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. 1996 Aug;74(3):468–473. doi: 10.1038/bjc.1996.384

The relationship between tumour glutathione concentration, glutathione S-transferase isoenzyme expression and response to single agent carboplatin in epithelial ovarian cancer patients.

S Ghazal-Aswad 1, L Hogarth 1, A G Hall 1, M George 1, D P Sinha 1, M Lind 1, A H Calvert 1, J P Sunter 1, D R Newell 1
PMCID: PMC2074632  PMID: 8695367

Abstract

There is evidence to suggest that glutathione (GSH) and glutathione-S-transferases (GST) are important factors in determining sensitivity to cytotoxic drugs in vitro and in preclinical in vivo model systems. To define the relationship between tumour GSH concentration, GST isoenzyme expression and response to carboplatin in epithelial ovarian cancer (EOC), tumour samples from 39 patients with assessable disease after primary surgery were analyzed for GSH content and GST expression. Response was assessed after completing six courses of single agent carboplatin therapy. GSH was measured by high performance liquid chromatography (HPLC) in fresh tumour samples taken at primary laparatomy. GST isoenzyme expression was assessed by immunohistochemistry of fixed tumour material using antibodies specific for pi, alpha and mu classes. GST isoenzyme expression was defined as positive if the staining intensity was strong and more than 10% of tumour cells were involved. The mean GSH concentrations were: 8351 +/- 4496, 7211 +/- 5026, 6559 +/- 4573 and 3758 +/- 1885 (nmol g-1 tissue dry weight mean +/- s.d.) for tumours from patients who subsequently achieved a complete response (CR, n = 18), partial response (PR, n = 10) or who had static disease (SD, n = 7) or progressive disease (PD, n = 4) respectively. There was no relationship between GSH concentration and response (ANOVA, P = 0.32). There were also no relationship between GST isoenzyme expression and response (P Fisher's exact test 0.51-0.55 and chi-squared test 0.98-0.99). In conclusion, there was no association between the concentration of GSH or expression of GST isoenzymes and response to single agent carboplatin in primary previously untreated EOC.

