Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-03

AUTHORS

N K Martin, I F Robey, E A Gaffney, R J Gillies, R A Gatenby, P K Maini

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. 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 7.1-7.2 is most promising. More... »

PAGES

1280

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/bjc.2012.58

DOI

http://dx.doi.org/10.1038/bjc.2012.58

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1010749946

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22382688


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1103", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Clinical Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Medical and Health Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Alkalosis", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Animals", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Bicarbonates", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Buffers", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Humans", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Hydrogen-Ion Concentration", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mice", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Models, Biological", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Neoplasms", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "University of Bristol", 
          "id": "https://www.grid.ac/institutes/grid.5337.2", 
          "name": [
            "Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles\u2019, Oxford OX1 3LB, UK", 
            "Department of Social Medicine, University of Bristol, Canynge Hall, 29 Whatley Road, Bristol BS8 2PS, UK"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Martin", 
        "givenName": "N K", 
        "id": "sg:person.013051535742.10", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.013051535742.10"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Arizona", 
          "id": "https://www.grid.ac/institutes/grid.134563.6", 
          "name": [
            "University of Arizona, Tucson, AZ, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Robey", 
        "givenName": "I F", 
        "id": "sg:person.0613462515.92", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0613462515.92"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Oxford", 
          "id": "https://www.grid.ac/institutes/grid.4991.5", 
          "name": [
            "Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles\u2019, Oxford OX1 3LB, UK"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Gaffney", 
        "givenName": "E A", 
        "id": "sg:person.0577003446.69", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0577003446.69"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Moffitt Cancer Center", 
          "id": "https://www.grid.ac/institutes/grid.468198.a", 
          "name": [
            "H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33162, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Gillies", 
        "givenName": "R J", 
        "id": "sg:person.014224135057.83", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014224135057.83"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Moffitt Cancer Center", 
          "id": "https://www.grid.ac/institutes/grid.468198.a", 
          "name": [
            "H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33162, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Gatenby", 
        "givenName": "R A", 
        "id": "sg:person.01251663701.28", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01251663701.28"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Oxford Centre", 
          "id": "https://www.grid.ac/institutes/grid.470387.f", 
          "name": [
            "Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles\u2019, Oxford OX1 3LB, UK", 
            "Oxford Centre for Integrative Systems Biology, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, UK"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Maini", 
        "givenName": "P K", 
        "id": "sg:person.01263171521.12", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01263171521.12"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "https://doi.org/10.1016/j.jtbi.2006.09.010", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1006274487"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1097/00005072-198203000-00006", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1006870743"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.2967/jnumed.107.047258", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1009941536"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/0008-5472.can-08-2394", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1010197012"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/sj.bjc.6604554", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1010689691", 
          "https://doi.org/10.1038/sj.bjc.6604554"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/0008-5472.can-07-5575", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1020159743"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1172/jci110425", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1021996620"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nm0297-177", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1025563287", 
          "https://doi.org/10.1038/nm0297-177"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.mbs.2010.12.002", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1026789202"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1186/1471-2407-11-235", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1029573936", 
          "https://doi.org/10.1186/1471-2407-11-235"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nrc2255", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1031460595", 
          "https://doi.org/10.1038/nrc2255"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nrc1478", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1032257073", 
          "https://doi.org/10.1038/nrc1478"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nrc1478", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1032257073", 
          "https://doi.org/10.1038/nrc1478"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/0008-5472.can-05-4193", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033095257"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nrc882", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1036705264", 
          "https://doi.org/10.1038/nrc882"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nrc882", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1036705264", 
          "https://doi.org/10.1038/nrc882"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/s1476-5586(03)80005-2", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1036742733"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/s10585-011-9415-7", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1041528062", 
          "https://doi.org/10.1007/s10585-011-9415-7"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ccr.2006.10.020", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1042406860"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1681/asn.2008111205", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1046593264"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1681/asn.2008111205", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1046593264"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1046/j.1523-1755.2003.00207.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1047786008", 
          "https://doi.org/10.1046/j.1523-1755.2003.00207.x"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1046/j.1523-1755.2003.00207.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1047786008"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/bf00047468", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1050057929", 
          "https://doi.org/10.1007/bf00047468"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/bf00047468", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1050057929", 
          "https://doi.org/10.1007/bf00047468"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1681/asn.2005070732", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1050475546"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1681/asn.2005070732", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1050475546"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1096/fj.07-9574lsf", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1052334407"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1172/jci105164", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1052487077"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1152/ajplegacy.1946.147.1.138", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1078266484"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1080712372", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1083020407", 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2012-03", 
    "datePublishedReg": "2012-03-01", 
    "description": "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.\nMETHODS: 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.\nRESULTS: 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.\nCONCLUSION: 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.", 
    "genre": "research_article", 
    "id": "sg:pub.10.1038/bjc.2012.58", 
    "inLanguage": [
      "en"
    ], 
    "isAccessibleForFree": true, 
    "isFundedItemOf": [
      {
        "id": "sg:grant.2699085", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2465687", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2699696", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2473639", 
        "type": "MonetaryGrant"
      }
    ], 
    "isPartOf": [
      {
        "id": "sg:journal.1017082", 
        "issn": [
          "0007-0920", 
          "1532-1827"
        ], 
        "name": "British Journal of Cancer", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "7", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "106"
      }
    ], 
    "name": "Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an\n                    integrative modelling study", 
    "pagination": "1280", 
    "productId": [
      {
        "name": "readcube_id", 
        "type": "PropertyValue", 
        "value": [
          "333697233c5abd59a18eb780a18de7780f548772dd90749ea0c2ba103cfc1687"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "22382688"
        ]
      }, 
      {
        "name": "nlm_unique_id", 
        "type": "PropertyValue", 
        "value": [
          "0370635"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1038/bjc.2012.58"
        ]
      }, 
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1010749946"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1038/bjc.2012.58", 
      "https://app.dimensions.ai/details/publication/pub.1010749946"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2019-04-10T17:20", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000001_0000000264/records_8672_00000434.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "https://www.nature.com/articles/bjc201258"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/bjc.2012.58'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/bjc.2012.58'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/bjc.2012.58'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/bjc.2012.58'


