Pharmacological Interference with DNA Repair

  • Arthur B. Pardee
  • Robert Schlegel
  • David A. Boothman


Many carcinogens and antineoplastic agents act primarily by damaging DNA. A very large portion of this damage is repaired by normal cells. Defects in these repair processes have serious consequences, as shown by xeroderma pigmentosum, ataxia telangiectasia and other cancer-prone genetic diseases. Drugs can also interfere with DNA repair pathways. They, like the genetic defects, increase the lethality of DNA damaging agents. Unlike these diseases, however, some drugs have been shown to decrease carcinogenicity. The basis for this paradoxical effect may be the ability of DNA repair inhibitors to convert normally sublethal misrepaired lesions into lethal ones. Drugs that interfere with DNA repair thus have promise not only for increasing the efficacy of chemotherapy, but also for decreasing carcinogenicity.


Xeroderma Pigmentosum Ataxia Telangiectasia Premature Chromosome Condensation Repair Inhibitor Thetic Cycle 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    B.A. Kihlman, Caffeine and chromosomes. Elsevier Scientific Publishing Co., New York and Amsterdam, 1977.Google Scholar
  2. 2.
    J. Timson, Caffeine. Mutat. Res. 47: 1–52, (1977).Google Scholar
  3. 3.
    J. J. Roberts, DNA repair. Radiat. Biol., 7: 211–436, (1978).Google Scholar
  4. 4.
    T. Nomura, Comparative inhibiting effects of methylxanthines on urethan-induced tumors, malformations, and presumed somatic mutations in mice. Cancer Res. 43: 1342–1346, (1983).PubMedGoogle Scholar
  5. 5.
    T. Kakunaga, Caffeine inhibits cell transformation by 4-nitro-quinoline-1-oxide. Nature (London) 258:248–250, (1975).CrossRefGoogle Scholar
  6. 6.
    P. J. Donovan, and J. A. DiPaolo, Caffeine enhancement of chemical carcinogen-induced transformation of cultured Syrian hamster cells. Cancer Res. 34: 2720–2727, (1974).PubMedGoogle Scholar
  7. 7.
    M. Fox, The effect of post-treatment with caffeine on survival and UV-induced mutation frequencies in Chinese hamster and mouse lymphoma cells in vitro. Mutat. Res. 24:187–204, (1974).PubMedCrossRefGoogle Scholar
  8. 8.
    D. Gaudin, and K.L. Yielding, Response of a “resistant” plasmacytoma to alkylating agents and X-ray in combination with the excision repair inhibitors caffeine and chloroquine. Proc. Soc. Exp. Biol. Med. 131:1413–1416, (1969).PubMedGoogle Scholar
  9. 9.
    T. Aida, and W.J. Bodell, Caffeine potentiates cytotoxicity and sister chromatid exchange induction in resistant rat brain tumor cells treated with 1,3-bis (2-chloroethyl)-l-nitrosourea. Cancer Res. 47: 1361–1366, (1987).PubMedGoogle Scholar
  10. 10.
    C.C. Lau, and A.B. Pardee, Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc. Natl. Acad. Sci. USA, 79:2942–2946, (1982).PubMedCrossRefGoogle Scholar
  11. 11.
    L. A. Zwelling, and K.W. Kohn, Platinum Complexes. In: Pharmacological Principles of Cancer Treatment (B. Chabner, Ed.), pp. 321. W. B. Saunders, Philadelphia, 1982.Google Scholar
  12. 12.
    H.J. Fingert, J.D. Chang, and A.B. Pardee, Cytotoxic, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents. Cancer Res.46:2463–2467, (1986).PubMedGoogle Scholar
  13. 13.
    J.E. Byfield, J. Murnane, J.F. Ward, P. Calabro-Jones, M. Lynch, and F. Kulhanian, Mice, men, mustards and methylxanthines: the potential role of caffeine and related drugs in the sensitization of human tumors to alkylating agents. Br. J. Cancer 43:669–683, (1981).PubMedCrossRefGoogle Scholar
