Skip to main content
SpringerLink
Log in

Combination effects of poly(ADP-ribose) polymerase inhibitors and DNA-damaging agents in ovarian tumor cell lines —with special reference to cisplatin

  • Original Paper
  • Experimental Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

The effects of the poly(ADP-ribose) polymerase inhibitors 4-amino-1,8-naphthalimide (4-ANI), 6(5H)-phenanthridinone (PHD), 1,5-isoquinolinediol (IQD), 3-aminobenzamide (3-AB) or 4-hydroxyquinazoline (4-HYA) on the cytotoxicity of cisplatin were investigated. The human ovarian tumor cell lines SK-OV-3 and OAW 42 and the rat ovarian tumor cell line O-342 as well as its cisplatin (DDP)-resistant subline O-342/DDP were used. Cytotoxicity was determined with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) plus its respective combinations with poly(ADP-ribose) polymerase inhibitors served as positive controls. In addition, the alkylating agentsl-threitol-1,4-bismethanesulfonate (DHB) and 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine) as well as two other DNA-repair inhibitors caffeine and theophylline were included in the investigations. The cytotoxicity of cisplatin could not be increased by 4-ANI, PHD, IQD, 4-HYA or 3-AB in any cell line investigated., while it was increased by caffeine in lines O-342/DDP and SK-OV-3 as well as by theophylline in lines O-342/DDP, SK-OV-3 and OAW 42. The cytotoxicity of MNNG was increased by combination with 4-ANI, PHD, IQD, 4-HYA, 3-AB or theophylline for all lines except OAW42; in the latter line, only 4-ANI, PHD and IQD increased MNNG cytotoxicity. The cytotoxicity of DHB was increased by 4-ANI, PHD, 4-HYA, theophylline and caffeine in line O-342/DDP; by 4-HYA, theophylline and caffeine in line SK-OV-3; and by theophylline and caffeine in line OAW42. The cytotoxicity of carmustine was increased only by 3-AB in two lines (SK-OV-3 and OAW 42). Results are discussed with regard to different DNA-repair mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

3-AB :

3-aminobenzamide

4-ANI :

4-amino-1,8-naphthalimide

Carmustine :

1,3-bis(2-chloroethyl)-1-nitrosourea

DHB :

l-threitol-1,4-bis-methanesulfonate

4-HYA :

4-hydroxyquinazoline

IQD:

1,5-isoquinolinediol

MNNG :

1-methyl-3-nitro-1-nitrosoguanidine

PARP :

poly(ADP-ribose) polymerase

PHD :

6(5H)-phenanthridinone

MTT :

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

References

  • Alaoui-Jamali M, Loubaba B-B, Robyn S, Tapiero H, Batist G (1994) Effect of DNA-repair-enzyme modulators on cytotoxicity ofl-phenylalanine mustard andcis-diamminedich-loroplatinum(II) in mammary carcinoma cells resistant to alkylating drugs. Cancer Chemother Pharmacol 34:153–158

    PubMed  Google Scholar 

  • Althaus FR, Richter C (1987) ADP-ribosylation of proteins. Enzymology and biological significance. Mol Biol Biochem Biophys 37:1–237

    PubMed  Google Scholar 

  • August EM, Cooper DL, Prusoff WH (1991) Inhibition of poly(adenosine diphosphate-ribose) polymerase by thymidine and thymidine analogues in L 1210 cells and its relationship to the potentiation of the antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea but not of 3′-[3-(2-chloroethyl)-3-nitrosoureido]-3′-deoxythymidine. Cancer Res 51:1586–1590

    PubMed  Google Scholar 

  • Banasik M, Komura H, Shimoyama M, Ueda K (1992) Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl) transferase. J Biol Chem 267:1569–1575

    PubMed  Google Scholar 

  • Berger NA, Catino DM, Vietti TJ (1982) Synergistic antileukemic effect of 6-aminonicotinamide and 1,3-bis(2-chloroethyl)-1-nitrosourea on L 1210 cells in vitro and in vivo. Cancer Res 42:4382–4386

    PubMed  Google Scholar 

  • Boike GM, Petru E, Sevin BU, Averette HE, Chou TC, Penalver M, Donato D, Schiano M, Hilsenbeck SG, Perras J (1990) Chemical enhancement of cisplatin cytotoxicity in a human ovarian and cervical cancer cell line. Gynecol Oncol 38:315–322

    PubMed  Google Scholar 

  • Boorstein RJ, Pardee AB (1984) Factors modifying 3-aminobenzamide cytotoxicity in normal and repair-deficient human fibroblasts. J Cell Physiol 120:335–344

