UNASSIGNED: We report herein the development, functional and molecular characterization of an isogenic, paired @entity150 cell culture model system for studying @entity902 drug resistance. The 5637 @entity1 @entity150 cell line was cultured over ten months with stepwise increases in @entity901 concentration to generate a drug resistant 5637R sub cell line. The @entity98 assay was used to measure the @entity137 of several @entity150 drugs. Liquid scintillation counting allowed quantification of cellular drug uptake and efflux of radiolabeled @entity901 and @entity3003 . The impact of intracellular drug inactivation was assessed by chemical modulation of @entity2041 levels. @entity901 - and @entity3003 -DNA adduct formation and repair was measured using accelerator mass spectrometry. Resistance factors including apoptosis, growth factor signaling and others were assessed with RNAseq of both cell lines and included confirmation of selected transcripts by RT-PCR. @entity901 , @entity3003 , @entity900 and @entity136 were significantly less cytotoxic to 5637R cells compared to the 5637 cells. In contrast, @entity632 , @entity1499 and @entity5713 had no cell line dependent difference in @entity137 . Upon exposure to therapeutically relevant doses of @entity901 , 5637R cells had lower drug-DNA adduct levels than 5637 cells. This difference was partially accounted for by pre-DNA damage mechanisms such as drug uptake and intracellular inactivation by @entity2041 , as well as faster @entity901 -DNA adduct repair. In contrast, both cell lines had no significant differences in @entity3003 cell uptake, efflux and drug-DNA adduct formation and repair, suggesting distinct resistance mechanisms for these two closely related drugs. The functional studies were augmented by RNAseq analysis, which demonstrated a significant change in expression of 83 transcripts, including 50 known genes and 22 novel transcripts. Most of the transcripts were not previously associated with @entity150 chemoresistance. This model system and the associated phenotypic and genotypic data has the potential to identify some novel details of resistance mechanisms of clinical importance to @entity150 .

Molecular Dissection of Induced @entity902 Resistance through Functional and Gene Expression Analysis in a Cell Culture Model of XXXX .

@entity1 :: ('9606', 'Species') :: ['human'] @entity901 :: ('MESH:C030110', 'Chemical') :: ['oxaliplatin', 'Oxaliplatin'] @entity632 :: ('MESH:D004317', 'Chemical') :: ['doxorubicin'] @entity137 :: ('MESH:D064420', 'Disease') :: ['cytotoxicity'] @entity3003 :: ('MESH:D016190', 'Chemical') :: ['carboplatin'] @entity900 :: ('MESH:D002945', 'Chemical') :: ['cisplatin'] @entity2041 :: ('MESH:D005978', 'Chemical') :: ['glutathione'] @entity136 :: ('MESH:C056507', 'Chemical') :: ['gemcitabine'] @entity98 :: ('CHEBI:53233', 'Chemical') :: ['MTT'] @entity150 :: ('MESH:D001749', 'Disease') :: ['bladder cancer'] @entity1499 :: ('MESH:D008727', 'Chemical') :: ['methotrexate'] @entity902 :: ('MESH:D010984', 'Chemical') :: ['platinum'] @entity5713 :: ('MESH:D014747', 'Chemical') :: ['vinblastine']
@entity150 :: (MESH:D001749,Disease) :: ['Bladder Cancer']