 

This table displays all metadata directly associated to this object as RDF triples.

250 TRIPLES      21 PREDICATES      65 URIs      30 LITERALS      18 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1038/bjc.2012.58 schema:about N01a1430f746a4e2da9070c7160d44871
2 N2040f47897334856adcfef78c82f9989
3 N2bd5bc992fc84f939906d9cb34c40ccb
4 N42b08b5d38804b95b726866c19895fc5
5 N4ab3805d78fc497ca5981b0f58f93047
6 N85c4294f1677429795ad2050f87c263a
7 N9a4bd40fcc714235b6302cdbfb186a35
8 N9b4c521de34040428e69985cde1860f1
9 Nbc28bf46115a466ab1f728daee599c6d
10 anzsrc-for:11
11 anzsrc-for:1103
12 schema:author N01cc6df4dec34937bab3b91cb31799ca
13 schema:citation sg:pub.10.1007/bf00047468
14 sg:pub.10.1007/s10585-011-9415-7
15 sg:pub.10.1038/nm0297-177
16 sg:pub.10.1038/nrc1478
17 sg:pub.10.1038/nrc2255
18 sg:pub.10.1038/nrc882
19 sg:pub.10.1038/sj.bjc.6604554
20 sg:pub.10.1046/j.1523-1755.2003.00207.x
21 sg:pub.10.1186/1471-2407-11-235
22 https://app.dimensions.ai/details/publication/pub.1080712372
23 https://app.dimensions.ai/details/publication/pub.1083020407
24 https://doi.org/10.1016/j.ccr.2006.10.020
25 https://doi.org/10.1016/j.jtbi.2006.09.010
26 https://doi.org/10.1016/j.mbs.2010.12.002
27 https://doi.org/10.1016/s1476-5586(03)80005-2
28 https://doi.org/10.1046/j.1523-1755.2003.00207.x
29 https://doi.org/10.1096/fj.07-9574lsf
30 https://doi.org/10.1097/00005072-198203000-00006
31 https://doi.org/10.1152/ajplegacy.1946.147.1.138
32 https://doi.org/10.1158/0008-5472.can-05-4193
33 https://doi.org/10.1158/0008-5472.can-07-5575
34 https://doi.org/10.1158/0008-5472.can-08-2394
35 https://doi.org/10.1172/jci105164
36 https://doi.org/10.1172/jci110425
37 https://doi.org/10.1681/asn.2005070732
38 https://doi.org/10.1681/asn.2008111205
39 https://doi.org/10.2967/jnumed.107.047258
40 schema:datePublished 2012-03
41 schema:datePublishedReg 2012-03-01
42 schema:description 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. 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 7.1-7.2 is most promising.
43 schema:genre research_article
44 schema:inLanguage en
45 schema:isAccessibleForFree true
46 schema:isPartOf N01df5ec6b03d41edb2bc8a272a7b7cd0
47 N05e19c0dc3594fe8a85ad83872c0582e
48 sg:journal.1017082
49 schema:name Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study
50 schema:pagination 1280
51 schema:productId N06bb17b57ed7430181503013afde6111
52 N1c6f897a3c0f48f48a508cd66881d7da
53 N5da5135724c74e7bbec4ddd53cc583f1
54 N8b703e5827ad49a0b59a9b7713a8cd07
55 N9c85ca0723734de1afc3d2ef0dae0ed1
56 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010749946
57 https://doi.org/10.1038/bjc.2012.58
58 schema:sdDatePublished 2019-04-10T17:20
59 schema:sdLicense https://scigraph.springernature.com/explorer/license/
60 schema:sdPublisher N1228fc7836344fedb9a104110352ea97
61 schema:url https://www.nature.com/articles/bjc201258
62 sgo:license sg:explorer/license/
63 sgo:sdDataset articles
64 rdf:type schema:ScholarlyArticle
65 N01a1430f746a4e2da9070c7160d44871 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
66 schema:name Hydrogen-Ion Concentration
67 rdf:type schema:DefinedTerm
68 N01cc6df4dec34937bab3b91cb31799ca rdf:first sg:person.013051535742.10
69 rdf:rest Naa17422de4f54117a52bf650e849ffa1
70 N01df5ec6b03d41edb2bc8a272a7b7cd0 schema:issueNumber 7
71 rdf:type schema:PublicationIssue
72 N05e19c0dc3594fe8a85ad83872c0582e schema:volumeNumber 106
73 rdf:type schema:PublicationVolume
