At present (putative) human carcinogens are identified via epidemiological studies and testing using the chronic 2-yr rodent bioassay. Both methods have severe limitations in that they are slow, insensitive, expensive, and are also hampered by many uncertainties. The development of methods to modify specific genes in the mammalian genome has provided promising new tools for use in identifying carcinogens and characterizing their (qualitative) risk. Several transgenic mouse lines are currently under study to test their possible use in short-term carcinogenicity testing. One such candidate alternative transgenic model is the XPA knock-out mouse. These mice have an almost complete deficiency in DNA nucleotide excision repair (NER). Nevertheless, XPA-deficient mice are viable and have a background of a low incidence of spontaneous development of cancers. Approximately 15% of the mice develop hepatocellular adenomas (only after 1.5 yr). After treatment with ultraviolet-B radiation or 7,12-dimethylbenz(a)anthracene, the XPA-deficient mice developed squamous cell carcinomas and papillomas, respectively, on their skin. Oral treatment of XPA-deficient mice with benzo[a]pyrene (B[a]P), 2-acetylaminofluorene (2-AAF), and 2-amino-l-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP) resulted in lymphomas (B[a]P), liver and bladder tumors (2-AAF), and intestinal adenomas plus lymphomas (PhIP). These results look encouraging, but it should be noted that the compounds and agents tested thus far have all been substrate for nucleotide excision repair. Animal studies with different genotoxic or nongenotoxic compounds, as organized for instance within the framework of the International Life Sciences Institute/Health and Environmental Sciences Institute program, are needed to further evaluate the suitability of the XPA model for short-term carcinogenicity testing.
Ames BN and Gold LS (1990). Chemical carcinogenesis: Too many rodent carcinogens . Proc. Natl. Acad. Sci. USA87: 7772-7776.
2.
Asahina H., Kuraoka I., Shirakawa M., Morita EH, Miura N., Miyamoto I., Ohtsuka E., Okada Y., and Tanaka K. (1994). The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage. Mutat. Res. 315: 229-237.
3.
Baker SM, Bronner CE, Zhang L., Plug AW, Robatzek M., Warren G., Elliott EA, Yu J., Ashley T., Arnheim N., Flavell RA, and Liskay RM (1995). Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell82: 309-319.
4.
Bohr VA, Smith CA, Okumoto DS, and Hanawalt PC (1985). DNA repair in an active gene: Removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell40: 359-369.
5.
Chen M., Tomkins DJ, Auerbach W., McKerlie C., Youssoufian H., Liu L., Gan O., Carreau M., Auerbach A., Groves T., Guidos CJ, Freedman MH, Cross J., Percy DH, Dick JE, Joyner AL, and Buchwald M. (1996). Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia . Nat. Genet. 12: 448-451.
6.
Cheo DL, Ruven HJ, Meira LB, Hammer RE, Bums DK, Tappe NJ, Van Zeeland AA, Mullenders LH, and Friedberg EC (1997). Characterization of defective nucleotide excision repair in XPC mutant mice. Mutat. Res. 374: 1-9.
7.
Chu G. and Mayne L. (1996). Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy: Do the genes explain the diseases? Trends Genet. 12: 187-192.
8.
Cleaver JE and Kraemer KH (1989). Xeroderma pigmentosum. In: The Metabolic Basis of Inherited Disease, Vol. 2, CR Scriver, AL Beaudet, WS Sly, and D Valle (eds). McGraw-Hill, New York , pp. 2949-2971.
9.
Cleaver JE and Kraemer KH (1995). Xeroderma pigmentosum and Cockayne syndrome. In: The Metabolic and Molecular Basis of Inherited Disease, CR Scriver, AL Beaudet, WS Sly, and D Valle (eds), Vol. III, 7th ed., McGraw-Hill, New York, pp. 4393-4419.
10.
Cooper PK, Nouspikel T., Clarkson SG, and Leadon SA (1997). Defective transcription-coupled repair of oxidative base damage in Cockayne syndrome patients from XP group G. Science275: 990-993.
11.
Croteau DL and Bohr VA (1997). Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J. Biol. Chem. 272:25409-25412.
12.
De Vries A. , Van Oostrom CThM , Dortant PM, Beems RB, Van Kreijl CF, Capel PJA, and Van Steeg H. (1997). Spontaneous liver tumours and benzo[a]pyrene-induced lymphomas in XPA-deficient mice. Mol. Carcinog. 19: 46-53.
13.
De Vries A. , Van Oostrom CThM , Hofhuis FMA , Dortant PM, Berg RJW, De Gruijl FR, Wester PW, Van Kreijl CF, Capel PJA, Van Steeg H., and Verbeek S. (1995). Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature377: 169-173.
14.
De Wind N., Dekker M., Berns A., Radman M., and Te Riele H. (1995). Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell82: 321-330.
15.
Donehower LA , Harvey M., Slagle BL, McArthur MJ, Montgomery CA, Butel JS, and Bradley A. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature356: 215-221.
16.
