We elaborate how this process has limitations and may introduce other dangers, but suggest that modest changes in tumour pHe may be sufficient in some cases or helpful in other circumstances to reduce chemoresistance to specific therapies that are stifled by tumour acidity. Acknowledgments NKM acknowledges that this work was funded by the National Cancer Institute, NIH grant U56CA113004. Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1C7.2. Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1C7.2 is most promising. studies to test a key model prediction, and predict the translational efficacy in humans. Our modelling predicts effective clinical treatments can be achieved using combination therapies, suggesting promising avenues for new discoveries. Materials and Methods Mathematical model To examine the effect of buffer administration on blood and tumour pHe, we apply and draw clinical insights from a previously developed simple, but realistic mathematical model of the CO2/HCO3? buffer system present in blood and tissues. In HD3 this analysis, we examine the impact of administration of bicarbonate on blood and tumour pHe in mice and humans. A schematic of the model is shown in Figure 1, details of the model and model verification are presented in the Supplementary Appendix, and a full mathematical asymptotic analysis examining the Trabectedin fast, medium and steady-state dynamics can be found in Martin (2011). Open in a separate window Figure 1 Schematic for the Trabectedin mathematical model. The model tracks concentrations of carbon dioxide, protons and bicarbonate in the blood and tumour compartments. Renal filtration regulates blood levels of bicarbonate through glomerular Trabectedin filtration and acid secretion. The blood receives a constant input of protons and carbon dioxide from the normal tissues. Excess carbon dioxide in the blood is lost through ventilation. The tumour produces acid Trabectedin and carbon dioxide, and all ions can enter and exit the tumour tissue via the tumour vasculature. Reproduced with permission from Martin (2011). We use a two-compartment model, representing, respectively, the arterial blood and tumour tissue with a diffusively dominated transport coupling given the small molecules under consideration (consistent with the conclusions that small hydrophilic molecular transport is diffusion dominated in the special case of brain tumours (Groothuis (2009). For more details on parameterisation, see Martin (2011). Model verification with bicarbonate administration in mice To verify whether the model accurately predicts tumour pHe with bicarbonate therapy, we estimate the tumour pHe with the bicarbonate dose administered in the Robey (2009) study of 36?mmol?kg?1 per day (an average of 4.2?ml per day per mouse consumption of 200?m bicarbonate water, and average mouse weight of 23?g). Model predictions were compared with the experimentally observed pHe, which was monitored using fluorescence ratio imaging of SNARF-1 in the dorsal skin-fold window chamber tumour xenografts (Robey (2009) study in mice would be achievable with the same equivalent dose in humans, we simulate the buffer therapy with human parameters and translate the bicarbonate dose. Dose translation from mice to humans is calculated from the Du Bois heightCweight formula to predict surface area: BSA (m2)=0.007184 height (cm)0.725 weight (kg)0.425 (Freireich (2009), simulations predict an increase of 0.07 pH units in the mouse tumour Trabectedin (from 7.0 to 7.07). This agrees with the observed pHe change recorded using imaging of SNARF-1 in a dorsal skin-fold window chamber, with a mean (s.e.) pHe of the peri-tumoural tissue of 7.0 (0.04) in the control group, and 7.07 (0.03) in the treated group (Figures 3A and B). However, simulations predict bicarbonate raises blood pHe by a smaller relative magnitude (0.04 and 0.07 pH units in mouse blood and tumour, respectively; 0.02 and 0.04 pH units in human blood and tumour, respectively). Open in a separate window Figure 2 Simulated bicarbonate therapy in a mouse and human over time. The dimensionless time unit is converted from time, in seconds, such that equals 10?h. (A) Mouse: administration of a bicarbonate dose of 36?mmol?kg?1 day (as in Robey (2009)). The pH is determined using fluorescence ratio imaging of SNARF-1 as described in Robey (2009). (C) Average urine pHe (vertical axis) for untreated (blue circles) and bicarbonate-treated (red squares) mice through time measured in days (horizontal axis). Measurements were taken at just.