Year: 1999
Type: dissertation
Abstract: Through exposure to melphalan or taxol, four novel multidrug resistant variants of the human nasal\ncarcinoma cell line, RPMI-2650 and human lung carcinoma cell line, DLKP, were established In vitro\ntoxicity tests revealed that the RPMI-2650 taxol-resistant variant exhibited significant resistance to taxol,\nvincristine, adriamycin and vinblastine. The RPMI-2650 melphalan-resistant variant exhibited significant\nresistance to melphalan, cadmium chlonde, adriamycin, vinblastine and VP-16. The DLKP long term\nmelphalan-selected variant exhibited significant resistance to melphalan, cadmium chlonde, cisplatin,\nadnamycm and vinblastine. A similar cross resistance profile was observed in the DLKP pulse selection\nvariant with the exception that this variant displayed no obvious cross resistance to vinblastine Adnamycm\ndistnbution studies revealed decreased intracellular adnamycm accumulation in the RPMI-2650 taxol- and\nmelphalan-resistant variants. However, intense nuclear fluorescence was observed following treatment with\nverapamil and cyclosporin A Charactensation studies demonstrated that the resistant phenotype in the\nRPMI-2650 taxol-resistant variant appeared to be mainly P-glycoprotem mediated Protein and mRNA\nanalysis by Western blotting, immunocytochemistry and RT-PCR demonstrated an overexpression of MRP1,\ncMOAT (MRP2) and MRP3 m the RPMI-2650 melphalan-resistant vanant compared to its parental cell line\nSulindac or indomethacin could reverse melphalan toxicity m this vanant Western blotting analysis also\nshowed the overexpression of MRP1 in the DLKP melphalan long term and pulse selection cells, suggesting\nthe involvement o f MRP family members in mediating melphalan resistance m these variants Significant\niterations in GST activity and metallothionem expression m these vanants were not observed.\n\nResults obtained from invasion assays demonstrated that the RPMI-2650 and DLKP melphalan-resistant\n/ariants were more invasive than their respective parental cells and the RPMI-2650 taxol-resistant vanant. It\nippears that increased expression o f a 2Pi, CX5P1, a 6P) and a,6^4 integrins, decreased expression of a 4p1;\nitronger adhesion to collagen type IV, lamirun, fibronectin and matngel and expression of MMP-2, MMP-9\nmd c-myc may all contribute to the high mvasiveness of the RPMI-2650 melphalan-resistant vanant\nncreased expression of a 2 and Pi integnn subunits and overexpression of MMP-2 and MMP-9 may be\nesponsible for the invasiveness of the DLKP melphalan-selected variants Decreased expression of a 2\nntegrin which may result in decreased attachment to collagen type IV, lack of cytokeratin 18 and no\nletectable expression of any proteases may be responsible for the non-invasiveness of the RPMI-2650 taxolssistant\nvanant.\n\nThese results suggest that exposure to melphalan can result in not only a multidrug resistance phenotype but\nould also make cancer cells more invasive and metastatic.
Author: Yizheng Liang
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W191206371