74 N06bb17b57ed7430181503013afde6111 schema:name doi
75 schema:value 10.1038/bjc.2012.58
76 rdf:type schema:PropertyValue
77 N1228fc7836344fedb9a104110352ea97 schema:name Springer Nature - SN SciGraph project
78 rdf:type schema:Organization
79 N1c6f897a3c0f48f48a508cd66881d7da schema:name dimensions_id
80 schema:value pub.1010749946
81 rdf:type schema:PropertyValue
82 N2040f47897334856adcfef78c82f9989 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
83 schema:name Humans
84 rdf:type schema:DefinedTerm
85 N231c86a16136443ca1f183d03c62300b rdf:first sg:person.01251663701.28
86 rdf:rest Nd468cffc04a14115b25ff12b5541ca2f
87 N2bd5bc992fc84f939906d9cb34c40ccb schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
88 schema:name Models, Biological
89 rdf:type schema:DefinedTerm
90 N42b08b5d38804b95b726866c19895fc5 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
91 schema:name Animals
92 rdf:type schema:DefinedTerm
93 N4ab3805d78fc497ca5981b0f58f93047 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
94 schema:name Bicarbonates
95 rdf:type schema:DefinedTerm
96 N5da5135724c74e7bbec4ddd53cc583f1 schema:name nlm_unique_id
97 schema:value 0370635
98 rdf:type schema:PropertyValue
99 N85c4294f1677429795ad2050f87c263a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
100 schema:name Neoplasms
101 rdf:type schema:DefinedTerm
102 N8b703e5827ad49a0b59a9b7713a8cd07 schema:name pubmed_id
103 schema:value 22382688
104 rdf:type schema:PropertyValue
105 N9a4bd40fcc714235b6302cdbfb186a35 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
106 schema:name Alkalosis
107 rdf:type schema:DefinedTerm
108 N9b4c521de34040428e69985cde1860f1 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
109 schema:name Mice
110 rdf:type schema:DefinedTerm
111 N9c85ca0723734de1afc3d2ef0dae0ed1 schema:name readcube_id
112 schema:value 333697233c5abd59a18eb780a18de7780f548772dd90749ea0c2ba103cfc1687
113 rdf:type schema:PropertyValue
114 Naa17422de4f54117a52bf650e849ffa1 rdf:first sg:person.0613462515.92
115 rdf:rest Nce65e95b5f5a4403aa519055a68caf78
116 Nbc28bf46115a466ab1f728daee599c6d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
117 schema:name Buffers
118 rdf:type schema:DefinedTerm
119 Nce65e95b5f5a4403aa519055a68caf78 rdf:first sg:person.0577003446.69
120 rdf:rest Nf1530d0142294a7a8035fb8e0389e296
121 Nd468cffc04a14115b25ff12b5541ca2f rdf:first sg:person.01263171521.12
122 rdf:rest rdf:nil
123 Nf1530d0142294a7a8035fb8e0389e296 rdf:first sg:person.014224135057.83
124 rdf:rest N231c86a16136443ca1f183d03c62300b
125 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
126 schema:name Medical and Health Sciences
127 rdf:type schema:DefinedTerm
128 anzsrc-for:1103 schema:inDefinedTermSet anzsrc-for:
129 schema:name Clinical Sciences
130 rdf:type schema:DefinedTerm
131 sg:grant.2465687 http://pending.schema.org/fundedItem sg:pub.10.1038/bjc.2012.58
132 rdf:type schema:MonetaryGrant
133 sg:grant.2473639 http://pending.schema.org/fundedItem sg:pub.10.1038/bjc.2012.58
134 rdf:type schema:MonetaryGrant
135 sg:grant.2699085 http://pending.schema.org/fundedItem sg:pub.10.1038/bjc.2012.58
136 rdf:type schema:MonetaryGrant
137 sg:grant.2699696 http://pending.schema.org/fundedItem sg:pub.10.1038/bjc.2012.58
138 rdf:type schema:MonetaryGrant
139 sg:journal.1017082 schema:issn 0007-0920
140 1532-1827
141 schema:name British Journal of Cancer
142 rdf:type schema:Periodical
