Summary
The present animal experiments were undertaken to clarify whether phenacetin (ph) exerts a complete solitary carcinogenic effect on the resting and rapidly proliferating urothelium of the lower urinary tract of the rat. Cyclophosphamide was repeatedly administered i.p. to stimulate proliferative activity of the urothelium in particular of the bladder. Phenacetin was either fed continuously or administered repeatedly by gavage at the time when cyclophosphamide-induced stimulation of proliferative activity was highest. After 16 months approximately one half of the surviving rats developed uni- and bilateral hyperplasias of the lining epithelium of the renal papilla which were characterised by an endophytic growth pattern and a urothelial differentiation. They were always associated with healed or-rarely-fresh micronecroses of the subjacent papillary tissue. The urothelial hyperplasia of the renal papilla cannot be considered as true preneoplastic, but rather as reactive proliferative lesion in the sense of a reparative hyperregeneration in response to the observed toxic micronecroses. The present experiments did not provide evidence for a solitary carcinogenic effect of ph in the entire lower urinary tract. It seems most likely that a metabolite of ph only plays a role as cocarcinogen with initiation-stimulating and/or initiation-promoting activity in multifactorial multistage carcinogenesis acting together with other causative factors. Thus, the assumption that ph represents a complete solitary carcinogen for the urothelium in man has to be reassessed. Prospective epidemiological investigations should not only consider the consumption of ph-containing analgesics alone, but also the entire occupational and non-occupational environment with its potential carcinogenic and cocarcinogenic hazards.
Similar content being viewed by others
References
Abrahams C, Rubinstein AH, Levin NW (1963) Phenacetin-induced papillary damage in experimental animals. Nature 200:695–696
Abrahams C, Rubinstein C, Levin NW, Wunderlich M (1964) Experimentally induced analgesic nephritis in rats. Arch Pathol 78:222–230
Angervall L, Bengtsson M, Zetterlund CG, Zsigmond M (1969) Renal pelvic carcinoma in a Swedish district with abuse of a phenacetin-containing drug. Br J Urol 41:401–405
Bengtsson M, Angervall L, Ekman H, Lehmann L (1968) Transitional cell tumors of the renal pelvis in analgesic abuser. Scand J Urol Nephrol 2:145–150
Bengtsson M, Johansson S, Angervall L (1978) Malignancies of the urinary tract and their relation to analgesic abuse. Kidney Int 13:107–113
Berenblum I (1974) Carcinogenesis as a biological problem. North-Holland, Amsterdam
Bluemle LW, Goldberg M (1968) Renal accumulation of salicylate and phenacetin. Possible mechanismus in the nephropathy of analgesic abuse. J Clin Invest 47:2507–2514
Boyd EM, Hottenroth SM (1968) The toxicity of phenacetin at the range of the oral LD50 (100 days) in albino rats. Toxicol Appl Pharmacol 12:80–93
Boyd EM, Krijnen CH (1969) Tolerated doses of phenacetin in relation to bodyweight and organ weights. Jpn J Pharmacol 19:386–393
Boyd EM (1970) A review of phenacetin toxicity in animals. Appl. Therapeut 12:9–15
Calder IC, Goss DE, Williams PJ, Funder CC, Green CR, Ham KN, Tange JD (1976) Neoplasia in the rat induced by N-hydroxyphenacetin, a metabolite of phenacetin. Pathology 8:1–6
Clausen E (1964) Histological changes in rabbit kidneys induced by phenacetin and acetylsalicylic acid. Lancet 2:123–124
Cohen SM (1979) Urinary bladder carcinogenesis: initiationpromotion. Semin Oncol 6:157–160
Craddock VM (1976) Cell proliferation and experimental liver cancer. In: Linsell CA, Warwick CP (eds) Liver cell cancer. Elsevier, Amsterdam New York Oxford, pp 152–201
Dubach UC, Raaflaub J (1969) Neue Aspekte zur Frage der Nephrotoxizität von Phenacetin. Experientia 25:956–958
Farber E, Cameron R (1980) The Sequential analysis of cancer development. Adv Cancer Res 31:125–226
Farsund T (1976) Cell kinetics of mouse urinary bladder epithelium. II. Changes in proliferation and nuclear DNA content during necrosis, regeneration and hyperplasia caused by a single dose of cyclophosphamide. Virchows Arch [Cell Pathol] 21:279–298
Farsund T (1978) Cell kinetics of mouse urinary bladder epithelium. V. Changes in the proportion of cells with various nuclear DNA content after repeated doses of cyclophosphamide. Virchows Arch [Cell Pathol] 26:369–373
