Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have associated pharmacological studies to a semi-quantitative evaluation of P-glycoprotein(s) expression, to establish if classical multidrug resistance (MDR) could account for the complete resistance phenotype exhibited by progressively doxorubicin-resistant rat glioblastoma cells. Three resistant variants (C6 0.001, C6 0.1 and C6 0.5) of the C6 glioblastoma cell line (C6 S) were selected by long-term culture in the presence of three concentrations of doxorubicin (0.001, 0.1 and 0.5 microgram.ml-1 respectively). The degree of doxorubicin resistance was respectively 7, 33 and 400, and all the cell variants were cross-resistant to m-AMSA, etoposide and vincristine. Doxorubicin incorporation was reduced similarly in all resistant cells, irrespective of the level of resistance. When exposed to their respective doxorubicin IC50, the 7-fold resistant cells had the same intracellular drug incorporation as the sensitive cells, whereas the 33-fold and 400-fold resistant cells could incorporate respectively 3.7 and 17 times more drug. The ratio of doxorubicin exposures required for 50% DNA synthesis inhibition and 50% growth inhibition was dependent on the degree of resistance; this ratio was 12.8 in C6 S, 11.6 in C6 0.001, 6.3 in C6 0.1 and 1.8 in C6 0.5. P-glycoprotein(s) overexpression was of the same magnitude as the resistance factor in variants C6 0.001 and C6 0.1, but was lower than resistance factor in variant C6 0.5. Reversal of drug incorporation by verapamil was complete in all resistant cell lines; however, reversal of doxorubicin cytotoxicity was complete only in the 7-fold resistant line and was only partial in the most resistant lines, which remained 10-fold and 20-fold resistant to doxorubicin. These results suggest that classical MDR was the first phenotype selected by doxorubicin in C6 0.001, whereas mechanism(s) of doxorubicin resistance other than classical MDR are added in the most resistant lines.
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PMID:P-glycoprotein overexpression cannot explain the complete doxorubicin-resistance phenotype in rat glioblastoma cell lines. 134 23

Antineoplastic intercalating agents such as 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) stabilize a cleavable complex between topoisomerase II and DNA. The production of protein-associated DNA cleavage in whole cells exposed to m-AMSA is thought to represent the cellular correlate of this topoisomerase II-mediated reaction. Protein-associated DNA cleavage can be quantified in mammalian cells by using alkaline elution technology. In an attempt to understand the impact of phenotypic and biochemical cellular characteristics on protein-associated DNA cleavage, we quantified m-AMSA-induced DNA cleavage in quiescent or proliferative normal human fibroblasts (cell strain 1508) and human glioblastoma cells (line T98G) as well as in asynchronously proliferating HeLa cells. The magnitude of DNA cleavage in quiescent fibroblasts and quiescent glioblastoma cells was identical and low relative to that observed in the HeLa cells. The magnitude of DNA cleavage was enhanced in both cell types following proliferation. This enhancement was greater in the glioblastoma cells than in the fibroblasts. These results were not due to alterations in cellular m-AMSA uptake. Chromatin was more elongated (open) in the quiescent glioblastoma cells than in the quiescent fibroblasts (as visualized by using the premature chromosome condensation assay), suggesting chromatin accessibility to drug per se may not be a critical determinant of the magnitude of m-AMSA-induced DNA cleavage. The onset of the enhanced m-AMSA-induced DNA cleavability that accompanied proliferation closely followed the formation of regions of localized chromatin decondensation, a late G1 event, and coincided with the onset of enhanced thymidine uptake, a marker for the onset of S phase. m-AMSA-induced cytotoxicity was also enhanced in proliferating compared with quiescent cells. The major finding of this study is that the cellular target for m-AMSA, putatively topoisomerase II, is more susceptible to drug action in proliferating cells than in quiescent cells. Effects of chromatin conformation or cellular phenotype upon topoisomerase II-mediated events such as m-AMSA-induced DNA cleavage are less certain.
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PMID:Effect of cell proliferation and chromatin conformation on intercalator-induced, protein-associated DNA cleavage in human brain tumor cells and human fibroblasts. 302 17