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Selected References

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  1. Bolton M. G., Colvin O. M., Hilton J. Specificity of isozymes of murine hepatic glutathione S-transferase for the conjugation of glutathione with L-phenylalanine mustard. Cancer Res. 1991 May 1;51(9):2410–2415. [PubMed] [Google Scholar]
  2. Bolton M. G., Colvin O. M., Hilton J. Specificity of isozymes of murine hepatic glutathione S-transferase for the conjugation of glutathione with L-phenylalanine mustard. Cancer Res. 1991 May 1;51(9):2410–2415. [PubMed] [Google Scholar]
  3. Calvert A. H., Newell D. R., Gumbrell L. A., O'Reilly S., Burnell M., Boxall F. E., Siddik Z. H., Judson I. R., Gore M. E., Wiltshaw E. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989 Nov;7(11):1748–1756. doi: 10.1200/JCO.1989.7.11.1748. [DOI] [PubMed] [Google Scholar]
  4. Calvert A. H., Newell D. R., Gumbrell L. A., O'Reilly S., Burnell M., Boxall F. E., Siddik Z. H., Judson I. R., Gore M. E., Wiltshaw E. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989 Nov;7(11):1748–1756. doi: 10.1200/JCO.1989.7.11.1748. [DOI] [PubMed] [Google Scholar]
  5. Cotgreave I. A., Moldéus P. Methodologies for the application of monobromobimane to the simultaneous analysis of soluble and protein thiol components of biological systems. J Biochem Biophys Methods. 1986 Nov;13(4-5):231–249. doi: 10.1016/0165-022x(86)90102-8. [DOI] [PubMed] [Google Scholar]
  6. Cotgreave I. A., Moldéus P. Methodologies for the application of monobromobimane to the simultaneous analysis of soluble and protein thiol components of biological systems. J Biochem Biophys Methods. 1986 Nov;13(4-5):231–249. doi: 10.1016/0165-022x(86)90102-8. [DOI] [PubMed] [Google Scholar]
  7. Godwin A. K., Meister A., O'Dwyer P. J., Huang C. S., Hamilton T. C., Anderson M. E. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3070–3074. doi: 10.1073/pnas.89.7.3070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Godwin A. K., Meister A., O'Dwyer P. J., Huang C. S., Hamilton T. C., Anderson M. E. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3070–3074. doi: 10.1073/pnas.89.7.3070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Green J. A., Robertson L. J., Clark A. H. Glutathione S-transferase expression in benign and malignant ovarian tumours. Br J Cancer. 1993 Aug;68(2):235–239. doi: 10.1038/bjc.1993.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Green J. A., Robertson L. J., Clark A. H. Glutathione S-transferase expression in benign and malignant ovarian tumours. Br J Cancer. 1993 Aug;68(2):235–239. doi: 10.1038/bjc.1993.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gulick A. M., Fahl W. E. Mammalian glutathione S-transferase: regulation of an enzyme system to achieve chemotherapeutic efficacy. Pharmacol Ther. 1995 May;66(2):237–257. doi: 10.1016/0163-7258(94)00079-i. [DOI] [PubMed] [Google Scholar]
  12. Gulick A. M., Fahl W. E. Mammalian glutathione S-transferase: regulation of an enzyme system to achieve chemotherapeutic efficacy. Pharmacol Ther. 1995 May;66(2):237–257. doi: 10.1016/0163-7258(94)00079-i. [DOI] [PubMed] [Google Scholar]
  13. Hall A. G., Autzen P., Cattan A. R., Malcolm A. J., Cole M., Kernahan J., Reid M. M. Expression of mu class glutathione S-transferase correlates with event-free survival in childhood acute lymphoblastic leukemia. Cancer Res. 1994 Oct 15;54(20):5251–5254. [PubMed] [Google Scholar]
  14. Hall A. G., Autzen P., Cattan A. R., Malcolm A. J., Cole M., Kernahan J., Reid M. M. Expression of mu class glutathione S-transferase correlates with event-free survival in childhood acute lymphoblastic leukemia. Cancer Res. 1994 Oct 15;54(20):5251–5254. [PubMed] [Google Scholar]
  15. Hall A. G., Matheson E., Hickson I. D., Foster S. A., Hogarth L. Purification of an alpha class glutathione S-transferase from melphalan-resistant Chinese hamster ovary cells and demonstration of its ability to catalyze melphalan-glutathione adduct formation. Cancer Res. 1994 Jul 1;54(13):3369–3372. [PubMed] [Google Scholar]
  16. Hall A. G., Matheson E., Hickson I. D., Foster S. A., Hogarth L. Purification of an alpha class glutathione S-transferase from melphalan-resistant Chinese hamster ovary cells and demonstration of its ability to catalyze melphalan-glutathione adduct formation. Cancer Res. 1994 Jul 1;54(13):3369–3372. [PubMed] [Google Scholar]
  17. Hall A., Foster S., Proctor S. J., Cattan A. R. Purification and characterization of a pi class glutathione S-transferase from human leukaemic cells. Br J Haematol. 1990 Dec;76(4):494–500. doi: 10.1111/j.1365-2141.1990.tb07906.x. [DOI] [PubMed] [Google Scholar]
