N-BENZYLADRIAMYCIN-14-VALERATE VERSUS PROGRESSIVELY DOXORUBICIN-RESISTANT MURINE TUMORS - CELLULAR PHARMACOLOGY AND CHARACTERIZATION OF CROSS-RESISTANCE INVITRO AND INVIVO

Publication type:
Journal article
Metadata:
Autoren
  • R GANAPATHI
  • D GRABOWSKI
  • TW SWEATMAN
  • R SESHADRI
  • M ISRAEL
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:A1989CD41400004&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1038/bjc.1989.373
Externe Identifier
  • Clarivate Analytics Document Solution ID: CD414
  • PubMed Identifier: 2605093
ISSN
0007-0920
Ausgabe der Veröffentlichung
6
Zeitschrift
BRITISH JOURNAL OF CANCER
Paginierung
819 - 826
Datum der Veröffentlichung
1989
Status
Published
Titel
N-BENZYLADRIAMYCIN-14-VALERATE VERSUS PROGRESSIVELY DOXORUBICIN-RESISTANT MURINE TUMORS - CELLULAR PHARMACOLOGY AND CHARACTERIZATION OF CROSS-RESISTANCE INVITRO AND INVIVO
Sub types
  • Article
Ausgabe der Zeitschrift
60

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • R Ganapathi
  • D Grabowski
  • TW Sweatman
  • R Seshadri
  • M Israel
DOI
10.1038/bjc.1989.373
eISSN
1532-1827
ISSN
0007-0920
Ausgabe der Veröffentlichung
6
Zeitschrift
British Journal of Cancer
Sprache
en
Paginierung
819 - 826
Datum der Veröffentlichung
1989
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1038/bjc.1989.373
Datum der Datenerfassung
2023
Titel
N-benzyladriamycin-14-valerate versus progressively doxorubicin-resistant murine tumours: cellular pharmacology and characterisation of cross-resistance in vitro and in vivo
Ausgabe der Zeitschrift
60

Data source: Crossref

Abstract
N-Benzyladriamycin-14-valerate (AD198) is a novel lipophilic anthracycline with greater in vivo antitumour activity than doxorubicin (DOX) in experimental model systems. Using sensitive and progressively DOX-resistant L1210 mouse leukaemia and B16-BL6 mouse melanoma lines, we have determined the cellular pharmacokinetics and cytotoxic response in vitro and in vivo of AD198. In the L1210 leukaemia model following 3 h drug exposure in vitro, the IC50 for AD198 was approximately 0.35 microgram ml-1 for the sensitive and 10-fold DOX resistant cells and 1.0 microgram ml-1 for the 40-fold DOX resistant cells. A similar pattern of cross-resistance to AD198 was also observed with the B16-BL6 melanoma, with and IC50 for AD198 with the sensitive and 10-fold DOX-resistant cells being similar, and about 2-fold higher with the 40-fold resistant cells. In the L1210 leukaemia model, cellular pharmacokinetics of AD198 revealed the following: (a) accumulation of AD198 was concentration but not time dependent, and cellular drug levels in the sensitive and resistant sublines were similar when treated with equimolar concentrations; (b) retention of AD 198 was 60% of the initial drug uptake and, in cells treated with the IC50 of AD198, cellular levels in the 40-fold DOX-resistant line were, as expected, 2-fold higher than in sensitive or 10-fold DOX-resistant cells; (c) in vitro biotransformation of AD 198 in the sensitive and resistant sublines was comparable. Studies in vivo with i.p. L1210 leukaemia (disseminating) and B16-BL6 melanoma (non-disseminating) tumour models evaluating therapeutic efficacy of DOX vs AD 198 in mice implanted with tumour i.p. on day 0 and treated i.p. on days 1-4 indicated: (a) DOX at 3 mg kg-1 administered once daily on days 1-4 resulted in a 55% ILS and 104% ILS with parent-sensitive B16-BL6 melanoma and L1210 leukaemia models respectively; however, similar doses of DOX in the resistant sublines were ineffective, with survival similar to the untreated control; (b) AD198 at 10-12.5 mg kg-1 day-1 for 4 days was extremely effective in the sensitive L1210 (189% ILS), and similar to DOX (61% ILS) in the sensitive B16-BL6; (c) AD198 (10-12.5 mg kg-1) was ineffective (survival similar to untreated control) in the 10-and 40-fold DOX-resistant L1210 leukaemia and 40-fold DOX resistant B16-BL6 melanoma, but produced a 76% ILS in the 10-fold DOX resistant B16-BL6 melanoma.(ABSTRACT TRUNCATED AT 400 WORDS)
Addresses
  • Research Institute, Cleveland Clinic Foundation, Ohio 44195.
Autoren
  • R Ganapathi
  • D Grabowski
  • TW Sweatman
  • R Seshadri
  • M Israel
DOI
10.1038/bjc.1989.373
eISSN
1532-1827
Externe Identifier
  • PubMed Identifier: 2605093
  • PubMed Central ID: PMC2247277
Funding acknowledgements
  • NCI NIH HHS: CA37209
  • NCI NIH HHS: CA37082
  • NCI NIH HHS: CA35531
Open access
true
ISSN
0007-0920
Ausgabe der Veröffentlichung
6
Zeitschrift
British journal of cancer
Schlüsselwörter
  • Animals
  • Mice, Inbred Strains
  • Mice
  • Leukemia L1210
  • Melanoma, Experimental
  • Doxorubicin
  • Antineoplastic Agents
  • Drug Screening Assays, Antitumor
  • Cell Survival
  • Biotransformation
  • Drug Resistance
  • Time Factors
  • Female
  • Male
  • In Vitro Techniques
Sprache
eng
Medium
Print
Open access status
Open Access
Paginierung
819 - 826
Datum der Veröffentlichung
1989
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
1989
Titel
N-benzyladriamycin-14-valerate versus progressively doxorubicin-resistant murine tumours: cellular pharmacology and characterisation of cross-resistance in vitro and in vivo.
Sub types
  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
60

