Research SectionEffect of urinary pH on the progression of urinary bladder tumours
Introduction
Since the beginning of this century, systemic alkalosis has been associated with a variety of malignant neoplasms and has been implicated as an enhancing factor in tumorigenesis. In contrast, a favourable influence of systemic acidosis on tumour control and regression has long been implicated (reviewed by Harguindey, 1982). Several reports have indicated that metabolic acidosis inhibits tumour growth in experimental tumours. Verne and Roth (1963)reported inhibition of the carcinogenicity of subcutaneous implantations of oestradiol benzoate in rabbits by acidification of drinking water. In another study it was found that lowering the systemic pH by ammonium chloride inhibited the growth of solid tumours and leukaemias in mice (Anghileri, 1975). Hydrochloric acid added to laboratory food has resulted in an increased rate of regression of subcutaneously implanted sarcoma 180 (Harguindey et al., 1979). Also in tissue culture, low environmental pH has been shown to inhibit cell proliferation, survival and activity of tumour cells (Tannock and Rotin, 1989; Wike-Hooley et al., 1984).
Spontaneous cell death has been observed to occur within regions of solid tumours. Although the causes of spontaneous cell death within tumours are not known, the poorly developed vasculature may contribute to this process, by failing to provide adequate nutrients or to remove catabolytes (Vaupel et al., 1989). Owing to the limited range of diffusion of oxygen within tissues, regions within solid tumours tend to become hypoxic. It is well known that the extracellular fluid in malignant tumours is acidic relative to that in normal tissue (Jähde et al., 1990; Wike-Hooley et al., 1984). Hypoxic regions of tumours are likely to be acidic because of dependence on glycolysis as a major source of metabolic energy, leading to accumulation of lactic acid and hydrolysis of ATP, with consequent reduction of extracellular pH (Hochachka and Mommsen, 1983; Maidorn et al., 1993). It has been hypothesized that the combination of hypoxia and lower extracellular pH may be responsible for cell death (Boyer et al., 1993; Rotin et al., 1986).
In the present study it was investigated whether tumour progression can be inhibited by a chronically decreased environmental pH. The urinary bladder was selected as target organ because, in contrast to the pH of blood and interstitial fluid which is controlled within narrow limits, the urinary pH can easily be manipulated.
Two-stage urinary bladder carcinogenesis, promoted by increases in both urinary sodium ion concentration and pH, could be inhibited by lowering the urinary pH through simultaneous oral administration of ammonium chloride during promotion (Fukushima et al., 1986; Hagiwara et al., 1994). The objective of the present study was to investigate the effect of low environmental pH on the progression of preneoplastic urinary bladder lesions initiated by BBN and promoted by short- (15 wk) or more long-term (25 wk) promotion with NaHCO3.
Section snippets
Chemicals
N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was purchased from Organische Chemicaliën Service (Haarlem, The Netherlands). Sodium hydrogen carbonate (NaHCO3, purity>99%) was obtained from Boom b.v. (Meppel, The Netherlands). Ammonium chloride (NH4Cl) was obtained from Merck (Germany) (Art. 1145; Zur Analyse).
Animals
Weanling, SPF-bred male Wistar rats (Crl:WI(WU)BR) were purchased from Charles River Wiga GmbH (Sulzfeld, Germany) and acclimatized for 7 days. At the start of the study the rats were about
Results
Five rats were killed in extremis or found dead during the course of the study. All deaths occurred in groups with prolonged promotion with NaHCO3; namely, one rat of group E (in wk 38), two rats of group F (in wk 42 and 45) and two rats of group G (in wk 42 and 45). Growth curves are presented in Fig. 2. In the final stage of the study, mean body weights in all groups were lower than in group B (which received the control diet during the major part of the study). These differences were
Discussion
Treatment with BBN (initiation), followed by treatment with NaHCO3 (promotion) appeared to be an effective way to induce urinary bladder carcinogenesis in rats, causing high incidences of simple and P/N hyperplasia, papillomas and carcinomas of the urothelium. These results confirm the well established correlation between increased urinary pH and sodium concentration, and the occurrence of cell proliferation, hyperplasia and neoplasia of bladder urothelium, both in vivo (Fukushima et al., 1986;
Acknowledgements
We would like to thank Dr A.J.M. Hagenaars for statistical evaluation and Professor Dr V.J. Feron for his advice and stimulation.
References (30)
Toxic and nontoxic changes induced in the urothelium by xenobiotics
Toxicology and Applied Pharmacology
(1989)- et al.
Induction of hyperplasia in the bladder epithelium of rats by a dietary excess of acid or base: implications for toxicity/carcinogenicity testing
Food and Chemical Toxicology
(1988) - et al.
Protection of cultured malignant cells from mitoxantrone cytotoxicity by low extracellular pH: A possible mechanism for chemoresistance in vivo
European Journal of Cancer
(1990) - et al.
Acetic acid, a potent agent of tumor progression in the multistage mouse skin model for chemical carcinogenesis
Cancer Letters
(1988) - et al.
Participation of urinary Na+, K+. pH, and l-ascorbic acid in the proliferative response of the bladder epithelium after the oral administration of various salts and/or ascorbic acid to rats
Food and Chemical Toxicology
(1989) - et al.
Rapid induction of hyperplasia in vitro in rat bladder explants by elevated sodium ion concentrations and pH
Toxicology and Applied Pharmacology
(1996) - et al.
The relevance of tumour pH to the treatment of malignant disease
Radiotherapy and Oncology
(1984) Tumour growth inhibition by ammonium chloride-induced acidosis
International Journal of Clinical Pharmacology Research
(1975)- et al.
Membrane potentials and sodium channels: Hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions
Journal of Theoretical Biology
(1986) - et al.
Regulation of internal pH in subpopulations of cells derived from spheroids and solid tumours
British Journal of Cancer
(1993)
The regulation of the intracellular pH in cells from vertebrates
European Journal of Biochemistry
Roles of urinary sodium ion concentration and pH in promotion by ascorbic acid of urinary bladder carcinogenesis in rats
Cancer Research
Are cancer cells acidic?
British Journal of Cancer
Inhibiting effects of diethylmaleate or NH4Cl on NaHCO3, but not butylated hydroxyanisole, promotion of urinary bladder carcinogenesis in male F344 rats initiated with N-butyl-N-(4-hydroxybutyl) nitrosamine
Journal of Toxicological Sciences
Hydrogen ion dynamics and cancer: An appraisal
Medical and Pediatric Oncology
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