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A Comparative Study of the Cytotoxic and Genotoxic Effects Exerted by the Bisdioxopiperazines, Bimolane and ICRF-154

  • Author(s): Vuong, Minh-Chau Thi
  • Advisor(s): Eastmond, David A
  • et al.
Abstract

Bimolane and ICRF-154 have been used for the treatment of cancer, psoriasis and uveitis in humans. Previous reports have revealed that the two drugs are topoisomerase II inhibitors, and patients treated with these agents have developed unique subtypes of secondary leukemia. Early studies have suggested that the therapeutic effects of bimolane were due to ICRF-154, an impurity present within the bimolane samples that may also be responsible for the toxic effects attributed to bimolane. To date, this hypothesis has not been tested. The objective of our study was to characterize the cytotoxic and genotoxic effects of bimolane and ICRF-154 in a series of in vitro tests in TK6 cells and to compare the results for the two chemicals. Bimolane and ICRF-154 were both cytotoxic exhibiting similar effects on cell proliferation across a number of endpoints. Clastogenic and aneugenic effects of both agents were assessed using the micronucleus (MN) assay with CREST staining. These drugs induced mainly chromosome breakage and, to a lesser extent, chromosome loss at very similar frequencies. In addition, the drugs' potentials to interfere with cytokinesis were detected by measuring binucleation. Very similar responses in the induction of binucleated cells were observed with the two agents. Three assays were used to screen for numerical chromosomal abnormalities. In our flow cytometry studies, both compounds induced hypodiploidy, hyperdiploidy, and polyploidy with pronounced effects at the highest test concentration. Fluorescence in situ hybridization (FISH) analyses with a chromosome 7 specific centromeric DNA probe were then performed to confirm the flow cytometry results. Bimolane and ICRF-154 induced similar frequencies of numerical aberrations including hypodiploidy and a combination of hyperdiploidy and polyploidy when either of the two FISH methods were used. The results of our study demonstrate that the bimolane and ICRF-154, topo II catalytic inhibitors, exhibit very similar cytotoxic and genotoxic effects at equimolar concentrations. The results of this study strongly suggest that bimolane is efficiently converted to ICRF-154 during cell culture, and that ICRF-154 is most likely responsible for bimolane's cytotoxic, genotoxic, and, possibly, leukemogenic effects.

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