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British Journal of Cancer logoLink to British Journal of Cancer
. 1991 Nov;64(5):843–849. doi: 10.1038/bjc.1991.411

Glutathione restores normal cell activation and cell cycle progression in cis-platinum treated human lymphocytes.

M Kubbies 1, B Goller 1, B Schetters 1, I Bartosek 1, W Albert 1
PMCID: PMC1977464  PMID: 1931604

Abstract

Cis-platinum (CDDP) induces severe inhibition of cell activation and cell cycle progression in PHA-stimulated human PBL's. Applying the novel BrdU/Hoechst flow cytometric technique for high resolution cell cycle analysis we show that CDDP induced multiple cell kinetic disturbances occur simultaneously comprising G0/G1-arrest, and slow down and arrest of cells in S and G2/M-phase. We investigated whether the administration of reduced glutathione (GSH) might rescue cells from proliferative disturbances induced by CDDP. GSH at 0.15 mg ml-1 only partially restored normal cell activation and cell cycle progression. However, at 1.5 mg ml-1 a complete normal proliferation pattern was obtained. At the highest GSH dose rescue from inhibition of cell activation (G0/G1-phase arrest) as well as of cell cycle progression (S- and G2/M-phase arrest) was also present after delayed addition of GSH (1, 4 and 20 h) to CDDP treated PBL's. In addition cell viability of CDDP exposed PBL's is restored after GSH treatment. Our in vitro experiments give evidence that an increase of WBC found in CDDP/GSH treated patients has a real underlying cellular physiological mechanism protecting human peripheral lymphocytes from CDDP toxicity.

