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

LETHAL mutations; CISPLATIN; PHYSIOLOGICAL effects of gamma rays; ETOPOSIDE; CELLS; MOLECULES; DNA repair; RADIOBIOLOGY

Purpose: We analysed the lethal and mutagenic interactions between γγ-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 γγ ++Pt ++ E combination determined maximal lethal and mutagenic synergism, followed by γγ ++ Pt and γγ ++ 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 γγ-exposure, was similar to that of γγ ++ Pt, γγ ++ E and γγ ++ 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. [ABSTRACT FROM AUTHOR]