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Comparative aneugenicity of doxorubicin and its derivative idarubicin using fluorescence in situ hybridization
1Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia. attiasm@yahoo.com
Abstract:
The present study was designed to evaluate and compare the aneugenicity of idarubicin and doxorubicin, topoisomerase-targeting anticancer anthracyclines, using fluorescence in situ hybridization techniques. It was found that idarubicin and doxorubicin treatment (12 mg/kg) induced sperm meiotic delay of 24h. To determine the frequencies of disomic and diploid sperm, groups of 5 male Swiss albino mice were treated with 3, 6 and 12 mg/kg idarubicin or doxorubicin. Significant increases in the frequencies of disomic and diploid sperm were caused by treatment with all doses of idarubicin and the two highest doses of doxorubicin compared with the controls. Moreover, both compounds significantly increased the frequency of diploid sperm, indicating that complete meiotic arrest occurred. The observation that XX- and YY-sperm significantly prevailed XY-sperm indicates missegregation during the second meiotic division. The results suggest also that earlier prophase stages contribute relatively less to idarubicin and doxorubicin-induced aneuploidy. Effects of the same doses were investigated by the bone-marrow micronucleus test. Significant increases in the frequencies of micronuclei were found after treatment with all doses of both compounds. The responses were also directly correlated with bone marrow suppression. Idarubicin was more toxic than doxorubicin. Exposure to 12 mg/kg of idarubicin and doxorubicin yielded 3.82 and 2.64% micronuclei, respectively, and of these an average of 58.3 and 62.8%, respectively, showed centromeric signals, indicating their formation by whole chromosomes and reflecting the aneugenic activity of both compounds. Correspondingly, about 41.7 and 37.2% of the induced micronuclei, respectively, were centromere-negative, demonstrating that both compounds not only induce chromosome loss but also DNA strand breaks. Based on our data, aneuploidy assays such as sperm-fluorescence in situ hybridization assay and micronucleus test complemented by fluorescence in situ hybridization with centromeric DNA probes have been to some extent validated to be recommended for the assessment of aneuploidogenic effects of chemicals.
Insights
Idarubicin and doxorubicin, anticancer drugs, cause aneuploidy by inducing genetic damage in sperm and bone marrow cells. These findings validate aneuploidy assays for chemical safety assessments.
Area of Science:
- Toxicology
- Genetics
- Pharmacology
Background:
- Idarubicin and doxorubicin are anthracyclines used in cancer chemotherapy.
- These drugs target topoisomerase enzymes.
- Their potential to induce aneuploidy (abnormal chromosome number) requires thorough investigation.
Purpose of the Study:
- To evaluate and compare the aneugenic potential of idarubicin and doxorubicin.
- To assess the induction of sperm meiotic abnormalities and micronuclei formation.
- To validate aneuploidy assays for chemical risk assessment.
Main Methods:
- Sperm fluorescence in situ hybridization (FISH) assay in Swiss albino mice.
- Bone-marrow micronucleus test with FISH analysis.
- Dose-response evaluation of idarubicin and doxorubicin (3-12 mg/kg).
Main Results:
- Both idarubicin and doxorubicin induced significant increases in disomic and diploid sperm frequencies.
- Complete meiotic arrest and missegregation during meiosis were observed.
- All tested doses of both compounds increased micronuclei formation, indicating genotoxicity.
- Idarubicin exhibited higher toxicity and aneugenic effects than doxorubicin.
- FISH analysis confirmed chromosome loss and DNA strand breaks.
Conclusions:
- Idarubicin and doxorubicin are aneugenic, causing genetic damage in germ and somatic cells.
- Sperm FISH and micronucleus tests are validated methods for assessing chemical aneugenicity.
- These assays are recommended for evaluating the safety of chemical compounds.