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Selected References

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  1. Anderson M. E., Naganuma A., Meister A. Protection against cisplatin toxicity by administration of glutathione ester. FASEB J. 1990 Nov;4(14):3251–3255. doi: 10.1096/fasebj.4.14.2227215. [DOI] [PubMed] [Google Scholar]
  2. Arrick B. A., Nathan C. F. Glutathione metabolism as a determinant of therapeutic efficacy: a review. Cancer Res. 1984 Oct;44(10):4224–4232. [PubMed] [Google Scholar]
  3. Bodenner D. L., Dedon P. C., Keng P. C., Katz J. C., Borch R. F. Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate. Cancer Res. 1986 Jun;46(6):2751–2755. [PubMed] [Google Scholar]
  4. Borch R. F., Katz J. C., Lieder P. H., Pleasants M. E. Effect of diethyldithiocarbamate rescue on tumor response to cis-platinum in a rat model. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5441–5444. doi: 10.1073/pnas.77.9.5441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Canetta R., Rozencweig M., Carter S. K. Carboplatin: the clinical spectrum to date. Cancer Treat Rev. 1985 Sep;12 (Suppl A):125–136. doi: 10.1016/0305-7372(85)90027-1. [DOI] [PubMed] [Google Scholar]
  6. Di Re F., Bohm S., Oriana S., Spatti G. B., Zunino F. Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer. Cancer Chemother Pharmacol. 1990;25(5):355–360. doi: 10.1007/BF00686237. [DOI] [PubMed] [Google Scholar]
  7. Eastman A. Cross-linking of glutathione to DNA by cancer chemotherapeutic platinum coordination complexes. Chem Biol Interact. 1987 Mar;61(3):241–248. doi: 10.1016/0009-2797(87)90004-4. [DOI] [PubMed] [Google Scholar]
  8. Filipski J., Kohn K. W., Prather R., Bonner W. M. Thiourea reverses cross-links and restores biological activity in DNA treated with dichlorodiaminoplatinum (II). Science. 1979 Apr 13;204(4389):181–183. doi: 10.1126/science.571145. [DOI] [PubMed] [Google Scholar]
  9. Fujikane T., Shimizu T., Tsuji T., Ishida S., Ohsaki Y., Onodera S. Flow cytometric analysis of the kinetic effects of cisplatin on lung cancer cells. Cytometry. 1989 Nov;10(6):788–795. doi: 10.1002/cyto.990100617. [DOI] [PubMed] [Google Scholar]
  10. Gandara D. R., Perez E. A., Weibe V., De Gregorio M. W. Cisplatin chemoprotection and rescue: pharmacologic modulation of toxicity. Semin Oncol. 1991 Feb;18(1 Suppl 3):49–55. [PubMed] [Google Scholar]
  11. Goel R., Cleary S. M., Horton C., Kirmani S., Abramson I., Kelly C., Howell S. B. Effect of sodium thiosulfate on the pharmacokinetics and toxicity of cisplatin. J Natl Cancer Inst. 1989 Oct 18;81(20):1552–1560. doi: 10.1093/jnci/81.20.1552. [DOI] [PubMed] [Google Scholar]
  12. Gringeri A., Keng P. C., Borch R. F. Diethyldithiocarbamate inhibition of murine bone marrow toxicity caused by cis-diamminedichloroplatinum(II) or diammine-(1,1-cyclobutanedicarboxylato)platinum(II). Cancer Res. 1988 Oct 15;48(20):5708–5712. [PubMed] [Google Scholar]
  13. Kanno S., Hyodo M., Suzuki K., Ohkido M. Effect of DNA-damaging agents on DNA replication and cell-cycle progression of cultured mouse mammary carcinoma cells. Jpn J Cancer Res. 1985 Apr;76(4):289–296. [PubMed] [Google Scholar]
  14. Kosower N. S., Kosower E. M. The glutathione status of cells. Int Rev Cytol. 1978;54:109–160. doi: 10.1016/s0074-7696(08)60166-7. [DOI] [PubMed] [Google Scholar]
  15. Kubbies M. Flow cytometric recognition of clastogen induced chromatin damage in G0/G1 lymphocytes by non-stoichiometric Hoechst fluorochrome binding. Cytometry. 1990;11(3):386–394. doi: 10.1002/cyto.990110309. [DOI] [PubMed] [Google Scholar]
  16. Kubbies M., Friedl R., Koehler J., Rabinovitch P. S., Hoehn H. Improvement of human lymphocyte proliferation and alteration of IL-2 secretion kinetics by alpha-thioglycerol. Lymphokine Res. 1990 Spring;9(1):95–106. [PubMed] [Google Scholar]
  17. Lazo J. S., Bahnson R. R. Pharmacological modulators of DNA-interactive antitumor drugs. Trends Pharmacol Sci. 1989 Sep;10(9):369–373. doi: 10.1016/0165-6147(89)90010-2. [DOI] [PubMed] [Google Scholar]
  18. Lippard S. J. New chemistry of an old molecule: cis-[Pt(NH3)2Cl2]. Science. 1982 Dec 10;218(4577):1075–1082. doi: 10.1126/science.6890712. [DOI] [PubMed] [Google Scholar]