143 sg:person.01251663701.28 schema:affiliation https://www.grid.ac/institutes/grid.468198.a
144 schema:familyName Gatenby
145 schema:givenName R A
146 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01251663701.28
147 rdf:type schema:Person
148 sg:person.01263171521.12 schema:affiliation https://www.grid.ac/institutes/grid.470387.f
149 schema:familyName Maini
150 schema:givenName P K
151 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01263171521.12
152 rdf:type schema:Person
153 sg:person.013051535742.10 schema:affiliation https://www.grid.ac/institutes/grid.5337.2
154 schema:familyName Martin
155 schema:givenName N K
156 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.013051535742.10
157 rdf:type schema:Person
158 sg:person.014224135057.83 schema:affiliation https://www.grid.ac/institutes/grid.468198.a
159 schema:familyName Gillies
160 schema:givenName R J
161 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014224135057.83
162 rdf:type schema:Person
163 sg:person.0577003446.69 schema:affiliation https://www.grid.ac/institutes/grid.4991.5
164 schema:familyName Gaffney
165 schema:givenName E A
166 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0577003446.69
167 rdf:type schema:Person
168 sg:person.0613462515.92 schema:affiliation https://www.grid.ac/institutes/grid.134563.6
169 schema:familyName Robey
170 schema:givenName I F
171 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0613462515.92
172 rdf:type schema:Person
173 sg:pub.10.1007/bf00047468 schema:sameAs https://app.dimensions.ai/details/publication/pub.1050057929
174 https://doi.org/10.1007/bf00047468
175 rdf:type schema:CreativeWork
176 sg:pub.10.1007/s10585-011-9415-7 schema:sameAs https://app.dimensions.ai/details/publication/pub.1041528062
177 https://doi.org/10.1007/s10585-011-9415-7
178 rdf:type schema:CreativeWork
179 sg:pub.10.1038/nm0297-177 schema:sameAs https://app.dimensions.ai/details/publication/pub.1025563287
180 https://doi.org/10.1038/nm0297-177
181 rdf:type schema:CreativeWork
182 sg:pub.10.1038/nrc1478 schema:sameAs https://app.dimensions.ai/details/publication/pub.1032257073
183 https://doi.org/10.1038/nrc1478
184 rdf:type schema:CreativeWork
185 sg:pub.10.1038/nrc2255 schema:sameAs https://app.dimensions.ai/details/publication/pub.1031460595
186 https://doi.org/10.1038/nrc2255
187 rdf:type schema:CreativeWork
188 sg:pub.10.1038/nrc882 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036705264
189 https://doi.org/10.1038/nrc882
190 rdf:type schema:CreativeWork
191 sg:pub.10.1038/sj.bjc.6604554 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010689691
192 https://doi.org/10.1038/sj.bjc.6604554
193 rdf:type schema:CreativeWork
194 sg:pub.10.1046/j.1523-1755.2003.00207.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1047786008
195 https://doi.org/10.1046/j.1523-1755.2003.00207.x
196 rdf:type schema:CreativeWork
197 sg:pub.10.1186/1471-2407-11-235 schema:sameAs https://app.dimensions.ai/details/publication/pub.1029573936
198 https://doi.org/10.1186/1471-2407-11-235
199 rdf:type schema:CreativeWork
200 https://app.dimensions.ai/details/publication/pub.1080712372 schema:CreativeWork
201 https://app.dimensions.ai/details/publication/pub.1083020407 schema:CreativeWork
202 https://doi.org/10.1016/j.ccr.2006.10.020 schema:sameAs https://app.dimensions.ai/details/publication/pub.1042406860
203 rdf:type schema:CreativeWork
204 https://doi.org/10.1016/j.jtbi.2006.09.010 schema:sameAs https://app.dimensions.ai/details/publication/pub.1006274487