  14. 14.
    R. Schlegel, and A.B. Pardee, Caffeine-induced uncoupling of mitosis from the completion of DNA replication in mammalian cells. Science 232: 1264–1266, (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    R.T. Johnson, and P.N. Rao, Mammalian cell fusion: induction of premature chromosome condensation in interphase nuclei. Nature (London), 226:717–722, (1970).CrossRefGoogle Scholar
  16. 16.
    T. Nishimoto, E. Ellen, and C. Basilico, Premature chromosome condensation in a ts DNA mutant of BHK cells. Cell, 15:475–483, (1978).PubMedCrossRefGoogle Scholar
  17. 17.
    R. Schlegel, R.G. Croy, and A.B. Pardee, Exposure to caffeine and suppression of DNA replication combine to stabilize the proteins and RNA required for premature mitotic events. J. Cell. Physiol., 131:85–91, (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    C. Borek, W.F. Morgan, A. Ong, and J.E. Cleaver, Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis. Proc. Natl. Acad. Sci. USA, 81:243–247, (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    P.J. Thraves, K.L. Mossman, T. Brennan, and A. Dritschilo, Differential radiosensitization of human tumor cells by 3-aminobenzamide and benzamide: inhibitors of poly(ADP-ribosylation). Int. J. Radiat. Biol. 50:961–972, (1986).CrossRefGoogle Scholar
  20. 20.
    J. Lunec, Introductory review: Involvement of ADP-ribosylation in cellular recovery from some forms of DNA damage. Br. J. Cancer, 49 (Suppl VI): 13–18, (1984).Google Scholar
  21. 21.
    D.M. Brown, J.W. Evans, and J.M. Brown, The influence of inhibitors of poly(ADP-ribose) polymerase on X-ray-induced potentially lethal damage repair. Br. J. Cancer, 40 (Suppl. VI): 27–31, (1984).Google Scholar
  22. 22.
    R.J. Boorstein, and A.B. Pardee, 3-Aminobenzamide is lethal to MMS-damaged human fibroblasts primarily during S phase. J. Cell. Physiol., 120:345–353, (1984).PubMedCrossRefGoogle Scholar
  23. 23.
    R.J. Boorstein, and A.B. Pardee, ß-Lapachone greatly enhances MMS lethality to human fibroblasts. Biochem. Biophys. Res. Commtin., 111:828–834, (1984).Google Scholar
  24. 24.
    D. A. Boothman, S. Greer, and A.B. Pardee, Potentiation of halogenated pyrimidine radiosensitizers by ß-lapachone, a novel DNA repair inhibitor. Cancer Res., (in press), (1987).Google Scholar
  25. 25.
    M.W. Heartlein, J.P. O’Neill, B.C. Pal, and R.J. Preston, The induction of specific-locus mutations and sister-chromatid exchanges by 5-bromo and 5-chlorodeoxyuridine. Mutat. Res. 92:411–414, (1982).PubMedCrossRefGoogle Scholar
  26. 26.
    C.R. Ashman, G.P.V. Reddy, and R.L. Davidson, Bromodeoxyuridine mutagenesis, ribonucleotide reductase activity, and deoxyribonucleotide pools in hydroxyurea-resistant mutants. Somat. Cell Genet. 7:751–768, (1981).PubMedCrossRefGoogle Scholar
  27. 27.
    R.A. Tobey, and H.A. Crissman, Preparation of large quantities of synchronized mammalian cells in late G1 in the pre-DNA replicative phase of the cell cycle. Exp. Cell Res. 75:460–464, (1972).PubMedCrossRefGoogle Scholar
  28. 28.
    J.L. Hamlin, and A.B. Pardee, S phase synchrony in monolayer CHO cultures. Exp Cell Res. 100:265–275, (1976).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Arthur B. Pardee
    • 1
  • Robert Schlegel
    • 1
  • David A. Boothman
    • 1
  1. 1.Dana-Farber Cancer InstituteBostonUSA

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