title: Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study.
abstract: BACKGROUND
  Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.
  
  
  METHODS
  We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.
  
  
  RESULTS
  The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo 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 non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1-7.2.
  
  
  CONCLUSIONS
  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 7.1-7.2 is most promising.
authors.affiliation: Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles', Oxford OX1 3LB, UK. Natasha.martin@bristol.ac.uk
authors.forename: N K
authors.initials: NK
authors.lastname: Martin
authors.forename: I F
authors.initials: IF
authors.lastname: Robey
authors.forename: E A
authors.initials: EA
authors.lastname: Gaffney
authors.forename: R J
authors.initials: RJ
authors.lastname: Gillies
authors.forename: R A
authors.initials: RA
authors.lastname: Gatenby
authors.forename: P K
authors.initials: PK
authors.lastname: Maini
mesh_terms: D000471:Alkalosis / Q000139:chemically induced; D000818:Animals; D001639:Bicarbonates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002021:Buffers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000378:metabolism* / Q000628:therapy / Q000652:urine
chemical_list: D001639:Bicarbonates; D002021:Buffers