Files

https://europepmc.org/articles/PMC2247277?pdf=render

Data source: Europe PubMed Central

Abstract
N-Benzyladriamycin-14-valerate (AD198) is a novel lipophilic anthracycline with greater in vivo antitumour activity than doxorubicin (DOX) in experimental model systems. Using sensitive and progressively DOX-resistant L1210 mouse leukaemia and B16-BL6 mouse melanoma lines, we have determined the cellular pharmacokinetics and cytotoxic response in vitro and in vivo of AD198. In the L1210 leukaemia model following 3 h drug exposure in vitro, the IC50 for AD198 was approximately 0.35 microgram ml-1 for the sensitive and 10-fold DOX resistant cells and 1.0 microgram ml-1 for the 40-fold DOX resistant cells. A similar pattern of cross-resistance to AD198 was also observed with the B16-BL6 melanoma, with and IC50 for AD198 with the sensitive and 10-fold DOX-resistant cells being similar, and about 2-fold higher with the 40-fold resistant cells. In the L1210 leukaemia model, cellular pharmacokinetics of AD198 revealed the following: (a) accumulation of AD198 was concentration but not time dependent, and cellular drug levels in the sensitive and resistant sublines were similar when treated with equimolar concentrations; (b) retention of AD 198 was 60% of the initial drug uptake and, in cells treated with the IC50 of AD198, cellular levels in the 40-fold DOX-resistant line were, as expected, 2-fold higher than in sensitive or 10-fold DOX-resistant cells; (c) in vitro biotransformation of AD 198 in the sensitive and resistant sublines was comparable. Studies in vivo with i.p. L1210 leukaemia (disseminating) and B16-BL6 melanoma (non-disseminating) tumour models evaluating therapeutic efficacy of DOX vs AD 198 in mice implanted with tumour i.p. on day 0 and treated i.p. on days 1-4 indicated: (a) DOX at 3 mg kg-1 administered once daily on days 1-4 resulted in a 55% ILS and 104% ILS with parent-sensitive B16-BL6 melanoma and L1210 leukaemia models respectively; however, similar doses of DOX in the resistant sublines were ineffective, with survival similar to the untreated control; (b) AD198 at 10-12.5 mg kg-1 day-1 for 4 days was extremely effective in the sensitive L1210 (189% ILS), and similar to DOX (61% ILS) in the sensitive B16-BL6; (c) AD198 (10-12.5 mg kg-1) was ineffective (survival similar to untreated control) in the 10-and 40-fold DOX-resistant L1210 leukaemia and 40-fold DOX resistant B16-BL6 melanoma, but produced a 76% ILS in the 10-fold DOX resistant B16-BL6 melanoma.(ABSTRACT TRUNCATED AT 400 WORDS)
Autoren
  • R Ganapathi
  • D Grabowski
  • TW Sweatman
  • R Seshadri
  • M Israel
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/2605093
DOI
10.1038/bjc.1989.373
Externe Identifier
  • PubMed Central ID: PMC2247277
Funding acknowledgements
  • NCI NIH HHS: CA35531
  • NCI NIH HHS: CA37082
  • NCI NIH HHS: CA37209
ISSN
0007-0920
Ausgabe der Veröffentlichung
6
Zeitschrift
Br J Cancer
Schlüsselwörter
  • Animals
  • Antineoplastic Agents
  • Biotransformation
  • Cell Survival
  • Doxorubicin
  • Drug Resistance
  • Drug Screening Assays, Antitumor
  • Female
  • In Vitro Techniques
  • Leukemia L1210
  • Male
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred Strains
  • Time Factors
Sprache
eng
Country
England
Paginierung
819 - 826
Datum der Veröffentlichung
1989
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
1990
Titel
N-benzyladriamycin-14-valerate versus progressively doxorubicin-resistant murine tumours: cellular pharmacology and characterisation of cross-resistance in vitro and in vivo.
Sub types
  • Comparative Study
  • Journal Article
  • Research Support, U.S. Gov't, P.H.S.
Ausgabe der Zeitschrift
60

Data source: PubMed

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