    PubMed  Google Scholar 

  • Borek C, Morgan WF, Ong A, Cleaver JE (1984) Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis. Proc Natl Acad Sci USA 81:243–247

    PubMed  Google Scholar 

  • Boulikas T (1991) Relation between carcinogenesis, chromatin structure and poly(ADP-ribosylation) (review). Anticancer Res 11:489–528

    PubMed  Google Scholar 

  • Bürkle A, Chen G, Küpper JH, Grube KH, Zeller WJ (1993) Increased poly(ADP-ribosyl)ation in intact cells by cisplatin treatment. Carcinogenesis 14:559–561

    PubMed  Google Scholar 

  • Calsou P, Salles B (1993) Role of DNA repair in the mechanisms of cell resistance to alkylating agents and cisplatin. Cancer Chemother Pharmacol 32:85–89

    PubMed  Google Scholar 

  • Chen G, Pan QC (1988) Potentiation of the antitumor activity of cisplatin in mice by 3-aminobenzamide and nicotinamide. Cancer Chemother Pharmacol 22:303–307

    PubMed  Google Scholar 

  • Chen G, Zeller WJ (1990) Enhancement of cisplatin (DDP) antitumor activity by 3-aminobenzamide in rat ovarian tumors sensitive and resistant to DDP in vivo. Cancer Chemother Pharmacol 26:37–41

    PubMed  Google Scholar 

  • Chen G, Zeller WJ (1991) Untersuchungen zum Synergismus von Buthionin-Sulfoximin und 3-Aminobenzamid bei der Überwindung einer Cisplatin-Resistenz. Tumor Diagn Ther 12:226–229

    Google Scholar 

  • Chen G, Zeller WJ (1992) Multiple effects of 3-aminobenzamide on DNA damage induced by cisplatin (DDP) in DDP-sensitive and resistant rat ovarian tumor cell lines. Cancer Lett 67:27–33

    PubMed  Google Scholar 

  • Chen G, Zeller WJ (1993) Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo. Cancer Chemother Pharmacol 33:157–162

    PubMed  Google Scholar 

  • Cleaver JE, Morgan WF (1991) Poly(ADP-ribose) polymerase: a perplexing participiant in cellular responses to DNA breakage. Mutat Res 257:1–18

    PubMed  Google Scholar 

  • Cleaver JE, Milam KM, Morgan WF (1985) Do inhibitor studies demonstrate a role for poly(ADP-ribose) in DNA repair? Radiat Res 101:16–28

    PubMed  Google Scholar 

  • Coppola S, Nosseri C, Maresca V, Ghibelli L (1995) Different basal NAD levels determine opposite effects of poly(ADP-ribosyl)polymerase inhibitors on H2O2-induced apoptosis. Exp Cell Res 221:462–469

    PubMed  Google Scholar 

  • Dijt FJ, Fichtinger-Schepman AMJ, Berends F, Reedijk J (1988) Formation and repair of cisplatin induced adducts to DNA in cultured normal and repair-deficient human fibroblasts. Cancer Res 48:6058–6062

    PubMed  Google Scholar 

  • Durkacz BW, Omidiji O, Gray DA, Shall S (1980) (ADP-Ribose)n participates in DNA excision repair. Nature 283:593–596

    PubMed  Google Scholar 

  • Erlichman C, Hanada P, Wu A (1984) Enhanced cytotoxicity of cisplatin by 3-aminobenzamide.. Proc Am Assoc Cancer Res 35:368

    Google Scholar 

  • Fogh J (ed) (1975) Human tumor cells in vitro, Plenum, New York, p 122

    Google Scholar 

  • Fox M (1984) Drug resistance and DNA repair. In: Fox BW, Fox M (eds) Antitumor drug resistance. Springer, New York Berlin Heidelberg, pp 335–369

    Google Scholar 

  • Fraval HNA, Rawlings CJ, Roberts JJ (1978) Increased sensitivity of UV-repair deficient human cells to DNA-bound platinum products which unlike thymidine dimers are not recognized by an endonuclease extracted fromMicrococcus luteus. Mutat Res 51:121–132

    PubMed  Google Scholar 

  • Hansson J, Wood RD (1989) Repair synthesis by human cell extracts in DNA bycis- andtrans-diamminedichloroplatinum(II). Nucleic Acids Res 17:8073–8091

    PubMed  Google Scholar 

  • Heim ME (1993) Platinum and non-platinum complexes in clinical trials. Current status and new developments. In: Keppler BK (ed) Metal complexes in cancer chemotherapy, VCH, Weinheim, pp 11–24

