FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2892954494> ?p ?o ?g. }

• W2892954494 endingPage "362" @default.
• W2892954494 startingPage "362" @default.
• W2892954494 abstract "The chemotherapeutic agent temozolomide (TMZ) kills tumor cells preferentially via alkylation of the O6-position of guanine. However, cells that express the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), or harbor deficient DNA mismatch repair (MMR) function, are profoundly resistant to this drug. TMZ is in clinical use for melanoma, but objective response rates are low, even when TMZ is combined with O6-benzylguanine (O6BG), a potent MGMT inhibitor. We used in vitro and in vivo models of melanoma to characterize the early events leading to cellular TMZ resistance. Melanoma cell lines were exposed to a single treatment with TMZ, at physiologically relevant concentrations, in the absence or presence of O6BG. Surviving clones and mass cultures were analyzed by Western blot, colony formation assays, and DNA methylation studies. Mice with melanoma xenografts received TMZ treatment, and tumor tissue was analyzed by immunohistochemistry. We found that MGMT-negative melanoma cell cultures, before any drug treatment, already harbored a small fraction of MGMT-positive cells, which survived TMZ treatment and promptly became the dominant cell type within the surviving population. The MGMT-negative status in individual cells was not stable, as clonal selection of MGMT-negative cells again resulted in a mixed population harboring MGMT-positive, TMZ-resistant cells. Blocking the survival advantage of MGMT via the addition of O6BG still resulted in surviving clones, although at much lower frequency and independent of MGMT, and the resistance mechanism of these clones was based on a common lack of expression of MSH6, a key MMR enzyme. TMZ treatment of mice implanted with MGMT-negative melanoma cells resulted in effective tumor growth delay, but eventually tumor growth resumed, with tumor tissue having become MGMT positive. Altogether, these data reveal stochastic expression of MGMT as a pre-existing, key determinant of TMZ resistance in melanoma cell lines. Although MGMT activity can effectively be eliminated by pharmacologic intervention with O6BG, additional layers of TMZ resistance, although considerably rarer, are present as well and minimize the cytotoxic impact of TMZ/O6BG combination treatment. Our results provide rational explanations regarding clinical observations, where the TMZ/O6BG regimen has yielded mostly disappointing outcomes in melanoma patients." @default.
• W2892954494 created "2018-10-05" @default.
• W2892954494 creator A5003363712 @default.
• W2892954494 creator A5032045457 @default.
• W2892954494 creator A5033008635 @default.
• W2892954494 creator A5041603329 @default.
• W2892954494 creator A5053306149 @default.
• W2892954494 creator A5088434731 @default.
• W2892954494 date "2018-09-28" @default.
• W2892954494 modified "2023-10-01" @default.
• W2892954494 title "Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo" @default.
• W2892954494 cites W1528791634 @default.
• W2892954494 cites W1597791301 @default.
• W2892954494 cites W1698181436 @default.
• W2892954494 cites W1780453311 @default.
• W2892954494 cites W1907871389 @default.
• W2892954494 cites W1917632054 @default.
• W2892954494 cites W1965410494 @default.
• W2892954494 cites W1971344938 @default.
• W2892954494 cites W1975104842 @default.
• W2892954494 cites W1982203628 @default.
• W2892954494 cites W1989103018 @default.
• W2892954494 cites W1990739350 @default.
• W2892954494 cites W1990973203 @default.
• W2892954494 cites W1996338823 @default.
• W2892954494 cites W1998023952 @default.
• W2892954494 cites W1999905403 @default.
• W2892954494 cites W2002266833 @default.
• W2892954494 cites W2007704672 @default.
• W2892954494 cites W2009143954 @default.
• W2892954494 cites W2009623159 @default.
• W2892954494 cites W2010511761 @default.
• W2892954494 cites W2011203407 @default.
• W2892954494 cites W2013001916 @default.
• W2892954494 cites W2013816626 @default.
• W2892954494 cites W2052100484 @default.
• W2892954494 cites W2056627178 @default.
• W2892954494 cites W2060123914 @default.
• W2892954494 cites W2064488040 @default.
• W2892954494 cites W2067944888 @default.
• W2892954494 cites W2068288481 @default.
• W2892954494 cites W2073947429 @default.
• W2892954494 cites W2079203845 @default.
• W2892954494 cites W2079345857 @default.
• W2892954494 cites W2081350269 @default.
• W2892954494 cites W2082561902 @default.
• W2892954494 cites W2086492419 @default.
• W2892954494 cites W2087904586 @default.
• W2892954494 cites W2088228543 @default.
• W2892954494 cites W2091716776 @default.
• W2892954494 cites W2096287682 @default.
• W2892954494 cites W2097478662 @default.
• W2892954494 cites W2106452645 @default.
• W2892954494 cites W2109765046 @default.
• W2892954494 cites W2113729674 @default.
• W2892954494 cites W2114124586 @default.
• W2892954494 cites W2115276344 @default.
• W2892954494 cites W2118731052 @default.
• W2892954494 cites W2121585125 @default.
• W2892954494 cites W2138157070 @default.
• W2892954494 cites W2140943866 @default.
• W2892954494 cites W2143272637 @default.
• W2892954494 cites W2145047381 @default.
• W2892954494 cites W2147482980 @default.
• W2892954494 cites W2158649478 @default.
• W2892954494 cites W2166382251 @default.
• W2892954494 cites W2171257495 @default.
• W2892954494 cites W2290497676 @default.
• W2892954494 cites W2302258827 @default.
• W2892954494 cites W2584430097 @default.
• W2892954494 cites W2594077503 @default.
• W2892954494 cites W2602724897 @default.
• W2892954494 cites W2603746838 @default.
• W2892954494 cites W2622499649 @default.
• W2892954494 cites W2744517306 @default.
• W2892954494 cites W2767034994 @default.
• W2892954494 cites W2770647635 @default.
• W2892954494 cites W2779098860 @default.
• W2892954494 cites W2790048004 @default.
• W2892954494 cites W2791810919 @default.
• W2892954494 cites W328172746 @default.
• W2892954494 cites W4237395025 @default.
• W2892954494 cites W4242475406 @default.
• W2892954494 doi "https://doi.org/10.3390/cancers10100362" @default.
• W2892954494 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6209933" @default.
• W2892954494 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30274152" @default.
• W2892954494 hasPublicationYear "2018" @default.
• W2892954494 type Work @default.
• W2892954494 sameAs 2892954494 @default.
• W2892954494 citedByCount "8" @default.
• W2892954494 countsByYear W28929544942020 @default.
• W2892954494 countsByYear W28929544942021 @default.
• W2892954494 countsByYear W28929544942022 @default.
• W2892954494 countsByYear W28929544942023 @default.
• W2892954494 crossrefType "journal-article" @default.
• W2892954494 hasAuthorship W2892954494A5003363712 @default.
• W2892954494 hasAuthorship W2892954494A5032045457 @default.
• W2892954494 hasAuthorship W2892954494A5033008635 @default.

• next