pH in human tumour xenografts: effect of intravenous administration of glucose

Abstract

pH frequency distributions of tumours grown s.c. from 30 human tumour xenograft lines in rnu/rnu rats were analysed with the use of H+ ion-sensitive semi-microelectrodes prior to and following stimulation of tumour cell glycolysis by i.v. infusion of glucose. At normoglycemia, the average pH of the tumours investigated was 6.83 (range, 6.72-7.01; n = 268). Without exception, all xenografts responded to the temporary increase in plasma glucose concentration (PGC) from 6 +/- 1 to 30 +/- 3 mM by an accumulation of acidic metabolites, as indicated by a pH reduction to an average value of 6.43 (range, 6.12-6.78; n = 292). This pH value corresponds to a ten-fold increase in H+ ion activity in tumour tissue as compared to arterial blood. Tumour pH approached minimum values at 2-4 h after the onset of glucose administration and could be maintained at acidic levels for 24 h by controlled glucose infusion. Irrespective of pH variations between tumours grown from individual xenograft lines, there was no major difference in pH response to glucose between the four main histopathological tumour entities investigated, i.e. breast, lung and gastrointestinal carcinomas, and sarcomas. In tumours from several xenograft lines, an increase in blood glucose to only 2.5-times the normal value (14 mM) was sufficient to reduce the mean pH to 6.4. Glucose-induced acidosis was tumour-specific. The pH frequency distributions in liver, kidney and skeletal muscle of tumour-bearing rnu/rnu rats were only marginally sensitive to hyperglycemia (average pH, 6.97 vs normal value of 7.14). Tumour-selective activation of pH-sensitive anti-cancer agents, e.g. alkylating drugs, acid-labile prodrugs or pH-sensitive immunoconjugates may thus be feasible in a wide variety of human cancers.

A pH-responsive prodrug delivery system of 10-HCPT for controlled release and tumor targeting

“…The hydrazone formation was confirmed by 1 H NMR (400 MHz), 13 C NMR (100 MHz), and high resolution mass spectrometry (ESI, Agilent 6540; Figure 5). 1 h NMr spectra (A), 13 c NMr spectra (B), and mass spectra (C) of compound B.…”

“…The ester formation was confirmed by 1 H NMR (400 MHz), 13 C NMR (100 MHz), and high resolution mass spectrometry (ESI, Agilent 6540; Figure 4). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet.…”

“…1 h NMr spectra (A), 13 c NMr spectra (B), and mass spectra (C) of compound B. Abbreviation: NMr, nuclear magnetic resonance.…”

“…11 Apart from introducing cell-targeting biomolecules for specific delivery, stimuli-responsive drug systems based on different internal environments in the human body can also enable controlled drug delivery and targeted therapeutics. 12 Owing to rapid proliferation-induced glucose consumption and lactic acid accumulation, the pH in tumor tissues is frequently 0.5-1.0 units less than that in healthy tissues, 13 and endosomes and lysosomes show lower pH values (4.5-6.5) than do normal extracellular matrices and blood (pH =7.4). As an important signal, an acid-sensitive chemical bond between drug and polymer can be considered an ideal trigger for selectively releasing drugs in tumor tissues or directly within tumor cells.…”

Potentiation of anti-cancer drug activity at low intratumoral pH induced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) and its analogue benzylguanidine (BG)

“…In tissue culture models, low pH is a promising target for improved chemotherapy (Wike-Hooley et al, 1984;Volk et al, 1993). An acidic environment enhances the uptake of weak acids (Mikkelsen et al, 1985;Jähde et al, 1989) and topoisomerase I inhibitors (Gabr et al, 1997), it also increases the activation of bioreductive agents (Gibson et al, 1992;Philips et al, 1992;Begleiter and Leith, 1993) and potentiates the interaction of alkylating agents and platinum-containing drugs with DNA Atema et al, 1993).…”