Comparative analysis of the mutagenic activity of oxaliplatin and cisplatin in the Hprt gene of CHO cells

Maria J. Silva, Paula Costa, Anabela Dias, Marco Valente, Henriqueta Louro, Maria G. Boavida

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Abstract

Oxaliplatin is a platinum-derived antitumor drug that is active against cisplatin-resistant tumors and has lower overall toxicity than does cisplatin. DNA adduct formation is believed to mediate the cytotoxic activity of both compounds; however, the adducts may also be responsible for mutagenic and secondary tumorigenic activities. In this study, we have compared the mutagenicity of oxaliplatin and cisplatin in the Hprt gene of CHO-K1 cells. Both drugs produced dose-related increases in mutant frequency. For 1-hr treatments, oxaliplatin was less mutagenic than cisplatin at equimolar doses, while similar mutant frequencies were induced at equitoxic doses. Sequencing of mutant Hprt genes indicated that the mutation spectra of both oxaliplatin and cisplatin were significantly different from the spontaneous mutation spectrum (P = 0.014 and P = 0.008, respectively). A significant difference was also observed between the spectra of oxaliplatin- and cisplatin-induced mutations (P = 0.033). Although G:C-→T:A transversion was the most common mutation produced by both compounds, oxaliplatin produced higher frequencies of A:T-→T:A transversion than did cisplatin, most commonly at nucleotide 307, and higher frequencies of small deletions/insertions. Also, cisplatin induced tandem base-pair substitutions, mainly at positions 135/136, and a higher frequency of G:C-→A:T transition than did oxaliplatin. These results provide the first evidence that oxaliplatin is mutagenic and that the profiles of cisplatin- and oxaliplatin-induced mutations display not only similarities but also distinctive features relating to the type and sequence-context preference for mutation.

Original languageEnglish
Pages (from-to)104-115
Number of pages12
JournalEnvironmental And Molecular Mutagenesis
Volume46
Issue number2
DOIs
Publication statusPublished - 1 Aug 2005

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oxaliplatin
CHO Cells
Cisplatin
mutation
Genes
gene
Mutation
drug
mutagenicity
platinum
tumor
analysis
substitution
DNA Adducts

Keywords

  • Cisplatin
  • Hprt/CHO
  • Mutant frequency
  • Mutation spectrum
  • Oxaliplatin

Cite this

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abstract = "Oxaliplatin is a platinum-derived antitumor drug that is active against cisplatin-resistant tumors and has lower overall toxicity than does cisplatin. DNA adduct formation is believed to mediate the cytotoxic activity of both compounds; however, the adducts may also be responsible for mutagenic and secondary tumorigenic activities. In this study, we have compared the mutagenicity of oxaliplatin and cisplatin in the Hprt gene of CHO-K1 cells. Both drugs produced dose-related increases in mutant frequency. For 1-hr treatments, oxaliplatin was less mutagenic than cisplatin at equimolar doses, while similar mutant frequencies were induced at equitoxic doses. Sequencing of mutant Hprt genes indicated that the mutation spectra of both oxaliplatin and cisplatin were significantly different from the spontaneous mutation spectrum (P = 0.014 and P = 0.008, respectively). A significant difference was also observed between the spectra of oxaliplatin- and cisplatin-induced mutations (P = 0.033). Although G:C-→T:A transversion was the most common mutation produced by both compounds, oxaliplatin produced higher frequencies of A:T-→T:A transversion than did cisplatin, most commonly at nucleotide 307, and higher frequencies of small deletions/insertions. Also, cisplatin induced tandem base-pair substitutions, mainly at positions 135/136, and a higher frequency of G:C-→A:T transition than did oxaliplatin. These results provide the first evidence that oxaliplatin is mutagenic and that the profiles of cisplatin- and oxaliplatin-induced mutations display not only similarities but also distinctive features relating to the type and sequence-context preference for mutation.",
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Comparative analysis of the mutagenic activity of oxaliplatin and cisplatin in the Hprt gene of CHO cells. / Silva, Maria J.; Costa, Paula; Dias, Anabela; Valente, Marco; Louro, Henriqueta; Boavida, Maria G.

In: Environmental And Molecular Mutagenesis, Vol. 46, No. 2, 01.08.2005, p. 104-115.

Research output: Contribution to journalArticle

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T1 - Comparative analysis of the mutagenic activity of oxaliplatin and cisplatin in the Hprt gene of CHO cells

AU - Silva, Maria J.

AU - Costa, Paula

AU - Dias, Anabela

AU - Valente, Marco

AU - Louro, Henriqueta

AU - Boavida, Maria G.

PY - 2005/8/1

Y1 - 2005/8/1

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KW - Cisplatin

KW - Hprt/CHO

KW - Mutant frequency

KW - Mutation spectrum

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