Edelmann W. , Cohen PE, Kane M., Lau K., Morrow B., Bennett S., Umar A., Kunkel T., Cattoretti G., Chaganti R., Pollard JW, Kolodner RD, and Kucherlapati R. (1996). Meiotic pachytene arrest in MLH1-deficient mice. Cell85: 1125-1134.
17.
Engelward BP , Weeda G., Wyatt MD, Broekhof JL, de Wit J., Donker I., Allan JM, Gold B., Hoeijmakers JHJ, and Samson LD (1997). Base excision repair deficient mice lacking the Aag alkyladenine DNA glycosylase. Proc. Natl. Acad. Sci. USA94: 13087-13092.
18.
Essers J., Hendriks RW, Swagemakers SM, Troelstra C., De Wit J., Bootsma D., Hoeijmakers JHJ, and Kanaar R. (1997). Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell89: 195-204.
19.
Esumi H., Ohgaki H., Kohzen E., Takayama S., and Sugimura T. (1989). Induction of lymphoma in CDF1 mice by the food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Jpn. J. Cancer Res. 80: 1176-1178.
20.
Flammang TJ , Tungeln LSV, Kadlubar FF, and Fu PP (1997). Neonatal mouse assay for tumorigenicity: Alternative to the chronic rodent bioassay. Regul. Toxicol. Pharmacol. 26: 230-240.
21.
Friedberg EC , Walker GC, and Siede W. (1995). DNA Repair and Mutagenesis . American Society for Microbiology Press, Washington, D.C.
22.
Gunz D., Hess MT, and Naegeli H. (1996). Recognition of DNA adducts by human nucleotide excision repair: Evidence for a thermodynamic probing mechanism. J. Biol. Chem. 271: 25089-25098.
23.
He Z., Henricksen LA, Wold MS, and Ingles CJ (1995). RPA involvement in the damage-recognition and incision steps of nucleotide excision repair. Nature374: 566-569.
24.
Hoeijmakers JHJ (1993). Nucleotide excision repair, I: From E. coli to yeast. Trends Genet. 9: 173-177.
25.
Hoeijmakers JHJ (1993). Nucleotide excision repair, II: From yeast to mammals. Trends Genet. 9: 211-217.
26.
Hoeijmakers JHJ and Bootsma D. (1990). Molecular genetics of eukaryotic DNA excision repair. Cancer Cells2: 311-320.
27.
Ivanov EL and Haber JE (1997). DNA repair: RAD alert. Curr. Biol . 7: R492-R495.
28.
Jacks T., Remington L., Williams BO, Schmitt EM, Halachmi S., Bronson RT, and Weinberg RA (1994). Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4: 1-7.
29.
Jones CJ and Wood RD (1993). Preferential binding of the xeroderma pigmentosum group A complementing protein to damaged DNA. Biochemistry32: 12096-12104.
30.
Kanaar R. and Hoeijmakers JHJ (1997). Recombination and joining: Different means to the same ends. Genes Function1: 165-174.
31.
Kerckaert GA , Brauninger R., LeBoeuf RA, and Isfort RJ (1996). Use of the Syrian hamster embryo cell transformation assay for carcinogenicity prediction of chemicals currently being tested by the national toxicology program in rodent bioassays . Environ. Health Perspect. 104(suppl.): S1075-S1084.
32.
Kolodner RD (1995). Mismatch repair: Mechanisms and relationship to cancer susceptibility. Trends Biochem. Sci. 20: 397-401.
33.
Kraemer KH (1997). Sunlight and skin cancer: Another link revealed . Proc. Natl. Acad. Sci. USA94: 11-14.
34.
Kraemer KH, Lee MM, and Scotto J. (1984). DNA repair protects against cutaneous and internal neoplasia: Evidence from xeroderma pigmentosum. Carcinogenesis5: 511-514.
35.
Leder A., Kuo A., Cardiff RD, Sinn E., and Leder P. (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: Effects of phorbol esters and retinoic acid. Proc. Natl. Acad. Sci. USA87: 9178-9182.
36.
Lehmann AR (1995). Nucleotide excision repair and the link with transcription . Trends Biochem. Sci. 20: 402-405.
37.
Littlefield NA, Cueto C., Davis AK, and Medlock K. (1975). Chronic dose-response studies in mice fed 2-AAFJ. Toxicol. Environ. Health1: 25-37.
38.
McGregor WG , Wei D., Chen RH, Maher VM, and McCormick JJ (1997). Relationship between adduct formation, rates of excision repair and the cytotoxic and mutagenic effects of structurally-related polycyclic aromatic carcinogens . Mutat. Res. 376: 143-152.
39.
McWhir J., Selfridge J., Harrison DJ, Squires S., and Melton DW (1993). Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. Nat. Genet . 5: 217-224.
40.
Mellon I., Spivak G., and Hanawalt PC (1987). Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell51: 241-249.
41.
Miyamoto I. , Miura N., Niwa H., Miyazaki J., and Tanaka K. (1992). Mutational analysis of the structure and function of the xeroderma pigmentosum group A complementing protein. J. Biol. Chem. 267: 12182-12187.
42.