    Google Scholar 

  • Horsman MR, Brown DM, Hirst DG, Brown JM (1986) Changes in the response of the RIF-1 tumor to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase. Br J Cancer 53:247–254

    PubMed  Google Scholar 

  • Kato T, Suzumura Y, Fukoshima M (1988) Enhancement of bleomycin activity by 3-aminobenzamide, a poly(ADP-ribose) synthesis inhibitor, in vitro and in vivo. Anticancer Res 8:239–243

    PubMed  Google Scholar 

  • Kaufmann SH (1989) Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res 49:5870–5878

    PubMed  Google Scholar 

  • Kubo S, Matsutani M, Nakagawa K, Ogura T, Esumi H, Saijo N (1992) Participation of poly(ADP-ribose) polymerase in the drug sensitivity in human lung cancer cell lines. J Cancer Res Clin Oncol 118:244–248

    PubMed  Google Scholar 

  • Küpper JH, Müller M, Jacobson MK, Tatsumi-Miyajima J, Coyle DL, Jacobson EL, Bürkle A (1995) trans-dominant inhibition of poly(ADP-ribosyl)ation sensitizes cells against gamma-irradiation andN-methyl-N′-nitro-N-nitrosoguanidine but does not limit DNA replication of a polyomavirus replicon. Mol Cell Biol 15:3154–3163

    PubMed  Google Scholar 

  • Lau CC, Pardee AB (1982) Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci USA 79:2942–2946

    PubMed  Google Scholar 

  • Lindahl T, Satoh MS, Poirier GG, Klungland A (1995) Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci 20:405–411

    PubMed  Google Scholar 

  • Loehrer PJ, Einhorn LH (1984) Drugs five years later: cisplatin. Ann Intern Med 100:704–713

    PubMed  Google Scholar 

  • Los G, Muggia FM (1994) Platinum resistance: experimental and clinical status. Hematol Oncol Clin North Am 8:411–429

    PubMed  Google Scholar 

  • Milam KM, Cleaver JE (1984) Inhibitors of poly(ādenosine diphosphate-ribose) synthesis: effect on other metabolic processes. Science 223:589–591

    PubMed  Google Scholar 

  • Molinete M, Vermeulen W, Bürkle A, Menissier-de Murcia J, Küpper JH, Hoeijmakers JHJ, Murcia G de (1993) Overproduction of the poly(ADP-ribose) polymerase DNA-binding domain blocks alkylation-induced DNA repair synthesis in mammalian cells. EMBO J 12:2109–2117

    PubMed  Google Scholar 

  • Moosman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 65:55–63

    PubMed  Google Scholar 

  • de Murcia G, Menissier de Murcia J (1994) Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci 19: 172–176

    PubMed  Google Scholar 

  • Moses K, Willimore E, Harris AL, Durkacz BW (1990) Correlation of enhanced 6-mercaptopurine cytotoxicity with increased phosphoribosylpyrophosphate levels in Chinese hamster ovary cells treated with 3-aminobenzamide. Cancer Res 50:1992–1996

    PubMed  Google Scholar 

  • Nicholson DW, Ali A, Thornberry NA Vaillancort, JP, Ding, CK, Gallant M, Goreau, Y, Griffin, PR, Labelle M, Lazebnik YA, et al (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43

    PubMed  Google Scholar 

  • Ozols RF, Young RC (1984) Chemotherapy of ovarian cancer. Semin Oncol 11:251–263

    PubMed  Google Scholar 

  • Plooy ACM, Dijl M van, Berends F, Lohman PHM (1985) Formation and repair of DNA interstrand crosslinks in relation to cytotoxicity and unscheduled DNA synthesis induced in control and mutant human cells treated with cís-diamminedichloro-platinum(II). Cancer Res 45:4178–4184

    PubMed  Google Scholar 

  • Poll EHA, Abrahams PJ, Anwert F, Ericksson AW (1984) Host cell reactivation ofcis-diamminedichloroplatinum(II) treated SV 40 DNA in normal human Fanconi anaemia and Xeroderma pigmentosum fibroblasts. Mutat Res 132:181–187

    PubMed  Google Scholar 

  • Purnell MR, Kidwell WR, Minshall L, Whish WJD, (1985) Specificity of poly(ADP-ribose) synthetase inhibitors. In: Althaus FR, Hilz H, Shall S (eds) ADP-ribosylation of proteins. Springer, Berlin Heidelberg New York, pp. 98–107

