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Anthracyclines
G Mazue1, G Williams, M Iatropoulos
1AMER HLTH FDN,VALHALLA,NY 10595.
Abstract:
The genotoxicity and carcinogenicity data from in vitro and in vivo studies conducted during preclinical safety assessment of doxorubicin (DOXO), epirubicin (EPI) and idarubicin (IDA), are reviewed. The genotoxicity assays included a) gene mutation in Salmonella typhimurium with 5 tester strains; b) gene mutation in the V79 mammalian (lung) cell line; c) chromosome aberrations in human lymphocytes cultured in vitro; and d) chromosome aberrations in mouse bone marrow cells after intravenous (i.v.) administration in vivo. The long-term toxicity studies in the rat included a) single dose administration (3 mg/kg DOXO, 3.6 EPI and 0.75 IDA) to female rats of two different age groups, i.e. younger (7 weeks old at dosing) and older (13 weeks old), followed by one-year observation; and b) multiple dose administration to male and female rats (7 weeks old at dosing), consisting of i.v. administration of 0.25, 0.5 and 1 mg/kg DOXO or EPI and 0.06, 0.125 and 0.25 mg/kg IDA, once every 3 weeks for 10 cycles, followed by 18 months of observation. The genotoxicity studies revealed activity in gene mutation assays in bacterial and mammalian cells, and in chromosome aberration assays in human lymphocytes in vitro and in mouse bone marrow in vivo. In the two long-term studies in the rat, only mammary tumors were present. This finding was expected and, according to the literature, can be considered as species specific and not directly compound-related. The lack of tumor induction at the usual target organs for DNA reactive compounds, which are almost the same as those considered as target organs in anthracycline-exposed animals, indicates that the type and the extent of DNA damage precludes stimulation for proliferation and induction of neoplasia. Although an epigenetic mechanism can be hypothesized, support for such a mechanism is lacking.
Insights
Anthracycline anticancer drugs doxorubicin, epirubicin, and idarubicin showed genotoxicity in bacterial and mammalian cell assays. Long-term rat studies revealed no significant tumor induction, suggesting a lack of carcinogenicity despite genotoxic potential.
Area of Science:
- Pharmacology and Toxicology
- Oncology Drug Safety
- Preclinical Research
Background:
- Anthracyclines like doxorubicin (DOXO), epirubicin (EPI), and idarubicin (IDA) are crucial in cancer therapy.
- Preclinical safety assessment is vital to understand their genotoxic and carcinogenic potential.
- Existing data on these endpoints for DOXO, EPI, and IDA require comprehensive review.
Purpose of the Study:
- To review genotoxicity and carcinogenicity data for DOXO, EPI, and IDA from preclinical safety studies.
- To evaluate the in vitro and in vivo genotoxic profiles of these anthracyclines.
- To assess long-term carcinogenicity in rats following single and multiple dose administrations.
Main Methods:
- Genotoxicity assays included bacterial gene mutation (Salmonella typhimurium), mammalian cell gene mutation (V79), and chromosome aberration tests (human lymphocytes in vitro, mouse bone marrow in vivo).
- Long-term carcinogenicity studies involved single and multiple intravenous (i.v.) dose administrations of DOXO, EPI, and IDA to rats of different ages and sexes.
- Animals were observed for 12 to 18 months post-dosing to monitor tumor development.
Main Results:
- Genotoxicity studies indicated activity in gene mutation assays (bacterial and mammalian) and chromosome aberration assays (in vitro and in vivo).
- Long-term rat studies identified mammary tumors, considered species-specific and not directly compound-related.
- Absence of tumor induction in typical target organs for DNA-reactive compounds suggests limited carcinogenic potential.
Conclusions:
- DOXO, EPI, and IDA exhibit genotoxic activity across various in vitro and in vivo assays.
- Despite genotoxicity, these anthracyclines did not demonstrate significant carcinogenicity in long-term rat studies.
- The observed genotoxicity does not appear to translate into neoplastic induction in standard carcinogenicity models.
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