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dc.creatorPrijović, Željko
dc.creatorLeu, Yuling
dc.creatorRoffler, Steve R.
dc.date.accessioned2021-03-03T11:15:29Z
dc.date.available2021-03-03T11:15:29Z
dc.date.issued2007
dc.identifier.issn0344-5704
dc.identifier.issn1432-0843
dc.identifier.urihttps://cer.ihtm.bg.ac.rs/handle/123456789/4306
dc.description.abstractPurpose: 9-aminocamptothecin glucuronide (9ACG) is a prodrug of 9-aminocamptothecin (9AC) that displays potent antitumor activity against human tumor xenografts in nude mice. Camptothecins exist in a pH dependent equilibrium between active lactone and inactive carboxy forms that can be altered by binding to human serum albumin (HSA). Here we investigated the influence of pH and HSA on the lactone-carboxy equilibrium, HSA binding, and cytotoxicity of 9ACG. Methods: Microfiltration and HPLC were used to measure the influence of pH on lactone to carboxy conversion and HSA binding of 9ACG as compared to other camptothecins. In vitro cytotoxicity of drugs was determined against EJ human bladder carcinoma cells and CL1-5 human lung cancer cells. Results: The rate of lactone to carboxy conversion was similar for 9ACG and 9AC. Decreasing the pH from 7.6 to 6.0 increased the equilibrium levels of the lactone forms of the drugs from 20 to almost 95% of total drug. HSA moderately diminished the amount of free 9ACG lactone but did not change the ratio of 9ACG lactone to 9ACG carboxy. Consistent with the effect of pH on lactone levels, lowering the pH of EJ human bladder carcinoma cells from 7.6 to 6.8 decreased the IC50 of 9ACG from 480 to 98 nM and 9AC from 33 to 12 nM. Activation of 9ACG by human β-glucuronidase anchored on the surface of EJ cells further decreased its IC50 value to 26 nM. Although HSA significantly decreased the cytotoxicity of 9AC and 9ACG, activation of 9ACG at cancer cells with an antibody-β-glucuronidase immunoconjugate produced greater cytotoxicity than 9AC. Conclusions: Acidification and targeted delivery of β-glucuronidase can enhance 9ACG cytotoxicity even in the presence of HSA.sr
dc.language.isoensr
dc.publisherSwitzerland : Springer Naturesr
dc.relationMNTR of Serbia No. 1795sr
dc.relationThe National Health Research Institutes (NHRI-EX95-9420B1)sr
dc.rightsrestrictedAccesssr
dc.sourceCancer Chemotherapy and Pharmacologysr
dc.subjectβ-Glucuronidasesr
dc.subjectCancer therapysr
dc.subject9-Aminocamptothecinsr
dc.subjectHuman serum albuminsr
dc.subjectpHsr
dc.subjectProdrugsr
dc.subjectTerapija karcinomasr
dc.subjectHuman serumski albuminsr
dc.titleEffect of pH and human serum albumin on the cytotoxicity of a glucuronide prodrug of 9-aminocamptothecinsr
dc.typearticlesr
dc.rights.licenseARRsr
dcterms.abstractЛеу, Yулинг; Пријовић, Жељко М.; Роффлер, Стеве Р.;
dc.citation.volume60
dc.citation.issue1
dc.citation.spage7
dc.citation.epage17
dc.citation.rankM22
dc.identifier.pmid16983566
dc.identifier.doi10.1007/s00280-006-0340-4
dc.identifier.scopus2-s2.0-34247390649
dc.identifier.wos000245869300002
dc.type.versionpublishedVersionsr


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