File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Toxicity and DNA binding of dextran-doxorubicin conjugates in multidrug-resistant KB-V1 cells: Optimization of dextran size

TitleToxicity and DNA binding of dextran-doxorubicin conjugates in multidrug-resistant KB-V1 cells: Optimization of dextran size
Authors
Issue Date2000
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.anti-cancerdrugs.com
Citation
Anti-Cancer Drugs, 2000, v. 11 n. 5, p. 377-384 How to Cite?
AbstractWe previously showed that conjugating doxorubicin to very large 70-500 kDa dextran decreased its removal rate from P-glycoprotein (P-gp) over-expressing, multidrug-resistant KB-V1 cells. Furthermore these conjugates could act synergistically with other cancer drugs. In the drug-sensitive 3-1 clone, but not in the V1 subclone which was 300-fold more resistant to free doxorubicin, conjugation led to a size-related decrease in toxicity. Here we identified the optimal size of dextran for avoiding P-gp-mediated efflux and yet preserving as much as possible doxorubicin toxicity. Chemically reduced, intracellularly stable 3.4-10 kDa conjugates were prepared. Confocal microscopy and fluorescence quenching experiments showed that these conjugates entered nuclei and interacted with DNA. In 3-1 cells, but not in V1 cells, cytotoxicity of conjugates decreased 14- to 45-fold linearly related to log size of the carrier (r = 0.95). In V1 cells toxicity of the 10 kDa conjugate exceeded that of free doxorubicin. After conjugation the equilibrium binding constant of the DNA-drug complex (KA) decreased only by up to 3-fold. In 3-1 cells, but not in V1 cells, DNA binding kinetics was an important factor and toxicity could be linearly correlated to 1/K(A) of conjugate (r = 0.94). Drug accumulation decreased with an increase in dextran size but drug removal was decreased only in V1 cells. It appeared that drug uptake was also sensitive to dextran conjugation. In V1 cells drug removal was sensitive to the P-gp inhibitor verapamil or energy starvation. Ratios of V1/3-1 toxicity, drug accumulation and drug removal correlated linearly with log dextran size. When these ratios equaled 1, dextran sizes were estimated to be 32, 103 and 21 kDa, respectively. (C) 2000 Lippincott Williams and Wilkins.
Persistent Identifierhttp://hdl.handle.net/10722/167643
ISSN
2015 Impact Factor: 2.268
2015 SCImago Journal Rankings: 0.795
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLam, Wen_US
dc.contributor.authorLeung, CHen_US
dc.contributor.authorChan, HLen_US
dc.contributor.authorFong, WFen_US
dc.date.accessioned2012-10-08T03:09:23Z-
dc.date.available2012-10-08T03:09:23Z-
dc.date.issued2000en_US
dc.identifier.citationAnti-Cancer Drugs, 2000, v. 11 n. 5, p. 377-384en_US
dc.identifier.issn0959-4973en_US
dc.identifier.urihttp://hdl.handle.net/10722/167643-
dc.description.abstractWe previously showed that conjugating doxorubicin to very large 70-500 kDa dextran decreased its removal rate from P-glycoprotein (P-gp) over-expressing, multidrug-resistant KB-V1 cells. Furthermore these conjugates could act synergistically with other cancer drugs. In the drug-sensitive 3-1 clone, but not in the V1 subclone which was 300-fold more resistant to free doxorubicin, conjugation led to a size-related decrease in toxicity. Here we identified the optimal size of dextran for avoiding P-gp-mediated efflux and yet preserving as much as possible doxorubicin toxicity. Chemically reduced, intracellularly stable 3.4-10 kDa conjugates were prepared. Confocal microscopy and fluorescence quenching experiments showed that these conjugates entered nuclei and interacted with DNA. In 3-1 cells, but not in V1 cells, cytotoxicity of conjugates decreased 14- to 45-fold linearly related to log size of the carrier (r = 0.95). In V1 cells toxicity of the 10 kDa conjugate exceeded that of free doxorubicin. After conjugation the equilibrium binding constant of the DNA-drug complex (KA) decreased only by up to 3-fold. In 3-1 cells, but not in V1 cells, DNA binding kinetics was an important factor and toxicity could be linearly correlated to 1/K(A) of conjugate (r = 0.94). Drug accumulation decreased with an increase in dextran size but drug removal was decreased only in V1 cells. It appeared that drug uptake was also sensitive to dextran conjugation. In V1 cells drug removal was sensitive to the P-gp inhibitor verapamil or energy starvation. Ratios of V1/3-1 toxicity, drug accumulation and drug removal correlated linearly with log dextran size. When these ratios equaled 1, dextran sizes were estimated to be 32, 103 and 21 kDa, respectively. (C) 2000 Lippincott Williams and Wilkins.en_US
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.anti-cancerdrugs.comen_US
dc.relation.ispartofAnti-Cancer Drugsen_US
dc.subject.meshCell Survival - Drug Effectsen_US
dc.subject.meshDna, Neoplasm - Drug Effects - Metabolismen_US
dc.subject.meshDextrans - Metabolism - Toxicityen_US
dc.subject.meshDoxorubicin - Analogs & Derivatives - Metabolism - Toxicityen_US
dc.subject.meshDrug Resistance, Multipleen_US
dc.subject.meshDrug Resistance, Neoplasmen_US
dc.subject.meshHumansen_US
dc.subject.meshKb Cells - Drug Effects - Metabolism - Pathologyen_US
dc.subject.meshP-Glycoprotein - Metabolismen_US
dc.subject.meshRegression Analysisen_US
dc.subject.meshRhodamines - Metabolismen_US
dc.subject.meshSpectrometry, Fluorescenceen_US
dc.subject.meshTime Factorsen_US
dc.titleToxicity and DNA binding of dextran-doxorubicin conjugates in multidrug-resistant KB-V1 cells: Optimization of dextran sizeen_US
dc.typeArticleen_US
dc.identifier.emailLeung, CH:duncanl@hkucc.hku.hken_US
dc.identifier.authorityLeung, CH=rp00730en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1097/00001813-200006000-00008en_US
dc.identifier.pmid10912954-
dc.identifier.scopuseid_2-s2.0-0033942026en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0033942026&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume11en_US
dc.identifier.issue5en_US
dc.identifier.spage377en_US
dc.identifier.epage384en_US
dc.identifier.isiWOS:000087988600008-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLam, W=7203021943en_US
dc.identifier.scopusauthoridLeung, CH=7402612570en_US
dc.identifier.scopusauthoridChan, HL=7403402315en_US
dc.identifier.scopusauthoridFong, WF=7102816013en_US

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats