Lethal and mutagenic interactions between γ-rays, cisplatin and etoposide at the cellular and molecular levels

Abstract

Purpose: We analysed the lethal and mutagenic interactions between γ-rays, cisplatin (Pt) and etoposide (E), three agents used in tumour chemoradiotherapy. Corresponding results at cellular and molecular levels could provide additional elements on involved mechanisms and, on antitumour activity and toxicity in combined cancer treatments.

Materials and methods: The yeast Saccharomyces cerevisiae SC7K(lys2–3) (auxotrophic for lysine) was used as eukaryotic model. Exponential growing cells were exposed to the mentioned agents, as single and combined treatments. Lethal and mutation interaction equations were determined as a function of doses according to quantitative models. DNA double-strand breaks were evaluated immediately after treatments, through pulsed-field electrophoresis and laser densitometry.

Results: All three agents induced significant mutant frequency. The γ +Pt + E combination determined maximal lethal and mutagenic synergism, followed by γ + Pt and γ + E combinations. Meanwhile, Pt + E combination showed lethal additivity and very low mutagenic synergism. Pt + E double combination determined moderate DNA degradation. DNA degradation after γ-exposure, was similar to that of γ + Pt, γ + E and γ + Pt + E combinations.

Conclusions: Synergistic lethal and mutagenic interactions indicate crosstalk between non-homologous end joining, homologous recombination and postreplicative repair pathways. Pt + E additivity indicate independence of involved repair pathways. Furthermore, the quantification of interactive events may be an additional suitable tool in tumour therapy planning.

Keywords:

• DNA repair
• drug-radiation interactions
• mutant frequency
• cellular radiobiology
• chemo/radiotherapy

Acknowledgements

We are grateful to Radiotherapy Department of Instituto Nacional del Cáncer-Uruguay and especially to Assistant Prof. G. Paolini (UR) for technical assistance. We also thank Dr W. Siede for critical reading of the manuscript. This work had financial support from PEDECIBA and Fundación Manuel Pérez (Uruguay).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.