Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-07

AUTHORS

William C. Rose, Punit H. Marathe, Graham R. Jang, Thomas M. Monticello, Balu N. Balasubramanian, Byron Long, Craig R. Fairchild, Monroe E. Wall, Mansukh C. Wani

ABSTRACT

PURPOSE: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential. METHODS: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. RESULTS: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. CONCLUSIONS: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development. More... »

PAGES

73-85

References to SciGraph publications

  • 1997-02. Preclinical antitumor activity of water-soluble paclitaxel derivatives in CANCER CHEMOTHERAPY AND PHARMACOLOGY
  • 1997-10. Clinical Pharmacokinetics of Irinotecan in CLINICAL PHARMACOKINETICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00280-005-0128-y

    DOI

    http://dx.doi.org/10.1007/s00280-005-0128-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1010752432

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/16228206


    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/2008/1115", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Pharmacology and Pharmaceutical 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": "Animals", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Antineoplastic Agents, Phytogenic", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Camptothecin", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Carcinoma", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Line, Tumor", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Survival", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Colonic Neoplasms", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Female", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Gastrointestinal Tract", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Humans", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Irinotecan", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Male", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Mammary Neoplasms, Experimental", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Mice", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Mice, Inbred C3H", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Mice, Nude", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Ovarian Neoplasms", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Prodrugs", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Rats", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Rats, Sprague-Dawley", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Tumor Burden", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Xenograft Model Antitumor Assays", 
            "type": "DefinedTerm"
          }
        ], 
        "author": [
          {
            "affiliation": {
              "alternateName": "Bristol-Myers Squibb (United States)", 
              "id": "https://www.grid.ac/institutes/grid.419971.3", 
              "name": [
                "Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA", 
                "Experimental Therapeutics Dept, Bristol-Myers Squibb Co, Inc, 4000, 08543, Princeton, NJ, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Rose", 
            "givenName": "William C.", 
            "id": "sg:person.01167506574.18", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01167506574.18"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bristol-Myers Squibb (United States)", 
              "id": "https://www.grid.ac/institutes/grid.419971.3", 
              "name": [
                "Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Marathe", 
            "givenName": "Punit H.", 
            "id": "sg:person.01363005503.37", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01363005503.37"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bristol-Myers Squibb (United States)", 
              "id": "https://www.grid.ac/institutes/grid.419971.3", 
              "name": [
                "Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Jang", 
            "givenName": "Graham R.", 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bristol-Myers Squibb (United States)", 
              "id": "https://www.grid.ac/institutes/grid.419971.3", 
              "name": [
                "Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Monticello", 
            "givenName": "Thomas M.", 
            "id": "sg:person.01003274603.15", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01003274603.15"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bristol-Myers Squibb (United States)", 
              "id": "https://www.grid.ac/institutes/grid.419971.3", 
              "name": [
                "Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Balasubramanian", 
            "givenName": "Balu N.", 
            "id": "sg:person.01136757121.86", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01136757121.86"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bristol-Myers Squibb (United States)", 
              "id": "https://www.grid.ac/institutes/grid.419971.3", 
              "name": [
                "Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Long", 
            "givenName": "Byron", 
            "id": "sg:person.01302605325.45", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01302605325.45"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bristol-Myers Squibb (United States)", 
              "id": "https://www.grid.ac/institutes/grid.419971.3", 
              "name": [
                "Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Fairchild", 
            "givenName": "Craig R.", 
            "id": "sg:person.010266154577.69", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010266154577.69"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "RTI International", 