  18. Hall A., Foster S., Proctor S. J., Cattan A. R. Purification and characterization of a pi class glutathione S-transferase from human leukaemic cells. Br J Haematol. 1990 Dec;76(4):494–500. doi: 10.1111/j.1365-2141.1990.tb07906.x. [DOI] [PubMed] [Google Scholar]
  19. Hamilton T. C., Winker M. A., Louie K. G., Batist G., Behrens B. C., Tsuruo T., Grotzinger K. R., McKoy W. M., Young R. C., Ozols R. F. Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem Pharmacol. 1985 Jul 15;34(14):2583–2586. doi: 10.1016/0006-2952(85)90551-9. [DOI] [PubMed] [Google Scholar]
  20. Hamilton T. C., Winker M. A., Louie K. G., Batist G., Behrens B. C., Tsuruo T., Grotzinger K. R., McKoy W. M., Young R. C., Ozols R. F. Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem Pharmacol. 1985 Jul 15;34(14):2583–2586. doi: 10.1016/0006-2952(85)90551-9. [DOI] [PubMed] [Google Scholar]
  21. Harrison D. J., Kharbanda R., Cunningham D. S., McLellan L. I., Hayes J. D. Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury. J Clin Pathol. 1989 Jun;42(6):624–628. doi: 10.1136/jcp.42.6.624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Harrison D. J., Kharbanda R., Cunningham D. S., McLellan L. I., Hayes J. D. Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury. J Clin Pathol. 1989 Jun;42(6):624–628. doi: 10.1136/jcp.42.6.624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hayes P. C., Harrison D. J., Bouchier I. A., McLellan L. I., Hayes J. D. Cytosolic and microsomal glutathione S-transferase isoenzymes in normal human liver and intestinal epithelium. Gut. 1989 Jun;30(6):854–859. doi: 10.1136/gut.30.6.854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hayes P. C., Harrison D. J., Bouchier I. A., McLellan L. I., Hayes J. D. Cytosolic and microsomal glutathione S-transferase isoenzymes in normal human liver and intestinal epithelium. Gut. 1989 Jun;30(6):854–859. doi: 10.1136/gut.30.6.854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hill B. T., Shellard S. A., Hosking L. K., Fichtinger-Schepman A. M., Bedford P. Enhanced DNA repair and tolerance of DNA damage associated with resistance to cis-diammine-dichloroplatinum (II) after in vitro exposure of a human teratoma cell line to fractionated X-irradiation. Int J Radiat Oncol Biol Phys. 1990 Jul;19(1):75–83. doi: 10.1016/0360-3016(90)90137-9. [DOI] [PubMed] [Google Scholar]
  26. Hill B. T., Shellard S. A., Hosking L. K., Fichtinger-Schepman A. M., Bedford P. Enhanced DNA repair and tolerance of DNA damage associated with resistance to cis-diammine-dichloroplatinum (II) after in vitro exposure of a human teratoma cell line to fractionated X-irradiation. Int J Radiat Oncol Biol Phys. 1990 Jul;19(1):75–83. doi: 10.1016/0360-3016(90)90137-9. [DOI] [PubMed] [Google Scholar]
  27. Inoue T., Ishida T., Sugio K., Maehara Y., Sugimachi K. Glutathione S transferase Pi is a powerful indicator in chemotherapy of human lung squamous-cell carcinoma. Respiration. 1995;62(4):223–227. doi: 10.1159/000196451. [DOI] [PubMed] [Google Scholar]
  28. Inoue T., Ishida T., Sugio K., Maehara Y., Sugimachi K. Glutathione S transferase Pi is a powerful indicator in chemotherapy of human lung squamous-cell carcinoma. Respiration. 1995;62(4):223–227. doi: 10.1159/000196451. [DOI] [PubMed] [Google Scholar]
  29. Ishikawa T., Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem. 1993 Sep 25;268(27):20116–20125. [PubMed] [Google Scholar]
  30. Ishikawa T., Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem. 1993 Sep 25;268(27):20116–20125. [PubMed] [Google Scholar]
  31. Ishikawa T., Wright C. D., Ishizuka H. GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. J Biol Chem. 1994 Nov 18;269(46):29085–29093. [PubMed] [Google Scholar]
  32. Ishikawa T., Wright C. D., Ishizuka H. GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. J Biol Chem. 1994 Nov 18;269(46):29085–29093. [PubMed] [Google Scholar]
  33. Lai G. M., Ozols R. F., Young R. C., Hamilton T. C. Effect of glutathione on DNA repair in cisplatin-resistant human ovarian cancer cell lines. J Natl Cancer Inst. 1989 Apr 5;81(7):535–539. doi: 10.1093/jnci/81.7.535. [DOI] [PubMed] [Google Scholar]
  34. Lai G. M., Ozols R. F., Young R. C., Hamilton T. C. Effect of glutathione on DNA repair in cisplatin-resistant human ovarian cancer cell lines. J Natl Cancer Inst. 1989 Apr 5;81(7):535–539. doi: 10.1093/jnci/81.7.535. [DOI] [PubMed] [Google Scholar]
  35. Leyland-Jones B. R., Townsend A. J., Tu C. P., Cowan K. H., Goldsmith M. E. Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene. Cancer Res. 1991 Jan 15;51(2):587–594. [PubMed] [Google Scholar]
  36. Leyland-Jones B. R., Townsend A. J., Tu C. P., Cowan K. H., Goldsmith M. E. Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene. Cancer Res. 1991 Jan 15;51(2):587–594. [PubMed] [Google Scholar]