Modrich P. and Lahue R. (1996). Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu. Rev. Biochem. 65: 101-133.
43.
Naegeli H. (1995). Mechanisms of DNA damage recognition in mammalian nucleotide excision repair. FASEB J. 9: 1043-1050.
44.
Nakane H., Takeuchi S., Yuba S., Saijo M., Nakatsu Y., Murai H., Nakatsuru Y., Ishikawa T., Hirota S., Kitamura Y., Kato Y., Tsunoda Y., Miyauchi H., Horio T., Tokunaga T., Matsunaga T., Nikaido O., Nishimune Y., Okada Y., and Tanaka K. (1995) High incidence of ultraviolet-B- or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene. Nature377: 165-168.
45.
Park CH, Bessho T., Matsunaga T., and Sancar A. (1995). Purification and characterization of the XPF-ERCC1 complex of human DNA repair excision nuclease. J. Biol. Chem . 270: 22657-22660.
46.
Pegg AE (1990). Mammalian O6-alkylguanine-DNA alkyltransferase: Regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 50: 6119-6129.
47.
Reardon JT, Bessho T., Chuan Kung H., Bolton PH, and Sancar A. (1997). In vitro repair of oxidative DNA damage by human nucleotide excision repair system: Possible explanation for neurodegeneration in xeroderma pigmentosum patients. Proc. Natl. Acad. Sci. USA94: 9463-9468.
48.
Reitmair AH , Schmits R., Ewel A., Bapat B., Redston M., Mitri A., Waterhouse P., Mittrucker HW, Wakeham A., Liu B., Thomason A., Griesser H., Gallinger S., Ballhausen WG, Fishel R., and Mak TW (1995). MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nat. Genet. 11: 64-70.
49.
Saitoh A., Kimura M., Takahashi R., Yokoyama M., Nomura T., Izawa M., Sekiya T., Nishimura S., and Katsuki M. (1990). Most tumors in transgenic mice with human c-Ha-ras gene contained somatically activated transgenes. Oncogene5: 1195-1200.
50.
Sands AT, Abuin A., Sanchez A., Conti CJ, and Bradley A. (1995). High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. Nature377: 162-165.
51.
Satoh MS, Jones CJ, Wood RD, and Lindahl T. (1993). DNA excision-repair defect of xeroderma pigmentosum prevents removal of a class of oxygen free radical-induced base lesions. Proc. Natl. Acad. Sci. USA90: 6335-6339.
52.
Schaeffer L. , Roy R., Humbert S., Moncollin V., Vermeulen W., Hoeijmakers JHJ, Chambon P., and Egly JM (1993). DNA repair helicase: A component of BTF2 (TFIIH) basic transcription factor. Science260: 58-63.
53.
Seeberg E., Eide L., and Bjoras M. (1995). The base excision repair pathway. Trends Biochem. Sci. 20: 391-397.
54.
Taylor EM, Broughton BC, Botta E., Stefanini M., Sarasin A., Jaspers NG, Fawcett H., Harcourt SA, Arlett CF, and Lehmann AR (1997). Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. Proc. Natl. Acad. Sci. USA94: 8658-8663.
55.
Tennant RW, French JE, and Spalding JW (1995). Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ. Health Perspect. 103: 942-950.
56.
Tennant RW, Spalding JW, and French JE (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and non-carcinogens. Mutat. Res. 365: 119-127.
57.
Tsuzuki T., Sakumi K., Shiraishi A., Kawate H., Igarashi H., Iwakuma T., Tominaga Y., Zhang SM, Shimizu S., Ishikawa T., Nakamura K., Nakao K., Katsuki M., and Sekuguchi M. (1996). Targeted disruption of the DNA repair methyltransferase gene renders mice hypersensitive to alkylating agent. Carcinogenesis17: 1215-1220.
58.
Van der Horst GT, Van Steeg H., Berg RJW, Van Gool AJ, De Wit J., Weeda G., Morreau H., Beems RB, Van Kreijl CF, De Gruijl FR, Bootsma D., and Hoeijmakers JHJ (1997 ). Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell89: 425-435.
59.
Van Oostrom CThM , De Vries A., Verbeek SJ, Van Kreijl CF, and Van Steeg H. (1994). Cloning and characterization of the mouse XPAC gene. Nucleic Acids Res. 22: 11-14.
60.
Weeda G., Donker I., de Wit J., Morreau H., Janssens R., Vissers CJ, Nigg A., Van Steeg H., Bootsma D., and Hoeijmakers JHJ (1997). Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence. Curr. Biol. 7: 427-439.
61.
Weeda G., van Ham RC, Vermeulen W., Bootsma D., van der Eb AJ, and Hoeijmakers JHJ (1990). A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome . Cell62: 777-791.
62.
Wood RD (1996). DNA repair in eukaryotes. Annu. Rev. Biochem. 65: 135-167.
63.
Yamamoto S. , Urano K., Koizumi H., Wakana S., Hioki K., Mitsumori K., Kurokawa Y., Hayashi Y., and Nomura T. (1998). Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Environ. Health Perspect. 106(suppl.): S57-S69.