              "id": "https://www.grid.ac/institutes/grid.62562.35", 
              "name": [
                "Research Triangle Institute, Research Triangle Park, NC, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Wall", 
            "givenName": "Monroe E.", 
            "id": "sg:person.0107666412.52", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0107666412.52"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "RTI International", 
              "id": "https://www.grid.ac/institutes/grid.62562.35", 
              "name": [
                "Research Triangle Institute, Research Triangle Park, NC, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Wani", 
            "givenName": "Mansukh C.", 
            "id": "sg:person.0736205174.90", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0736205174.90"
            ], 
            "type": "Person"
          }
        ], 
        "citation": [
          {
            "id": "sg:pub.10.2165/00003088-199733040-00001", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1003829209", 
              "https://doi.org/10.2165/00003088-199733040-00001"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s002800050603", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1016905058", 
              "https://doi.org/10.1007/s002800050603"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/s0168-3659(99)00267-9", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1018358839"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1093/jnci/88.17.1240", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1046738075"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1021/bi00208a002", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1055165282"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1021/jm00027a005", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1055932980"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1021/jm00123a038", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1055935964"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1021/jm9902279", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1055959478"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1021/jm9902279", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1055959478"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1093/jnci/81.14.1088", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1059815226"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1093/jnci/87.24.1876", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1059819678"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1074813248", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1074859792", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1200/jco.1992.10.8.1225", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1075554481"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1078123936", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1200/jco.1990.8.11.1907", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1078512752"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1082668221", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1083287827", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1083304138", 
            "type": "CreativeWork"
          }
        ], 
        "datePublished": "2006-07", 
        "datePublishedReg": "2006-07-01", 
        "description": "PURPOSE: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential.\nMETHODS: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters.\nRESULTS: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309.\nCONCLUSIONS: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development.", 
        "genre": "research_article", 
        "id": "sg:pub.10.1007/s00280-005-0128-y", 
        "inLanguage": [
          "en"
        ], 
        "isAccessibleForFree": false, 
        "isPartOf": [
          {
            "id": "sg:journal.1088364", 
            "issn": [
              "0344-5704", 
              "1432-0843"
            ], 
            "name": "Cancer Chemotherapy and Pharmacology", 
            "type": "Periodical"
          }, 
          {
            "issueNumber": "1", 
            "type": "PublicationIssue"
          }, 
          {
            "type": "PublicationVolume", 
            "volumeNumber": "58"
          }
        ], 
        "name": "Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization", 
        "pagination": "73-85", 
        "productId": [
          {
            "name": "readcube_id", 
            "type": "PropertyValue", 
            "value": [
              "33399394db505730c696e545daa89632224613f41e63a4d7a84fbb8a1f31a6c3"
            ]
          }, 
          {
            "name": "pubmed_id", 
            "type": "PropertyValue", 
            "value": [
              "16228206"
            ]
          }, 
          {
            "name": "nlm_unique_id", 
            "type": "PropertyValue", 
            "value": [
              "7806519"
            ]
          }, 
          {
            "name": "doi", 
            "type": "PropertyValue", 
            "value": [
              "10.1007/s00280-005-0128-y"
            ]
          }, 
          {
            "name": "dimensions_id", 
            "type": "PropertyValue", 
            "value": [
              "pub.1010752432"
            ]
          }
        ], 
        "sameAs": [
          "https://doi.org/10.1007/s00280-005-0128-y", 
          "https://app.dimensions.ai/details/publication/pub.1010752432"
        ], 
        "sdDataset": "articles", 
        "sdDatePublished": "2019-04-11T12:11", 
        "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/v90/0000000361_0000000361/records_53984_00000000.jsonl", 
        "type": "ScholarlyArticle", 
        "url": "http://link.springer.com/10.1007%2Fs00280-005-0128-y"
      }
    ]
     

