Abstract:
:Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS(2) (a) (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC(50) (drug concentration for 50% reduction in colony formation) was 0.1 microM for MCF-7 and 1 microM for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC(50) concentration was 0.1 microM for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endo-lysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR.
journal_name
Int J Cancerjournal_title
International journal of cancerauthors
Lou PJ,Lai PS,Shieh MJ,Macrobert AJ,Berg K,Bown SGdoi
10.1002/ijc.22098subject
Has Abstractpub_date
2006-12-01 00:00:00pages
2692-8issue
11eissn
0020-7136issn
1097-0215journal_volume
119pub_type
杂志文章abstract::Mucin-associated sialylated Lewis antigens are implicated in tumor cell metastasis and are used in several tests for pancreatic cancer. Despite their clinical importance, little is known about the structures of the oligosaccharides of pancreatic cancer mucins or about the regulation of their synthesis or of the synthe...
journal_title:International journal of cancer
pub_type: 杂志文章
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更新日期:2011-07-01 00:00:00
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