Skip to main content
SpringerLink
Log in

Effects of Amifostine on Cisplatin Induced DNA Adduct Formation and Toxicity in Malignant Glioma and Normal Tissues in Rat

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The chemoprotective effect of amifostine (WR2721) was studied in a BDIX rat model with intracerebral BT4C glioma implants. Twenty-one rats were given cisplatin 5 mg/kg i.p., 21 were given amifostine 200 mg/kg i.p.+cisplatin 5 mg/kg i.p. Ten rats served as untreated controls. An immunohistochemical method for analysis of cisplatin–DNA adducts was used to elucidate the adduct formation in tumor, normal brain and kidney. Tumor volume and serum creatinine level were analysed 10 days after treatment. In animals pretreated with amifostine there was a delayed adduct formation rate in the normal brain, and in the kidney cortex the number of tubular cells with extremely high adduct level was reduced. No difference in adduct formation was seen in tumors. Tumor volume was significantly larger following amifostine+cisplatin (66% of controls) compared to cisplatin alone (38% of controls). Weight loss was, however, severe in rats given cisplatin alone. In the tumor growth study only 3 out of 11 rats treated with cisplatin 5 mg/kg alone survived until time of sacrifice at 10 days, whereas all those pretreated with amifostine survived. Mean serum creatinine was 48 µmol/l (controls), 146 µmol/l (cisplatin) and 59 µmol/l (amifostine+cisplatin). A marked reduction of histopathological renal changes was found when amifostine was added. Amifostine thus significantly reduced general and renal toxicity of cisplatin. The tumor growth retardation was stronger when cisplatin was given alone but this is probably related to general toxicity and malnutrition indirectly supported by the fact that amifostine did not significantly reduce cisplatin–DNA adduct formation in tumors. The results of the present study suggest that amifostine may have a role in increasing the therapeutic ratio of cisplatin, also in the treatment of malignant glioma.

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

References

  1. Spencer CM, Goa KL: Amifostine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential as a radioprotector and cytotoxic chemoprotector. Drugs 50(6): 1001–1031, 1995

    Google Scholar 

  2. Budd GT, Bukowski RM, Murthy S, Adelstein D, Pelley D, Olencki T, Petrus J, Lorenzi V, McLain D, Egorin M, Conlon J, Graden D, Reynolds R: Randomized trial of carboplatin (CBDCA) vsCBDCACamifostine (AMI) in advanced malignancy (abstract 1524). Proc Am Soc Cancer Oncol 13: 442, 1994

    Google Scholar 

  3. Glick J, Kemp G, Rose P, Mitchell E, Reynolds R, Scheffler B, Capizzi R: A randomized trial of cyclophosphamide and cisplatin ± amifostine in the treatment of advanced epithelial ovarian cancer (abstract 1485). Proc Am Soc Clin Oncol 13: 432, 1994

    Google Scholar 

  4. Glover D, Glick JK, Weiler C, Hurowitz S, Kligerman MM: WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol 4: 584–588, 1986

    Google Scholar 

  5. Poplin EA, LoRosso P, Lokich JJ, Gullo JJ, Leming PD, Schultz JJ, Veach SR, McCulloch W, Baker L, Schein P: Randomized clinical trial of mitomycin C with or without pretreatment with WR2721 in patients with advanced colorectal cancer. Cancer Chemother Pharmacol 33: 415–419, 1994

    Google Scholar 

  6. Glover D, Grabelsky S, Fox K, Weiler C, Cannon L, Glick J: Clinical trials of WR-2721 and cis-platinum. Int J Radiat Oncol Biol Phys 16: 1201–1204, 1989

    Google Scholar 

  7. Glover D, Glick JK, Weiler C, Fox K, Turrisi A, Kligerman MM: Phase I/Il trials of WR-2721 and cisplatinum. Int J Oncol Biol Phys 12: 1509–1512, 1986

    Google Scholar 

  8. Avril MF, Ortoli JC, Fortier-Beaulieu M, Turz T, Guillaume JC, McCulloch W, Toy J, Schein P: High dose cisplatin (c) and WR2721 in metastatic melanoma (abstract 1181). Proc Am Soc Clin Oncol 11: 344, 1992

    Google Scholar 

  9. Jordan SW, Yuhas JM, Glick J: Modulation of cis-platinum renal toxicity by the radioprotective agent WR2721. Exp Mol Pathol 36: 297–305, 1982

    Google Scholar 

  10. Treskes M, Boven M, Holwerda U, Pinedo HM, van der Vijgh WJ: Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse. Cancer Res 52: 2257–2260, 1992

    Google Scholar 

  11. Treskes M, Nijtmans LGJ, Fichtinger-Schepman AMJ, van derVijgh WJ: Effects of the modulating agentWR2721and its main metabolites on the formation and stability of cisplatin– DNA adducts in vitro in comparison to the effects of thiosulfate and diethyldithiocarbamate. Biochem Pharmacol 43: 1013–1019, 1992

    Google Scholar 

  12. Stewart DJ, Molepo JM, Eapen L, Montpetit VA, Goel R, Wong PT, Popovic P, Taylor KD, Raaphorst GP: Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies. Int J Radiat Oncol Biol Phys 28: 531–542, 1994

    Google Scholar 

  13. Laerum OD, Rajewsky MF, Schachner M, Stavrou D, Haglid KG, Haugen Å: Phenotypic properties of neoplastic cell lines developed from fetal rat brain cells in culture after exposure to ethylnitrosourea in vivo. Zellular Krebsforschung 89: 273–295, 1977

