Abstract
The neurotoxicity of cisplatin and ORG.2766, both separately and in combination, was investigated using serum-free chick embryonic brain cell cultures. At low cisplatin concentrations glial cells were affected more than nerve cells. The onset of cisplatin toxicity was delayed, the major effects only being seen after the treatment was finished and when no free cisplatin was present in the culture medium. The data further indicate that the area under the graph of free cisplatin concentration in the culture medium against time (AUC) is a measure of cisplatin toxicity. The AUC of free cisplatin in the culture medium which causes a 50% reduction in the expression of glial fibrillary associated protein (GFAP) was similar to blood AUC values in humans known to induce neurotoxic effects in around 80% of patients. ORG.2766 at very high concentrations increased lysosomal activity, as measured by neutral red uptake, and the expression of GFAP. ORG.2766 did not influence the toxicity of cisplatin in culture.
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Abbreviations
- MAP5:
-
microtubule-associated protein type 5
- NF68kD:
-
neurofilament with 68 kiloDalton size
- GFAP:
-
glial fibrillary acidic protein
- ORG.2766:
-
H-Met(O2)-Glu-His-Phe-(d-)Lys-Phe-OH
- MTT:
-
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium
- IC50 :
-
concentration at which the measured parameter is reduced by 50%
- Nc:
-
cooperativity constant (steepness) of the concentration effect curve
- AUC:
-
area under the graph of concentration against time
References
Andrews PA, Velury S, Mann SC, Howell SB (1988) cis-Diamminedichloroplatinum(II) accumulation in sensitive and resistant human ovarian carcinoma cells. Cancer Res 48: 68–73
Bertolone SJ, Baum ES, Krivit W, Hammond GD (1989) A phase II study of cisplatin therapy in recurrent childhood brain tumors. J Neuro-Oncol 7: 5–11
Bijlsma WA, Jennekens FGI, Schotman P, Gispen WH (1984) Neurotrophic factors and regeneration in the peripheral nervous system. Psychoneuroendocrinology 9: 199–215
Bruinink A (1992) Serum-free monolayer cultures of embryonic chick brain and retinal immunoassays of developmental markers, mathematical data analysis and establishment of optimal culture conditions. In: Zbinden G (ed) The brain in bits and pieces. MTC Verlag, Zollikon, pp 23–50
Bruinink A, Reiser P (1991) Ontogeny of MAP2 and GFAP antigens in primary cultures of embryonic chick brain. Effect of substratum, oxygen tension, serum and ARA-C. Int J Dev Neurosci 9: 269–279
Daley-Yates PT, McBrain DCH (1984) Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumor activity of cisplatin. Biochem Pharmacol 33: 3063–3070
Daugaard GK, Petrera J, Trojaborg W (1987) Electrophysiological study of the peripheral and central neurotoxic effect of cisplatin. Acta Neurol Scand 76: 86–93
De Koning P, Neijt JP, Jennekens FGI, Gispen WH (1987) ORG.2766 protects from cisplatin-induced neurotoxicity in rats. Exp Neurol 97: 746–750
Edwards PM, Gispen WH (1985) Melanocortin peptides and neural plasticity. In: Traber J, Gispen WH (eds) Senile dementia of Alzheimer type. Springer-Verlag, Berlin, pp 231–240
Fauchon F, Chiras J, Poisson M, Rose M, Terrier L, Bories J, Guérin RA (1986) Chimiothérapie intra-artérielle par le cisplatine et la cytarabine après rupture temporaire hémato-encéphalique dans le traitement des gliomes malins de l'adulte. J Neuroradiol 13: 151–162
Gastaut TJ, Pellisier JF (1985) Neuropathie au cisplatine: étude clinique, électrophysiologique et morphologique. Rev Neurol (Paris) 141: 624–626
Guarino AM, Miller DS, Arnold ST, Pritchard JB, Davis RD, Urbanek MA, Miller TJ, Litterst CL (1979) Platinate toxicity; past present and prospects. Cancer Treat Rep 63: 1475–1483
Hadley D, Herr HW (1979) Peripheral neuropathy associated with cisdichlorodiammineplatinum(II) treatment. Cancer 44: 2026–2028
Hamburger V, Hamilton HL (1951) A series of normal stages in the development of the chick embryo. J Morphol 88: 49–92
Hansen SW, Helweg-Larsen S, Trojaborg W (1989) Long-term neurotoxicity in patients treated with cisplatin, vinblastine, and bleomycin for metastatic germ cell cancer. J Clin Oncol 7: 1457–1461
Kupersmith MJ, Frohman LP, Choi IS, Foo SH, Hiesinger E, Berenstein A, Wise A, Carr RE, Ransohoff J (1988) Visual system toxicity following intra-arterial chemotherapy. Neurology 38: 284–289
Müller LJ, Gerritsen van der Hoop R, Moorer-van Delft CM, Gispen WH, Roubos EW (1990) Morphological and electrophysiological study of the effects of cisplatin and ORG.2766 on rat spinal ganglion neurons. Cancer Res 50: 2437–2442
Patton TF, Repta AJ, Sternson LA, Belt RJ (1982) Pharmacokinetics of intact cisplatin in plasma; infusion versus bolus dosing. Int J Pharmaceut 10: 77–85
Roelofs RI, Hrushesky W, Rogin J, Rosenberg L (1984) Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology 34: 934–938
Stewart DJ, Leavens M, Maor M, Feun L, Luna M, Bonura J, Capriolo R, Loo TL, Benjamin S (1982) Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Cancer Res 42: 2474–2479
Terheggen PMAB, Floot BGJ, Scherer E, Begg AC, Fichtinger-Schepman AMJ, den Engelse L (1987) Immunocytochemical detection of interaction products of cis-diamminechloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) with DNA in rodent tissue sections. Cancer Res 47: 6719–6725
Terheggen PMAB, Gerritsen van der Hoop R, Floot BGJ, Gispen WH (1989) Cellular distribution of cis-diamminechloroplatinum(II)-DNA binding in rat dorsal root spinal ganglia: effect of the neuroprotecting peptide ORG.2766. Toxicol Appl Pharmacol 99: 334–343
Thompson SW, Davis LE, Kornfeld M, Hilgers RD, Standefer JC (1984) Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer 54: 1269–1275
Van der Zee CEEM, Brakkee JH, Gispen WH (1988) α-MSH and ORG.2766 in peripheral regeneration: different routes of delivery. Eur J Pharmacol 147: 351–357
Verhaagen J, Edwards PM, Jennekens FGI, Schotman P, Gispen WH (1987) Early effect of an ACTH4-9 analog (ORG.2766) on regenerative sprouting demonstrated by the use of neurofilament-binding antibodies isolated from a serum raised by α-MSH immunization. Brain Res 404: 142–150
Von Hoff DD, Schilsky R, Reichert CM, Reddick RL, Rozencweig M, Young RC, Muggia FM (1979) Toxic effects of cis-dichlorodiam-mineplatinum(II) in man. Cancer Treat Rep 63: 1527–1531
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Bruinink, A., Birchler, F. Effects of cisplatin and ORG.2766 in chick embryonic brain cell cultures. Arch Toxicol 67, 325–329 (1993). https://doi.org/10.1007/BF01973703
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DOI: https://doi.org/10.1007/BF01973703