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Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts: Mutations at Cross-Linkable Sites Indu

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Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts: Mutations at Cross-Linkable Sites Indu [CANCER RESEARCH 55, 1283-1288, March 15, 1995] Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts: Mutations at Cross-Linkable Sites Induced by Monoadducts as well as Cross-Links1 Edward J. Günther,Toni M. Yeasky, Francis P. Gasparro, and Peter M. Glazer2 Departments of Therapeutic Radiology ¡E.J. G., T. M. Y.. P. M. G.] and Dermatology ¡F.P. G.I, Yale University School of Medicine, New Haven, Connecticut 06520-8040 ABSTRACT center PUVA trial, Stem et al. (4) showed a statistically significant increase in the incidence of squamous cell carcinoma in PUVA Psoralens are used clinically in the treatment of several skin diseases, patients. A comparative analysis of the incidence of squamous cell including psoriasis, vitíligo,and cutaneous T cell lymphoma. However, psoralen treatment has been associated with an increased risk of squa- carcinoma in the U.S. and European trials was recently reported (5). nious cell carcinoma of the skin. To elucidate molecular events that may While in earlier comparisons there appeared to be differences between play a role in the psoralen-related carcinogenesis, we examined psoralen- the European and American experience with PUVA-induced inci induced mutagenesis in a mouse fibroblast cell line carrying a recoverable, dence of squamous cell carcinoma, the ongoing periodic reanalysis of chromosomally integrated A phage shuttle vector. Using the stipi- gene as each set of data with a longer follow-up period now indicates com a mutation reporter gene, we determined the spectrum of mutations parable findings. induced by photoactivation of 8-methoxypsoralen and of 5-methylangeli- It is likely that these cancers arise from the mutagenic psoralen cin. Both psoralens generated predominately I : Vto A: I and some T:A to photoadducts (and their lack of repair or misrepair) formed in kera- G:C transversions. Most of the mutations occurred at either 5' TpA or 5' tinocytes during photochemotherapy (6). Studies of lymphocytes ob ApT sites, both of which are conducive to interstrand cross-link forma tion. However, 5-methylangelicin produces only monoadducts, whereas tained from patients receiving PUVA for either psoriasis or vitíligo S-methoxypsoralen generated 20% cross-links and 80% monoadducts have shown a significant increase in the number of 6-thioguanine- under the conditions of our experiments, as measured by direct HPLC resistant cells (7). These studies were performed on lymphocytes analysis of the DNA from the treated cells. Although most of the mutations obtained from patients who were receiving PUVA therapy, and thus occurred at potentially cross-linkable sites, these results implicate mono the lymphocytes were only exposed indirectly to significantly atten adducts, as well as cross-links, as critical premutagenic lesions in psor- uated UVA doses. It is likely that directly irradiated human lympho alen-treated mammalian cells. These findings may help in the identifica cytes (as in photopheresis) and human keratinocytes (as in PUVA) tion of carcinogenic changes induced by psoralen, and they may aid in the would reveal higher levels of mutations. improved design of psoralen-based treatment regimens in the future. In order to design treatment regimens with reduced risk of cancer induction, an understanding of psoralen mutagenesis is needed. Al INTRODUCTION though several studies on the mutagenicity of psoralens in mammalian Psoralens constitute a group of three-ringed heterocyclic furocou- cells have been performed, there have been deficiencies in most of marins that can intercalate into DNA and undergo photo-induced these studies (8-12). The distribution of psoralen photoadducts can cycloaddition with pyrimidines to generate either MA3 or interstrand vary greatly depending on the treatment regimen used, but many cross-links. Psoralen photochemotherapies have been used for the studies have lacked characterization of the extent of 8-MOP phoload- treatment of three diseases: psoriasis and vitíligo(PUVA therapy; duct formation or the distribution of monoadducts and cross-links Refs. 1 and 2), and cutaneous T cell lymphoma (photophoresis; Ref. under the conditions used in vivo. The mutagenic data have been 3). For psoriasis, 8-MOP is ingested (or applied topically) and then interpreted in terms of presumed rather than measured levels of 1-2 h later the affected skin area is exposed to long wavelength UV monoadducts and cross-links, and inferences have been made based radiation (UVA). Clearing can be achieved over an 8-12-week period solely on the sites of mutations. Often, high doses of psoralen and with treatments three times a week. PUVA therapy can be gradually UVA (probably overdoses) have been used and thus may have led to tapered so that only maintenance therapy at monthly intervals (or less) molecular