    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.10.1007/s00280-005-0128-y'

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

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1007/s00280-005-0128-y'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1007/s00280-005-0128-y'

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

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1007/s00280-005-0128-y'


     

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

    266 TRIPLES      21 PREDICATES      69 URIs      43 LITERALS      31 BLANK NODES

    Subject Predicate Object
    1 sg:pub.10.1007/s00280-005-0128-y schema:about N148ae95b56254c82947d658bc2ece209
    2 N4023332af9b844ef92f3c2fde53f0062
    3 N4f8268e250234d04ae64014560ca5e3a
    4 N53249edc51354d5887479abf7c1cad6f
    5 N5606baa049e74f908d65a82f8f5694c1
    6 N7cc88305d80741eab919760d713db609
    7 N821e3a463dd5474f81e3cfe0f493ac2a
    8 N87b17fc1dfc047069e19e5ca40f6e6c4
    9 N8df370e61c654c84b09df3f044c4eafc
    10 N9d18057c402f4508939bbb1459e2e350
    11 Na13939d9b4d0439e9a25aaa543c7cd85
    12 Na77191e0f55a45669e6e6f1f5f79ac80
    13 Naa060995492747f5972479665f7c481e
    14 Nac3d567a9b8245f29ff1c17ec5423239
    15 Nb5c0ddfd43464d0d98c800c997e5bf4a
    16 Nb671fe11e94a4d7fb3c7517d4ec4b84c
    17 Nd4b1d287f99b40eea4ccb14c10260823
    18 Ne07347e51449484fb6236729c2d6a457
    19 Ne0d1c42ca75041c6a051a7fbbba138fd
    20 Ne77a43005e2c471aaea6c77b232fadb9
    21 Neddea8a62b374426b9de292238a5dd0f
    22 Nf0b35eb7175e41d1a2820fbb21a723fb
    23 anzsrc-for:11
    24 anzsrc-for:1115
    25 schema:author Ncc30e9c01d8147c6b5ee2c8a8d677f9e
    26 schema:citation sg:pub.10.1007/s002800050603
    27 sg:pub.10.2165/00003088-199733040-00001
    28 https://app.dimensions.ai/details/publication/pub.1074813248
    29 https://app.dimensions.ai/details/publication/pub.1074859792
    30 https://app.dimensions.ai/details/publication/pub.1078123936
    31 https://app.dimensions.ai/details/publication/pub.1082668221
    32 https://app.dimensions.ai/details/publication/pub.1083287827
    33 https://app.dimensions.ai/details/publication/pub.1083304138
    34 https://doi.org/10.1016/s0168-3659(99)00267-9
    35 https://doi.org/10.1021/bi00208a002
    36 https://doi.org/10.1021/jm00027a005
    37 https://doi.org/10.1021/jm00123a038
    38 https://doi.org/10.1021/jm9902279
    39 https://doi.org/10.1093/jnci/81.14.1088
    40 https://doi.org/10.1093/jnci/87.24.1876
    41 https://doi.org/10.1093/jnci/88.17.1240
    42 https://doi.org/10.1200/jco.1990.8.11.1907
    43 https://doi.org/10.1200/jco.1992.10.8.1225
    44 schema:datePublished 2006-07
    45 schema:datePublishedReg 2006-07-01
    46 schema:description PURPOSE: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential. METHODS: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. RESULTS: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. CONCLUSIONS: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development.
    47 schema:genre research_article
    48 schema:inLanguage en
    49 schema:isAccessibleForFree false
    50 schema:isPartOf Nb570fc7ac763415980d9a2625aa87213
    51 Nb8112ae2171a41c4b7fb861ce80204fb
    52 sg:journal.1088364
    53 schema:name Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization
    54 schema:pagination 73-85
    55 schema:productId N098900a00ff44ccb87480742610fa7e8
    56 N1756851a73694570be4751feefbd1d23
    57 N79c5fb7ae970489ab028857b1654ff4a
    58 Nac8ab94b298b46b79fdc2d10397da6a6
    59 Ndd90d90704634cc386ea9ff5ed264041
    60 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010752432
    61 https://doi.org/10.1007/s00280-005-0128-y
    62 schema:sdDatePublished 2019-04-11T12:11
    63 schema:sdLicense https://scigraph.springernature.com/explorer/license/
    64 schema:sdPublisher Nd481e99501ed401da0c6f4b361e5d917
    65 schema:url http://link.springer.com/10.1007%2Fs00280-005-0128-y
    66 sgo:license sg:explorer/license/