  37. Mantle T. J., McCusker F. M., Phillips M., Boyce S. Glutathione S-transferases. Biochem Soc Trans. 1990 Apr;18(2):175–177. doi: 10.1042/bst0180175. [DOI] [PubMed] [Google Scholar]
  38. Mantle T. J., McCusker F. M., Phillips M., Boyce S. Glutathione S-transferases. Biochem Soc Trans. 1990 Apr;18(2):175–177. doi: 10.1042/bst0180175. [DOI] [PubMed] [Google Scholar]
  39. Meyer D. J., Gilmore K. S., Harris J. M., Hartley J. A., Ketterer B. Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases. Br J Cancer. 1992 Sep;66(3):433–438. doi: 10.1038/bjc.1992.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Meyer D. J., Gilmore K. S., Harris J. M., Hartley J. A., Ketterer B. Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases. Br J Cancer. 1992 Sep;66(3):433–438. doi: 10.1038/bjc.1992.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Mistry P., Kelland L. R., Abel G., Sidhar S., Harrap K. R. The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines. Br J Cancer. 1991 Aug;64(2):215–220. doi: 10.1038/bjc.1991.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Mistry P., Kelland L. R., Abel G., Sidhar S., Harrap K. R. The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines. Br J Cancer. 1991 Aug;64(2):215–220. doi: 10.1038/bjc.1991.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Mulder T. P., Verspaget H. W., Sier C. F., Roelofs H. M., Ganesh S., Griffioen G., Peters W. H. Glutathione S-transferase pi in colorectal tumors is predictive for overall survival. Cancer Res. 1995 Jun 15;55(12):2696–2702. [PubMed] [Google Scholar]
  44. Mulder T. P., Verspaget H. W., Sier C. F., Roelofs H. M., Ganesh S., Griffioen G., Peters W. H. Glutathione S-transferase pi in colorectal tumors is predictive for overall survival. Cancer Res. 1995 Jun 15;55(12):2696–2702. [PubMed] [Google Scholar]
  45. Murphy D., McGown A. T., Hall A., Cattan A., Crowther D., Fox B. W. Glutathione S-transferase activity and isoenzyme distribution in ovarian tumour biopsies taken before or after cytotoxic chemotherapy. Br J Cancer. 1992 Nov;66(5):937–942. doi: 10.1038/bjc.1992.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Murphy D., McGown A. T., Hall A., Cattan A., Crowther D., Fox B. W. Glutathione S-transferase activity and isoenzyme distribution in ovarian tumour biopsies taken before or after cytotoxic chemotherapy. Br J Cancer. 1992 Nov;66(5):937–942. doi: 10.1038/bjc.1992.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Nakagawa K., Saijo N., Tsuchida S., Sakai M., Tsunokawa Y., Yokota J., Muramatsu M., Sato K., Terada M., Tew K. D. Glutathione-S-transferase pi as a determinant of drug resistance in transfectant cell lines. J Biol Chem. 1990 Mar 15;265(8):4296–4301. [PubMed] [Google Scholar]
  48. Nakagawa K., Saijo N., Tsuchida S., Sakai M., Tsunokawa Y., Yokota J., Muramatsu M., Sato K., Terada M., Tew K. D. Glutathione-S-transferase pi as a determinant of drug resistance in transfectant cell lines. J Biol Chem. 1990 Mar 15;265(8):4296–4301. [PubMed] [Google Scholar]
  49. Randall B. J., Angus B., Akiba R., Hall A., Cattan A. R., Proctor S. J., Jones R. A., Horne C. H. Glutathione S-transferase (placental) as a marker of transformation in the human cervix uteri: an immunohistochemical study. Br J Cancer. 1990 Oct;62(4):614–618. doi: 10.1038/bjc.1990.340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Saburi Y., Nakagawa M., Ono M., Sakai M., Muramatsu M., Kohno K., Kuwano M. Increased expression of glutathione S-transferase gene in cis-diamminedichloroplatinum(II)-resistant variants of a Chinese hamster ovary cell line. Cancer Res. 1989 Dec 15;49(24 Pt 1):7020–7025. [PubMed] [Google Scholar]
  51. de Graeff A., Slebos R. J., Rodenhuis S. Resistance to cisplatin and analogues: mechanisms and potential clinical implications. Cancer Chemother Pharmacol. 1988;22(4):325–332. doi: 10.1007/BF00254240. [DOI] [PubMed] [Google Scholar]
  52. de Graeff A., Slebos R. J., Rodenhuis S. Resistance to cisplatin and analogues: mechanisms and potential clinical implications. Cancer Chemother Pharmacol. 1988;22(4):325–332. doi: 10.1007/BF00254240. [DOI] [PubMed] [Google Scholar]
  53. van der Zee A. G., van Ommen B., Meijer C., Hollema H., van Bladeren P. J., de Vries E. G. Glutathione S-transferase activity and isoenzyme composition in benign ovarian tumours, untreated malignant ovarian tumours, and malignant ovarian tumours after platinum/cyclophosphamide chemotherapy. Br J Cancer. 1992 Nov;66(5):930–936. doi: 10.1038/bjc.1992.388. [DOI] [PMC free article] [PubMed] [Google Scholar]

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