimens that also included alkylating agents or teniposide-containing regimens in combination with etoposide. In these studies, the possibility cannot be excluded that the excess risk for leukaemia was partly or wholly due to the other agents.
5.3 Animal carcinogenicity data
No data were available to the Working Group.
5.4 Other relevant data
In humans, teniposide is eliminated biphasically, with a terminal half-time of 6–10 h in adults and children. The pharmacokinetics of teniposide is linear at doses up to 1000 mg/m2. The oral bioavailability is about 40%. About 45% of a radiolabelled dose of teniposide was excreted in the urine, 4–14% occurring as the parent drug. There are few data on the metabolism of teniposide in humans. Teniposide is highly protein-bound in plasma (99%).
In mice, the pharmacokinetics of teniposide differs from that of etoposide, a closely related drug, with lower clearance, a larger volume of distribution and a longer terminal elimination half-time. The accumulation of teniposide in leukaemic cells in vitro was some 15 times higher than that of etoposide applied at the same concentration. Metabolism to the catechol and quinone metabolites in vitro has been described.
The major dose-limiting toxic effect of teniposide in clinical trials is myelosuppression, manifest mainly as leukopenia. Less severe effects, including nausea and vomiting, diarrhoea and alopecia, are common; less common effects include transient increases in liver enzyme activity, hypertension and hypersensitivity reactions. Embryotoxicity and teratogenicity, especially in the heart and central nervous system, have been observed in mice.
Teniposide is orders of magnitude more toxic in mammalian than in microbial cells and is mutagenic in mammalian cells. The effects in mammals arise primarily because teniposide is a poison of DNA topoisomerase II enzymes. Teniposide causes accumulation of protein-masked double-stranded DNA breaks in cells and, with time, a variety of chromosomal aberrations. It is also an effective recombinogen. The predominant mutagenic effects in mammalian cells appear to involve deletion and/or interchange of large DNA segments. Teniposide also induces aneuploidy and polyploidy. It may affect gene expression through hypomethylation of DNA.
Teniposide-containing regimens are strongly related to leukaemia in which the cells contain chromosomal translocations similar to those induced by etoposide and other DNA topoisomerase II inhibitors. The translocations are key events in leukaemogenesis.
5.5 Evaluation
There is limited evidence in humans for the carcinogenicity of teniposide.
There is inadequate evidence in experimental animals for the carcinogenicity of teniposide.
Overall evaluation
Teniposide is probably carcinogenic to humans (Group 2A).
In reaching this conclusion, the Working Group noted that teniposide 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 animal cells in vivo.
For definition of the italicized terms, see Preamble Evaluation.
Synonyms
See Also:
Toxicological Abbreviations