    67 sgo:sdDataset articles
    68 rdf:type schema:ScholarlyArticle
    69 N098900a00ff44ccb87480742610fa7e8 schema:name readcube_id
    70 schema:value 33399394db505730c696e545daa89632224613f41e63a4d7a84fbb8a1f31a6c3
    71 rdf:type schema:PropertyValue
    72 N11cd368454e645b08531723cf9bdf340 rdf:first Nb6ad7375ee3d4003a113001cb5c012e3
    73 rdf:rest N92f852fcbd7b491981a4dcb513660784
    74 N1350e21b209149b18519de86024364ad rdf:first sg:person.0736205174.90
    75 rdf:rest rdf:nil
    76 N148ae95b56254c82947d658bc2ece209 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    77 schema:name Animals
    78 rdf:type schema:DefinedTerm
    79 N1756851a73694570be4751feefbd1d23 schema:name doi
    80 schema:value 10.1007/s00280-005-0128-y
    81 rdf:type schema:PropertyValue
    82 N4023332af9b844ef92f3c2fde53f0062 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    83 schema:name Cell Line, Tumor
    84 rdf:type schema:DefinedTerm
    85 N4f8268e250234d04ae64014560ca5e3a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    86 schema:name Mice
    87 rdf:type schema:DefinedTerm
    88 N52283f6dfacd4cb0bdad3f3e1f8b8db5 rdf:first sg:person.010266154577.69
    89 rdf:rest Na9c0e86673a1413d9dc9c51dee8b892b
    90 N53249edc51354d5887479abf7c1cad6f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    91 schema:name Cell Survival
    92 rdf:type schema:DefinedTerm
    93 N53e32ea265c0410bb318d687f8cab93f rdf:first sg:person.01363005503.37
    94 rdf:rest N11cd368454e645b08531723cf9bdf340
    95 N5606baa049e74f908d65a82f8f5694c1 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    96 schema:name Xenograft Model Antitumor Assays
    97 rdf:type schema:DefinedTerm
    98 N79c5fb7ae970489ab028857b1654ff4a schema:name pubmed_id
    99 schema:value 16228206
    100 rdf:type schema:PropertyValue
    101 N7cc88305d80741eab919760d713db609 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    102 schema:name Ovarian Neoplasms
    103 rdf:type schema:DefinedTerm
    104 N821e3a463dd5474f81e3cfe0f493ac2a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    105 schema:name Mammary Neoplasms, Experimental
    106 rdf:type schema:DefinedTerm
    107 N87b17fc1dfc047069e19e5ca40f6e6c4 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    108 schema:name Prodrugs
    109 rdf:type schema:DefinedTerm
    110 N8df370e61c654c84b09df3f044c4eafc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    111 schema:name Antineoplastic Agents, Phytogenic
    112 rdf:type schema:DefinedTerm
    113 N92f852fcbd7b491981a4dcb513660784 rdf:first sg:person.01003274603.15
    114 rdf:rest Nf67a9e3342b44b159e958625754c83c8
    115 N9d18057c402f4508939bbb1459e2e350 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    116 schema:name Tumor Burden
    117 rdf:type schema:DefinedTerm
    118 Na13939d9b4d0439e9a25aaa543c7cd85 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    119 schema:name Camptothecin
    120 rdf:type schema:DefinedTerm
    121 Na77191e0f55a45669e6e6f1f5f79ac80 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    122 schema:name Humans
    123 rdf:type schema:DefinedTerm
    124 Na9c0e86673a1413d9dc9c51dee8b892b rdf:first sg:person.0107666412.52
    125 rdf:rest N1350e21b209149b18519de86024364ad
    126 Naa060995492747f5972479665f7c481e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    127 schema:name Colonic Neoplasms
    128 rdf:type schema:DefinedTerm
    129 Nac3d567a9b8245f29ff1c17ec5423239 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    130 schema:name Rats, Sprague-Dawley
    131 rdf:type schema:DefinedTerm
    132 Nac8ab94b298b46b79fdc2d10397da6a6 schema:name dimensions_id
    133 schema:value pub.1010752432
    134 rdf:type schema:PropertyValue
    135 Nb570fc7ac763415980d9a2625aa87213 schema:volumeNumber 58
    136 rdf:type schema:PublicationVolume
    137 Nb5c0ddfd43464d0d98c800c997e5bf4a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    138 schema:name Carcinoma