  19. Mangioni C., Bolis G., Pecorelli S., Bragman K., Epis A., Favalli G., Gambino A., Landoni F., Presti M., Torri W. Randomized trial in advanced ovarian cancer comparing cisplatin and carboplatin. J Natl Cancer Inst. 1989 Oct 4;81(19):1464–1471. doi: 10.1093/jnci/81.19.1464. [DOI] [PubMed] [Google Scholar]
  20. Markman M., Cleary S., Pfeifle C. E., Howell S. B. High-dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity. Cancer. 1985 Nov 15;56(10):2364–2368. doi: 10.1002/1097-0142(19851115)56:10<2364::aid-cncr2820561003>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  21. Meister A., Anderson M. E. Glutathione. Annu Rev Biochem. 1983;52:711–760. doi: 10.1146/annurev.bi.52.070183.003431. [DOI] [PubMed] [Google Scholar]
  22. Mistry P., Harrap K. R. Historical aspects of glutathione and cancer chemotherapy. Pharmacol Ther. 1991;49(1-2):125–132. doi: 10.1016/0163-7258(91)90026-i. [DOI] [PubMed] [Google Scholar]
  23. Mitchell J. B., Cook J. A., DeGraff W., Glatstein E., Russo A. Glutathione modulation in cancer treatment: will it work? Int J Radiat Oncol Biol Phys. 1989 May;16(5):1289–1295. doi: 10.1016/0360-3016(89)90301-5. [DOI] [PubMed] [Google Scholar]
  24. Oriana S., Böhm S., Spatti G., Zunino F., Di Re F. A preliminary clinical experience with reduced glutathione as protector against cisplatin-toxicity. Tumori. 1987 Aug 31;73(4):337–340. doi: 10.1177/030089168707300403. [DOI] [PubMed] [Google Scholar]
  25. Pfeifle C. E., Howell S. B., Felthouse R. D., Woliver T. B., Andrews P. A., Markman M., Murphy M. P. High-dose cisplatin with sodium thiosulfate protection. J Clin Oncol. 1985 Feb;3(2):237–244. doi: 10.1200/JCO.1985.3.2.237. [DOI] [PubMed] [Google Scholar]
  26. Rabinovitch P. S. Regulation of human fibroblast growth rate by both noncycling cell fraction transition probability is shown by growth in 5-bromodeoxyuridine followed by Hoechst 33258 flow cytometry. Proc Natl Acad Sci U S A. 1983 May;80(10):2951–2955. doi: 10.1073/pnas.80.10.2951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Roberts J. J., Friedlos F. Quantitative estimation of cisplatin-induced DNA interstrand cross-links and their repair in mammalian cells: relationship to toxicity. Pharmacol Ther. 1987;34(2):215–246. doi: 10.1016/0163-7258(87)90012-x. [DOI] [PubMed] [Google Scholar]
  28. Salles B., Butour J. L., Lesca C., Macquet J. P. cis-Pt(NH3)2Cl2 and trans-Pt(NH3)2Cl2 inhibit DNA synthesis in cultured L1210 leukemia cells. Biochem Biophys Res Commun. 1983 Apr 29;112(2):555–563. doi: 10.1016/0006-291x(83)91500-0. [DOI] [PubMed] [Google Scholar]
  29. Shrieve D. C., Harris J. W. Protection against cis-dichlorodiammine Pt (II) cytotoxicity in vitro by cysteamine. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):585–588. doi: 10.1016/0360-3016(82)90689-7. [DOI] [PubMed] [Google Scholar]
  30. Sorenson C. M., Eastman A. Mechanism of cis-diamminedichloroplatinum(II)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks. Cancer Res. 1988 Aug 15;48(16):4484–4488. [PubMed] [Google Scholar]
  31. Wellner V. P., Anderson M. E., Puri R. N., Jensen G. L., Meister A. Radioprotection by glutathione ester: transport of glutathione ester into human lymphoid cells and fibroblasts. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4732–4735. doi: 10.1073/pnas.81.15.4732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zunino F., Pratesi G., Micheloni A., Cavalletti E., Sala F., Tofanetti O. Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug. Chem Biol Interact. 1989;70(1-2):89–101. doi: 10.1016/0009-2797(89)90065-3. [DOI] [PubMed] [Google Scholar]
  33. Zunino F., Tofanetti O., Besati A., Cavalletti E., Savi G. Protective effect of reduced glutathione against cis-dichlorodiammine platinum (II)-induced nephrotoxicity and lethal toxicity. Tumori. 1983 Apr 30;69(2):105–111. doi: 10.1177/030089168306900204. [DOI] [PubMed] [Google Scholar]
  34. Zwelling L. A., Filipski J., Kohn K. W. Effect of thiourea on survival and DNA cross-link formation in cells treated with platinum(II) complexes, L-phenylalanine mustard, and bis(2-chloroethyl)methylamine. Cancer Res. 1979 Dec;39(12):4989–4995. [PubMed] [Google Scholar]

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