    Google Scholar 

  • Rosenberg B (1985) Fundamental studies with cisplatin. Cancer 55:2303–2316

    PubMed  Google Scholar 

  • Satoh MS, Poirier GG, Lindahl T (1993) NAD+-dependent repair of damaged DNA by human cell extracts. J. Biol Chem 268:5480–5487

    PubMed  Google Scholar 

  • Schreiber V, Hunting D, Trucco C Gowans B, Grunwald D, De-Murcia G, De-Murcia JM (1995) A dominant-negative mutant of human poly(ADP-ribose) polymerase affects cell recovery, apoptosis, and sister chromatid exchange following DNA damage. Proc Natl Acad Sci USA 92:4753–4757

    PubMed  Google Scholar 

  • Sebold-Leopold JS, Scavone SV (1992) Enhancement of alkylating agent activity in vitro by PD 128763, a potent Poly(ADP-ribose)synthesis inhibitor. Int J Radiat Oncol Biol Phys 22:619–621

    PubMed  Google Scholar 

  • Shall S (1984) ADP-ribose in DNA repair: a new component of DNA excision repair. Adv Radiat Biol 11:1–69

    Google Scholar 

  • Shinomiya N, Shinomiya M, Wakiyama H, Katsura Y, Rokutanda M (1994) Enhancement of CDDP cytotoxicity by caffeine is characterized by apoptotic cell death. Exp Cell Res 210:236–242

    PubMed  Google Scholar 

  • Sibghat-Ullah, Hussain I, Carlton W, Sancar A (1989) Human nucleotide excision repair in vitro: repair of pyrimidine dimers, psoralen and cisplatin adducts by HeLa cell-free extract. Nucleic Acids Res 17:4471–4484

    PubMed  Google Scholar 

  • Swinnen LJ, Ellis N, Erickson LC (1991) Sensitization of resistant human tumor cells to cisplatin or carboplatin by inhibitors of DNA excision repair. In: Howell SB (ed) Platinum and other metal coordination compounds in cancer chemotherapy. Plenum, New York, pp 253–268

    Google Scholar 

  • Swinnen LJ Fisher SG, Eickson LC (1989) Ultraviolet irradiation produces cytotoxic synergy and increased DNA interstrand crosslinking withcis-andtrans-diamminedichloroplatin. Carcinogenesis 10:1465–1470

    PubMed  Google Scholar 

  • Tewari M, Quan LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM (1995) Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81:801–809

    PubMed  Google Scholar 

  • Umbach G, Poethen J, Umbach U (1985a) Effect of 3-aminobenzamide on the cytotoxicity of cisplatin in a human ovarian cancer cell line. Proc Am Assoc Cancer Res 26:26

    Google Scholar 

  • Umbach GE, Poethen J, Matthiesen H von, Koldovsky U (1985b) Effect of aminobenzamide on the cytotoxic efficacy of cisplatin in two human ovarian cancer cell lines. IRCS Med Sci 13:578

    Google Scholar 

  • Vaux DL, Strasser A (1996) The molecular biology of apoptosis. Proc Natl Acad Sci USA 93:2239–2244

    PubMed  Google Scholar 

  • Vilpo JA, Vilpo LM, Szymkowsky DE, O'Donovan A, Wood RD (1995) An XPGDNA repair defect causing mutagen hypersensitivity in mouse leukemia L1210 cells. Mol Cell Biol 15:290–297

    PubMed  Google Scholar 

  • Wang Z, Wu X, Friedberg EC (1993) Nucleotide excision repair of DNA in cell-free extracts of the yeast Saccaromyces cerevisiae. Proc Natl Acad Sci USA 90:4907–4911

    PubMed  Google Scholar 

  • Wang Z, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M, Wagner EF (1995) Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev 9:509–520

    PubMed  Google Scholar 

  • Wilson AP (1984) Characterization of a cell line derived from the ascites of a patient with papillary serous cystadenocarcinoma of the ovary. J Natl Cancer Inst 72:513–521

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. German Cancer Research Center, Division 0420, D-69120, heidelberg, Germany

    Frithjof Bernges & W. Jens Zeller

Authors
  1. Frithjof Bernges
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Jens Zeller
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernges, F., Zeller, W.J. Combination effects of poly(ADP-ribose) polymerase inhibitors and DNA-damaging agents in ovarian tumor cell lines —with special reference to cisplatin. J Cancer Res Clin Oncol 122, 665–670 (1996). https://doi.org/10.1007/BF01209029

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01209029

Key words

Search

Navigation