    139 rdf:type schema:DefinedTerm
    140 Nb671fe11e94a4d7fb3c7517d4ec4b84c schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    141 schema:name Irinotecan
    142 rdf:type schema:DefinedTerm
    143 Nb6ad7375ee3d4003a113001cb5c012e3 schema:affiliation https://www.grid.ac/institutes/grid.419971.3
    144 schema:familyName Jang
    145 schema:givenName Graham R.
    146 rdf:type schema:Person
    147 Nb8112ae2171a41c4b7fb861ce80204fb schema:issueNumber 1
    148 rdf:type schema:PublicationIssue
    149 Ncc30e9c01d8147c6b5ee2c8a8d677f9e rdf:first sg:person.01167506574.18
    150 rdf:rest N53e32ea265c0410bb318d687f8cab93f
    151 Nd481e99501ed401da0c6f4b361e5d917 schema:name Springer Nature - SN SciGraph project
    152 rdf:type schema:Organization
    153 Nd4b1d287f99b40eea4ccb14c10260823 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    154 schema:name Rats
    155 rdf:type schema:DefinedTerm
    156 Ndd90d90704634cc386ea9ff5ed264041 schema:name nlm_unique_id
    157 schema:value 7806519
    158 rdf:type schema:PropertyValue
    159 Ne07347e51449484fb6236729c2d6a457 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    160 schema:name Male
    161 rdf:type schema:DefinedTerm
    162 Ne0d1c42ca75041c6a051a7fbbba138fd schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    163 schema:name Female
    164 rdf:type schema:DefinedTerm
    165 Ne77a43005e2c471aaea6c77b232fadb9 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    166 schema:name Mice, Nude
    167 rdf:type schema:DefinedTerm
    168 Neddea8a62b374426b9de292238a5dd0f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    169 schema:name Mice, Inbred C3H
    170 rdf:type schema:DefinedTerm
    171 Nf0b35eb7175e41d1a2820fbb21a723fb schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    172 schema:name Gastrointestinal Tract
    173 rdf:type schema:DefinedTerm
    174 Nf2bf8eb83cd7493b9c608648261fc878 rdf:first sg:person.01302605325.45
    175 rdf:rest N52283f6dfacd4cb0bdad3f3e1f8b8db5
    176 Nf67a9e3342b44b159e958625754c83c8 rdf:first sg:person.01136757121.86
    177 rdf:rest Nf2bf8eb83cd7493b9c608648261fc878
    178 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
    179 schema:name Medical and Health Sciences
    180 rdf:type schema:DefinedTerm
    181 anzsrc-for:1115 schema:inDefinedTermSet anzsrc-for:
    182 schema:name Pharmacology and Pharmaceutical Sciences
    183 rdf:type schema:DefinedTerm
    184 sg:journal.1088364 schema:issn 0344-5704
    185 1432-0843
    186 schema:name Cancer Chemotherapy and Pharmacology
    187 rdf:type schema:Periodical
    188 sg:person.01003274603.15 schema:affiliation https://www.grid.ac/institutes/grid.419971.3
    189 schema:familyName Monticello
    190 schema:givenName Thomas M.
    191 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01003274603.15
    192 rdf:type schema:Person
    193 sg:person.010266154577.69 schema:affiliation https://www.grid.ac/institutes/grid.419971.3
    194 schema:familyName Fairchild
    195 schema:givenName Craig R.
    196 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010266154577.69
    197 rdf:type schema:Person
    198 sg:person.0107666412.52 schema:affiliation https://www.grid.ac/institutes/grid.62562.35
    199 schema:familyName Wall
    200 schema:givenName Monroe E.
    201 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0107666412.52
    202 rdf:type schema:Person
    203 sg:person.01136757121.86 schema:affiliation https://www.grid.ac/institutes/grid.419971.3
    204 schema:familyName Balasubramanian
    205 schema:givenName Balu N.
    206 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01136757121.86
    207 rdf:type schema:Person
    208 sg:person.01167506574.18 schema:affiliation https://www.grid.ac/institutes/grid.419971.3
    209 schema:familyName Rose
    210 schema:givenName William C.
    211 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01167506574.18