Foley WA, Jones DCL, Osborn GK, Kimeldorf DJ (1964) A renal lesion associated with diuresis in the aging Sprague-Dawley rat. Lab Invest 13:439–450
Fordham CC, Huffines W, Welt LG (1965) Penacetin-induced renal disease in rats. Ann Int Med 62:738–743
Güller R, Dubach MC (1972) Tumoren der Harnwege nach regelmäßiger Einnahme phenacetinhaltiger Analgetika? Helv Med Acta 36:247–250
Hecker E (1975) Carcinogenesis and cocarcinogenesis. In: Grundmann E (ed) Handbuch der allgemeinen Pathologie. Geschwülste II. Springer, Berlin Heidelberg New York, pp 651–676
Hecker E (1981) Cocarcinogenesis and tumor promoters of the diterpene ester type as possible carcinogenic risk factors. J Cancer Res Clin Oncol 99:103–124
Hicks RM, Wakefield JSJ, Chowaniec J (1975) Evaluation of a new model to detect bladder carcinogens or co-carcinogens; results obtained with saccharin, cyclamate and cyclophosphamide. Chem Biol Interac 11:225–233
Hicks RM, Chowaniec J (1977) The importance of synergy between weak carcinogens in the induction of bladder cancer in experimental animals and humans. Cancer Res 37:2943–2949
Hicks RM (1980) Multistage carcinogenesis in the urinary bladder. Br Med Bull 36:39–46
Hicks RM (1981) Carcinogenesis in the urinary bladder: A multistage process. In: Connolly JG (ed) Carcinoma of the bladder. Progress in Cancer Research and Therapy, vol. 18. Raven Press, New York, pp 75–89
Hultengren N, Lagergren C, Ljungqvist A (1965) Carcinoma of the renal pelvis in renal papillary necrosis. Acta Chir Scand 130:314–320
Isaka H, Yoshii H, Otsuji A, Koike M, Nagai Y, Koura M, Sugiyasu K, Kanabayashi T (1979) Tumors of Sprague-Dawley rats induced by long-term feeding of phenacetin. Gann 70:29–36
Johansson S, Angervall L, Bengtsson M, Wahlqvist L (1974) Uroepithelial tumors of the renal pelvis associated with abuse of phenacetin-containing analgesics. Cancer 33:743–752
Johansson S, Angervall L (1976) Urothelial hyperplasia of the renal papillae in female Sprague-Dawley rats induced by long term feeding of phenacetin. Acta Pathol Microbiol Scand [A] 84:353–354
Johansson S, Angervall L, (1976) Urothelial changes of the renal papillae in Sprague-Dawley rats induced by long term feeding of phenacetin. Acta Pathol Microbiol Scand [A] 84:375–383
Johansson S, Wahlqvist L (1977) Tumors of urinary bladder and ureter associated with abuse of phenacetin-containing analgesics. Acta Pathol Microbiol Scand [A] 83:768–774
Johansson S (1978) Urothelial hyperplasia of the urinary bladder of the rat induced by mechanical perforation and phenacetin treatment. Acta Pathol Microbiol Scand [A] 86:333–335
Johansson S (1981) Carcinogenicity of analgesics in long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetaminophen). Int J Cancer 27:521–529
Kennedy GC (1957) Effects of old age and over-nutrition on the kidney. Br Med Bull 13:67–70
Kincaid-Smith P, Saker BM, McKenzie IFC, Muriden KD (1968) Lesions in the blood supply of the papilla in experimental analgesics nephrophaty. Med J Aust 1:203–206
Kincaid-Smith P (1969) Analgesic nephropathy-A common form of renal disease in Australia. Med J Aust 2:1131–1135
Koss LG, Lavin P (1971) Studies of experimental bladder carcinoma in Fisher 344 female rats. I. Induction of tumors with diet low in vitamin B6 containing N-2-fluorenylacetamide after single dose of cyclophosphamide. J Natl Cancer Inst 46:585–595
Kunze E (1979) Development of urinary bladder cancer in the rat. Curr Top Pathol 67:145–232
Kunze E, Albrecht H, Wöltjen H-H, Schauer A (1979) Die reparative Regeneration des Rattenurothels nach partieller Cystectomie und ihre Bedeutung für die Carcinogenese. J Cancer Res Clin Oncol 95:159–175
Kunze E, Engelhardt W, Steinröder H, Wöltjen HH, Schauer A (1980) Proliferationskinetik regenerierender Urothelzellen in der Rattenharnblase nach Applikation von Cyclophosphamid. Virchows Arch [Cell Pathol] 33:47–66
Kunze E, Wöltjen HH, Albrecht H (1982) Absence of a complete carcinogenic effect of phenacetin on the quiescent and proliferating urothelium stimulated by partial cystectomy. A 2-year feeding study in rats. Urol Int (in press)
Lalich JJ, Paik WCW, Pradhan B (1974) Epithelial hyperplasia in the renal papilla of rats. Arch Pathol 97:29–32
Landmann-Kolbert C, Rutishauser G, Dubach MC (1975) Phenacetin-Abusus und Harnwegstumoren. Urologe [A] 14:75–79
