Cytogenetic toxicity of cycloplatam in human lymphocytes: detection by the micronucleus test and fluorescence in situ hybridization

Abstract

Cycloplatam has been shown to be effective in the treatment of pleural mesothelioma, myeloma and ovarian carcinoma. Cycloplatam is not nephrotoxic with respect to the platinum-based anti-tumor agents. We have investigated the mechanism underlying the induction of micronuclei (MN) in human lymphocytes by cycloplatam compared to that by its parent drugs cisplatin and carboplatin. The cytokinesis-block micronucleus assay in human lymphocytes was applied in combination with fluorescence in situ hybridization (FISH) with an all-chromosome centromeric probe allowing discrimination between MN due to chromosomal fragments (centromere negative, C) and those containing whole chromosomes (centromere positive, C). A statistically significant increase of MN frequency (P<0.001) was detected for cisplatin, carboplatin and cycloplatam. However, cycloplatam was active at a much lower dose (0.1 micromol/l) than cisplatin or carboplatin (1 micromol/l). No significant increase in the frequency of C or C MN was observed for cisplatin and carboplatin compared to the controls. A statistically significant (P<0.001) increase in the percentage of C MN was observed in cycloplatam-treated cells. The results obtained suggest different mechanisms for cytogenetic damage induced by platinum drugs. Cycloplatam induces one type of MN and it could be considered a clastogenic agent, whereas cisplatin and carboplatin appear to induce both chromosome breakage and numerical chromosomal abnormalities.