    212 rdf:type schema:Person
    213 sg:person.01302605325.45 schema:affiliation https://www.grid.ac/institutes/grid.419971.3
    214 schema:familyName Long
    215 schema:givenName Byron
    216 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01302605325.45
    217 rdf:type schema:Person
    218 sg:person.01363005503.37 schema:affiliation https://www.grid.ac/institutes/grid.419971.3
    219 schema:familyName Marathe
    220 schema:givenName Punit H.
    221 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01363005503.37
    222 rdf:type schema:Person
    223 sg:person.0736205174.90 schema:affiliation https://www.grid.ac/institutes/grid.62562.35
    224 schema:familyName Wani
    225 schema:givenName Mansukh C.
    226 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0736205174.90
    227 rdf:type schema:Person
    228 sg:pub.10.1007/s002800050603 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016905058
    229 https://doi.org/10.1007/s002800050603
    230 rdf:type schema:CreativeWork
    231 sg:pub.10.2165/00003088-199733040-00001 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003829209
    232 https://doi.org/10.2165/00003088-199733040-00001
    233 rdf:type schema:CreativeWork
    234 https://app.dimensions.ai/details/publication/pub.1074813248 schema:CreativeWork
    235 https://app.dimensions.ai/details/publication/pub.1074859792 schema:CreativeWork
    236 https://app.dimensions.ai/details/publication/pub.1078123936 schema:CreativeWork
    237 https://app.dimensions.ai/details/publication/pub.1082668221 schema:CreativeWork
    238 https://app.dimensions.ai/details/publication/pub.1083287827 schema:CreativeWork
    239 https://app.dimensions.ai/details/publication/pub.1083304138 schema:CreativeWork
    240 https://doi.org/10.1016/s0168-3659(99)00267-9 schema:sameAs https://app.dimensions.ai/details/publication/pub.1018358839
    241 rdf:type schema:CreativeWork
    242 https://doi.org/10.1021/bi00208a002 schema:sameAs https://app.dimensions.ai/details/publication/pub.1055165282
    243 rdf:type schema:CreativeWork
    244 https://doi.org/10.1021/jm00027a005 schema:sameAs https://app.dimensions.ai/details/publication/pub.1055932980
    245 rdf:type schema:CreativeWork
    246 https://doi.org/10.1021/jm00123a038 schema:sameAs https://app.dimensions.ai/details/publication/pub.1055935964
    247 rdf:type schema:CreativeWork
    248 https://doi.org/10.1021/jm9902279 schema:sameAs https://app.dimensions.ai/details/publication/pub.1055959478
    249 rdf:type schema:CreativeWork
    250 https://doi.org/10.1093/jnci/81.14.1088 schema:sameAs https://app.dimensions.ai/details/publication/pub.1059815226
    251 rdf:type schema:CreativeWork
    252 https://doi.org/10.1093/jnci/87.24.1876 schema:sameAs https://app.dimensions.ai/details/publication/pub.1059819678
    253 rdf:type schema:CreativeWork
    254 https://doi.org/10.1093/jnci/88.17.1240 schema:sameAs https://app.dimensions.ai/details/publication/pub.1046738075
    255 rdf:type schema:CreativeWork
    256 https://doi.org/10.1200/jco.1990.8.11.1907 schema:sameAs https://app.dimensions.ai/details/publication/pub.1078512752
    257 rdf:type schema:CreativeWork
    258 https://doi.org/10.1200/jco.1992.10.8.1225 schema:sameAs https://app.dimensions.ai/details/publication/pub.1075554481
    259 rdf:type schema:CreativeWork
    260 https://www.grid.ac/institutes/grid.419971.3 schema:alternateName Bristol-Myers Squibb (United States)
    261 schema:name Experimental Therapeutics Dept, Bristol-Myers Squibb Co, Inc, 4000, 08543, Princeton, NJ, USA
    262 Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA
    263 rdf:type schema:Organization
    264 https://www.grid.ac/institutes/grid.62562.35 schema:alternateName RTI International
    265 schema:name Research Triangle Institute, Research Triangle Park, NC, USA
    266 rdf:type schema:Organization
     




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


    ...