Leistenschneider W, Nagel R (1977) Urotheltumoren und Phenazetinabusus. Therapiewoche 27:4221–4230
Mihatsch MJ, Manz T, Knüsli C, Hofer HO, Rist M, Guetg R, Rutishauser G, Zollinger HM (1980) Phenacetinabusus III. Maligne Harnwegstumoren bei Phenacetinabusus in Basel 1963–1977. Schweiz Med Wochenschr 110:255–264
Miller JA, Miller EC (1969) The metabolic activation of carcinogenic aromatic amines and amides. Prog Exp Tumor Res 11:273–301
Miller JA, Miller EC (1979) Perspectives on the metabolism of chemical carcinogens. In: Emmelot PE, Kriek E (eds) Environmental carcinogenesis. Occurrence, risk, evaluation and mechanism. Elsevier/North-Holland Biomed Press, Amsterdam New York Oxford, pp 25–50
Miller EC, Miller JA (1981) Mechanism of chemical carcinogenesis. Cancer 47:1055–1064
Nakanishi K, Fukushima S, Shibata M, Shirai T, Ogiso T, Ito N (1978) Effect of phenacetin and caffeine on the urinary bladder of rats treated with N-butyl-N-(4-hydroxbutyl)nitrosamine. Gann 69:395–400
Nanra RS, Kincaid-Smith P (1970) Papillary necrosis in rats caused by aspirin and aspirin-containing mixtures. Br Med J 3:559–561
Nery R (1971a) The possible role of N-hydroxylation in the biological effects of phenacetin. Xenobiotica 1:339–343
Nery R (1971b) Some new aspects of the metabolism of phenacetin in the rat. Biochem J 122:317–326
O'Connor PJ (1981) Interaction of chemical carcinogens with macromolecules. J Cancer Res Clin Oncol 167–186
Oehlert W (1973) Cellular proliferation in carcinogenesis. Cell Tissue Kinet 6:325–335
Rathert P, Melchior H, Lutzeyer W (1975) Phenacetin: a carcinogen for the urinary tract? J Urol 113:653–657
Raaflaub J, Dubach UC (1969) Dose-dependent change in the pattern of phenacetin metabolism in man and its possible significance in analgesic nephropathy. Klin Wochenschr 47:1286–1287
Raaflaub J, Dubach UC (1972) Zur Frage der Pathogenese der chronisch interstitiellen Nephritis nach protrahiertem Schmerzmittelabusus. Klin Wochenschr 55:489–497
Rabes HM (1979) Proliferative Vorgänge während der Frühstadien der malignen Transformation. Verh Dtsch Ges Pathol 63:18–39
Saker BM, Kincaid-Smith P (1969) Papillary necrosis in experimental analgesic nephropathy. Br Med J 1:161–162
Schnitzer B, Smith EB, Golden A (1965) The effects of phenacetin and its contaminant on the kidney of the rat. Am J Pathol 46:917–927
Sivak A (1979) Cocarcinogenesis. Biochem Biophys Acta 560:67–89
Skrabanek P, Walsh A (1981) Bladder cancer: UICC Technical Report Series, vol 60
Smith RL, Timbrell JA (1974) Factors affecting the metabolism of phenacetin. I. Influence of dose, chronic dosage, route of administration and species on the metabolism of (1-14C-acetyl) phenacetin. Xenobiotica 4:489–501
Smith GE, Griffiths LA (1976) Comparative metabolic studies of phenacetin and structurally-related compounds in the rat. Xenobiotica 6:217–236
Studer A, Zbinden G, Schärer K, Fust B (1958a) Tierexperimentelle Untersuchungen zur Frage der interstitiellen Nephritis bei Mißbrauch phenacetinhaltiger Schmerzmittel. Schweiz Akad Med Wissensch Bull 14:154–165
Studer A, Zbinden G, Furt B (1958b) Weitere tierexperimentelle Untersuchungen zur Frage des Schmerzmittelmißbrauchs und interstitieller Nephritis. Schweiz Med Wochenschr 88:469–470
Van Lancker JL (1977) DNA injuries, their repair and carcinogenesis Curr Top Pathol 64:65–127
Vahlsing HL, Kim SK, Feinga ER (1977) Cyclophosphamide-induced abnormalities in the incisors of the rat. J Dent Res 56:809–816
Warwick GP (1971) Effect of the cell cycle on carcinogenesis. Fed Proc 30:1760–1765
Weinstein IB, Lee LS, Fisher PB, Mufson A, Yamasaki H (1979) The mechanism of action of tumor promoters and a molecular model of two stage carcinogenesis. In: Emmelot P, Kriek E (eds) Environmental carcinogenesis. Occurrence, risk evaluation and mechanisms. Elsevier/North-Holland Biomed Press, Amsterdam New York Oxford, pp 265–285
Author information
Authors and Affiliations
Additional information
Supported by the Deutsche Forschungsgemeinschaft (Ku 410/1-3)
Rights and permissions
About this article
Cite this article
Kunze, E., Wöltjen, HH., Hartmann, B. et al. Animal experiments regarding a possible carcinogenic effect of phenacetin on the resting and proliferating urothelium stimulated by cyclophosphamide. J Cancer Res Clin Oncol 105, 38–47 (1983). https://doi.org/10.1007/BF00391830
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00391830