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


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.
Department of Biophysics, Laboratory of Radiobiology, Faculty of Medicine, Universidad de la República, Montevideo, Uruguay. lucefa@adinet.com.uy
Olga
O
Lillo
Nelson
N
Bracesco
Elia
E
Nunes
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology*; D005057:Eukaryotic Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D005720:Gamma Rays; D008954:Models, Biological; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D009153:Mutagens; D005047:Etoposide; D002945:Cisplatin