events that may not occur in human photochemotherapies. is required. In vitíligo,thetreatment regimen is similar. Repigmenta- In some studies, adduci formation has been measured by indirect tion of the affected areas may require 200-300 treatments (2). In methods: renaturation kinetics (13), hydroxyapatite chromatography photopheresis, after the ingestion of the drug, the patient's blood is (14), and alkaline elution analysis (15). These methods are useful leukapheresed. Plasma and leukocytes are combined and then exposed indicators of DNA photomodification but do not provide information to UVA radiation prior to reinfusion. about specific photoadducts. In previous work, we developed sensi The clinical uses of psoralens and UVA, however, are not without tive HPLC techniques to detect the number and distribution of psor potential drawbacks. Dermatologists have long been concerned about alen photoadducts in the DNA of treated cells. We have now quan the potential risk of skin cancer induction by PUVA. In the most tified 8-MOP photoadducts in cells affected by PUVA treatment, recent follow-up study of the patients from the original U.S. multi- including lymphocytes (16), keratinocytes (6), and fibroblasts (this study). We have demonstrated a uniform susceptibility to adduci Received 10/14/94; accepted 1/19/95. formation and the correlation of a certain level of adduci formation The costs of publication of this article were defrayed in part by the payment of page (1-10 adducts per megabasepair) wilh the inhibilion of cell prolifer charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ation. In a recent study we showed that conditions which others had 1 This work was supported by grants from the Charles E. Culpeper Foundation, used to produce MA alone were also producing significant numbers of Leukemia Society of America, NIH (ES05775, P. M. G.), and Yale Skin Disease Research cross-links (17), calling into queslion conclusions aboul the relative Center (F. P. G., P. M. G.). We also acknowledge support from Therakos, Inc. (F. P. G.). 2 To whom requests for reprints should be addressed, at Department of Therapeutic mutagenicily of MA and cross-links. Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT In Ihis sludy, we combine a HPLC analysis of Ihe dislribution 06520-8040. 3 The abbreviations used are: MA, monoadducts; PUVA, 8-methoxypsoralen and UVA of psoralen photoadducts in the DNA of the trealed cells with a irradiation; 8-MOP, 8-methoxypsoralen; 5-MeA, 5-methylangelicin. determination of the frequency and spectra of psoralen-induced 1283 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1995 American Association for Cancer Research. PSORALEN MUTAGENESIS mutations in a A phage shuttle vector, \supF, chromosomally inte RESULTS grated in mouse fibroblasts. To aid in the correlation of photoadducts A mouse L cell-derived line, LN12, containing approximately 100 with mutations, we used two different furocoumarins, 8-MOP and 5-MeA. 5-MeA was selected because it forms only MA and thus chromosomally integrated copies of a A phage shuttle vector, AsupF (Fig. 1) was previously constructed for the purpose of studying provides a method to analyze the effects of MA alone in our system (18-20). 8-MOP, which is in widespread clinical use, can produce mutagenesis in mammalian cells (22). The supF gene, an amber both MA and cross-links (21). We also examined the effects of suppressor tyrosine tRNA gene of E. coli, was used as a mutation reporter gene. The small size of the supF gene makes it amenable to repeated psoralen/UVA doses on the induced mutation frequencies DNA sequence analysis, and it is a well-studied reporter gene with and spectra. minimal bias in the detection of the different types of point mutations (25). In this A shuttle vector-based system, the AsupF DNA is rescued from within the mouse cell DNA by incubation of the mouse DNA in MATERIALS AND METHODS A in vitro packaging extracts which can identify, cut out, and package Vectors. The construction of the shuttle vector \supF, carrying the supF A DNA from within mouse DNA into viable phage particles for amber suppressor tyrosine tRNA of Escherichia coli as a mutation reporter growth and analysis in bacteria (22, 23, 26). Mutations in the supF gene, was described previously (22). gene that occur in the mouse cells are detected using standard pro- Cells. Mouse LN12 cells carrying approximately 100 copies of the \supF caryotic genetic techniques to detect mutants among the rescued shuttle vector DNA i n their genome were generated previously by transfection phage vectors. The mutants are identified by an altered phage plaque of mouse L cells with AsupF DNA (22). The LN12 cells were isolated by phenotype (22). Phage with functional supF genes yield blue plaques selection and screening for cells incorporating multiple copies of the A vector because they can suppress the amber mutation in the host lacZ gene, DNA into their genome (22). generating ß-galactosidase enzyme which can metabolize 5-bromo- Mutagenesis Protocol.
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