205 rdf:type schema:CreativeWork
206 https://doi.org/10.1016/j.mbs.2010.12.002 schema:sameAs https://app.dimensions.ai/details/publication/pub.1026789202
207 rdf:type schema:CreativeWork
208 https://doi.org/10.1016/s1476-5586(03)80005-2 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036742733
209 rdf:type schema:CreativeWork
210 https://doi.org/10.1046/j.1523-1755.2003.00207.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1047786008
211 rdf:type schema:CreativeWork
212 https://doi.org/10.1096/fj.07-9574lsf schema:sameAs https://app.dimensions.ai/details/publication/pub.1052334407
213 rdf:type schema:CreativeWork
214 https://doi.org/10.1097/00005072-198203000-00006 schema:sameAs https://app.dimensions.ai/details/publication/pub.1006870743
215 rdf:type schema:CreativeWork
216 https://doi.org/10.1152/ajplegacy.1946.147.1.138 schema:sameAs https://app.dimensions.ai/details/publication/pub.1078266484
217 rdf:type schema:CreativeWork
218 https://doi.org/10.1158/0008-5472.can-05-4193 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033095257
219 rdf:type schema:CreativeWork
220 https://doi.org/10.1158/0008-5472.can-07-5575 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020159743
221 rdf:type schema:CreativeWork
222 https://doi.org/10.1158/0008-5472.can-08-2394 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010197012
223 rdf:type schema:CreativeWork
224 https://doi.org/10.1172/jci105164 schema:sameAs https://app.dimensions.ai/details/publication/pub.1052487077
225 rdf:type schema:CreativeWork
226 https://doi.org/10.1172/jci110425 schema:sameAs https://app.dimensions.ai/details/publication/pub.1021996620
227 rdf:type schema:CreativeWork
228 https://doi.org/10.1681/asn.2005070732 schema:sameAs https://app.dimensions.ai/details/publication/pub.1050475546
229 rdf:type schema:CreativeWork
230 https://doi.org/10.1681/asn.2008111205 schema:sameAs https://app.dimensions.ai/details/publication/pub.1046593264
231 rdf:type schema:CreativeWork
232 https://doi.org/10.2967/jnumed.107.047258 schema:sameAs https://app.dimensions.ai/details/publication/pub.1009941536
233 rdf:type schema:CreativeWork
234 https://www.grid.ac/institutes/grid.134563.6 schema:alternateName University of Arizona
235 schema:name University of Arizona, Tucson, AZ, USA
236 rdf:type schema:Organization
237 https://www.grid.ac/institutes/grid.468198.a schema:alternateName Moffitt Cancer Center
238 schema:name H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33162, USA
239 rdf:type schema:Organization
240 https://www.grid.ac/institutes/grid.470387.f schema:alternateName Oxford Centre
241 schema:name Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles’, Oxford OX1 3LB, UK
242 Oxford Centre for Integrative Systems Biology, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, UK
243 rdf:type schema:Organization
244 https://www.grid.ac/institutes/grid.4991.5 schema:alternateName University of Oxford
245 schema:name Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles’, Oxford OX1 3LB, UK
246 rdf:type schema:Organization
247 https://www.grid.ac/institutes/grid.5337.2 schema:alternateName University of Bristol
248 schema:name Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles’, Oxford OX1 3LB, UK
249 Department of Social Medicine, University of Bristol, Canynge Hall, 29 Whatley Road, Bristol BS8 2PS, UK
250 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...