    Google Scholar 

  14. Johnsson A, Olsson C, Nygren O, Nilsson M, Seiving B, Cavallin-Ståhl E: Pharmacokinetics and tissue distribution of cisplatin in nude mice: platinum levels and cipslatin–DNA adducts. Cancer Chemother Pharmacol 37: 23–31, 1995

    Google Scholar 

  15. Terheggen PMAB, Floot BGJ, Scherer E, Begg AC, Fichtinger-Schepman AMJ, Engelse I: Immunocytochemical detection of interaction products of cis-diaminedichloroplatinum (II) and cis-diammine (1,1-cyclobutanedicarboxylato) platinum (II) with DNA in rodent tissues. Cancer Res 47: 6719–6725, 1987

    Google Scholar 

  16. Johnsson A, Olsson C, Andersson H, Cavallin-Ståhl E: Evaluation of a method for quantitative immunohistochemical analysis of cisplatin–DNA adducts in tissues from nude mice. Cytometry 17: 142–150, 1994

    Google Scholar 

  17. Bacus JW, Grace LJ: Optical microscope system for standardized cell measurements and analyses. Applied Optics 26: 3280–3293, 1987

    Google Scholar 

  18. Bergström P, Johnsson A, Cavallin-Ståhl E, Bergenheim T, Henriksson R: Effects of Amphotericin B on DNA adduct formation and toxicity in malignant glioma and normal tissue in rat. Eur J Cancer 33(1): 153–159, 1997

    Google Scholar 

  19. Washburn LC, Carlton JE, Hayes RL: Distribution of WR-2721 in normal and malignant tissues of mice and rats bearing solid tumors: dependence on tumour type, drug, dose and species. Radiat Res 59: 475–483, 1974

    Google Scholar 

  20. Utley JF, Marlowe C, Waddell WJ: Distribution of 35Slabeled WR-2721 in normal and malignant tissues of the mouse. Radiat Res 68: 284–291, 1976

    Google Scholar 

  21. Korst AEC, Boven E, van der Sterre MLT, Fichtinger-Schepman AMJ, van der Vijgh WJF: Pharmacokinetics of cisplatin with and without amifostine in tumour-bearing nude mice. Eur J Cancer 34(3): 412–416, 1998

    Google Scholar 

  22. Calabro-Jones PM, Aguilera JA, Ward JF, Smoluk GD, Fahey RC: Uptake of WR-2721 derivatives by cells in culture: Identification of the transported form of the drug. Cancer Res 48: 3634–3640, 1988

    Google Scholar 

  23. Lauk S, Denekamp J: Identification of vasculature. Enzyme histochemistry. Gray laboratory annual report 56, 1985

  24. Kennedy KA, Reicher BA, Rockwell S, Sartorelli JR. In: AC Sartorelli, JR Bertino, J Slazo (eds) Molecular Targets and Actions for Cancer Chemotherapeutic Agents. Academic press, New York, 1981, pp 85–101

    Google Scholar 

  25. Vaupel PW, Frinak S, Bicher HI: Heterogenous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 41: 2008–2013, 1981

    Google Scholar 

  26. Mies G, Paschen W, Csiba L, Krajewski S, Wechsler W, Hossman KA: Comparison of regional tissue pH measured with the umbelliferone and 14C-DMO technique in rat brain. J Cereb Blood Flow Metab 19 (suppl): 247–248, 1985

    Google Scholar 

  27. Rottenberg DA, Ginos JZ, Kearfott KJ, Junck L, Bigner DD: In vivo measurement of regional brain tissue pH using positron emission tomography. Ann Neurol 15 (suppl): 98–102, 1984

    Google Scholar 

  28. Vaupel P, Kallinowski F, Adams GE: Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449–6465, 1989

    Google Scholar 

  29. Steiger E, Oram-Smith J, Miller E, Kuo L, Vars HM: Effects of nutrition on tumour growth and tolerance to chemotherapy. J Surg Res 18: 455–461, 1975

    Google Scholar 

  30. Daly JM, Reynolds HM, Rowlands BJ, Dudrick SJ, Copeland EM: Tumour growth in Experimental animals. Nutritional manipulation and chemotherapeutic response in the rat. Ann Surg 191: 316–322, 1980

    Google Scholar 

  31. Daly JM, Copeland EM, Dudrick SS, Delaney MS: Nutritional repletion of malnourished tumour-bearing and nontumor-bearing rats: effects on body weight, liver, muscle and tumour. J Surg Res 28: 507–518, 1980

    Google Scholar 

  32. Karpeh MS, Kehne JA, Seung Hoon Choi BS, Ziegler MM: Tumour immunogenicity, nutritional repletion and cancer. Surgery 102: 283–290, 1987.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, University Hospital, Umeå, Sweden

    P. Bergström & R. Henriksson

  2. Department of Oncology, University Hospital, Lund, Sweden

    A. Johnsson

  3. Department of Neurosurgery, University Hospital, Umeå, Sweden

    T. Bergenheim

Authors
  1. P. Bergström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Johnsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Bergenheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Henriksson
    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

Bergström, P., Johnsson, A., Bergenheim, T. et al. Effects of Amifostine on Cisplatin Induced DNA Adduct Formation and Toxicity in Malignant Glioma and Normal Tissues in Rat. J Neurooncol 42, 13–21 (1999). https://doi.org/10.1023/A:1006152103476

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006152103476

Search

Navigation