Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts

Mutations at Cross-Linkable Sites Induced by Monoadducts as well as Cross-Links

Edward Gunther, Toni M. Yeasky, Peter M. Glazer, Francis P. Gasparro

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Psoralens are used clinically in the treatment of several skin diseases, including psoriasis, vitiligo, and cutaneous T cell lymphoma. However, psoralen treatment has been associated with an increased risk of squamous cell carcinoma of the skin. To elucidate molecular events that may play a role in the psoralen-related carcinogenesis, we examined psoralen-induced mutagenesis in a mouse fibroblast cell line carrying a recoverable, chromosomally integrated λ phage shuttle vector. Using the supF gene as a mutation reporter gene, we determined the spectrum of mutations induced by photoactivation of 8-methoxypsoralen and of 5-methylangelicin. Both psoralens generated predominately T:A to A:T and some T:A to G:C transversions. Most of the mutations occurred at either 5′ TpA or 5′ ApT sites, both of which are conducive to interstrand cross-link formation. However, 5-methylangelicin produces only monoadducts, whereas 8-methoxypsoralen generated 20% cross-links and 80% monoadducts under the conditions of our experiments, as measured by direct HPLC analysis of the DNA from the treated cells. Although most of the mutations occurred at potentially cross-linkable sites, these results implicate monoadducts, as well as cross-links, as critical premutagenic lesions in psoralen-treated mammalian cells. These findings may help in the identification of carcinogenic changes induced by psoralen, and they may aid in the improved design of psoralen-based treatment regimens in the future.

Original languageEnglish (US)
Pages (from-to)1283-1288
Number of pages6
JournalCancer Research
Volume55
Issue number6
StatePublished - Mar 15 1995

Fingerprint

Methoxsalen
Ficusin
Mutagenesis
Fibroblasts
Mutation
Cutaneous T-Cell Lymphoma
Genetic Vectors
Vitiligo
Reporter Genes
Psoriasis
Skin Diseases
Bacteriophages
5-methylangelicin
Squamous Cell Carcinoma
Carcinogenesis
High Pressure Liquid Chromatography
Cell Line
Skin
DNA
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts: Mutations at Cross-Linkable Sites Induced by Monoadducts as well as Cross-Links",
abstract = "Psoralens are used clinically in the treatment of several skin diseases, including psoriasis, vitiligo, and cutaneous T cell lymphoma. However, psoralen treatment has been associated with an increased risk of squamous cell carcinoma of the skin. To elucidate molecular events that may play a role in the psoralen-related carcinogenesis, we examined psoralen-induced mutagenesis in a mouse fibroblast cell line carrying a recoverable, chromosomally integrated λ phage shuttle vector. Using the supF gene as a mutation reporter gene, we determined the spectrum of mutations induced by photoactivation of 8-methoxypsoralen and of 5-methylangelicin. Both psoralens generated predominately T:A to A:T and some T:A to G:C transversions. Most of the mutations occurred at either 5′ TpA or 5′ ApT sites, both of which are conducive to interstrand cross-link formation. However, 5-methylangelicin produces only monoadducts, whereas 8-methoxypsoralen generated 20{\%} cross-links and 80{\%} monoadducts under the conditions of our experiments, as measured by direct HPLC analysis of the DNA from the treated cells. Although most of the mutations occurred at potentially cross-linkable sites, these results implicate monoadducts, as well as cross-links, as critical premutagenic lesions in psoralen-treated mammalian cells. These findings may help in the identification of carcinogenic changes induced by psoralen, and they may aid in the improved design of psoralen-based treatment regimens in the future.",
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Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts : Mutations at Cross-Linkable Sites Induced by Monoadducts as well as Cross-Links. / Gunther, Edward; Yeasky, Toni M.; Glazer, Peter M.; Gasparro, Francis P.

In: Cancer Research, Vol. 55, No. 6, 15.03.1995, p. 1283-1288.

Research output: Contribution to journalArticle

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T1 - Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts

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AU - Gunther, Edward

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