Modulation of drug and radiation resistance in small cell lung cancer cells by paclitaxel.

Locke, VL; Davey, RA; Davey, MW

Modulation of drug and radiation resistance in small cell lung cancer cells by paclitaxel.

Locke, VL Davey, RA Davey, MW

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Publication Type:: Journal Article
Citation:: Anticancer Drugs, 2003, 14 (7), pp. 523 - 531
Issue Date:: 2003-08

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Field	Value	Language
dc.contributor.author	Locke, VL	en_US
dc.contributor.author	Davey, RA	en_US
dc.contributor.author	Davey, MW	en_US
dc.date.issued	2003-08	en_US
dc.identifier.citation	Anticancer Drugs, 2003, 14 (7), pp. 523 - 531	en_US
dc.identifier.issn	0959-4973	en_US
dc.identifier.uri	http://hdl.handle.net/10453/12557
dc.description.abstract	Small cell lung cancer (SCLC) responds to treatment with cisplatin and etoposide, but relapse is rapid and survival rates are low. Our aims were to determine the mechanisms of resistance and the potential for paclitaxel (Taxol) to overcome any drug or radiation resistance. To mimic clinical treatment, H69 SCLC cells, representative of the classic form of the disease, and H82 cells, with the phenotype of the more resistant variant disease, were treated intermittently with 100 ng/ml cisplatin or 500 ng/ml etoposide (approximate IC50 drug doses) to produce stable sublines. Drug and radiation resistance were determined using the MTT assay. Protein expression was determined by Western blot. The effect of paclitaxel on drug resistance was determined by cytotoxicity assays. Intermittent 4-day treatment with 100 ng/ml cisplatin caused 2- to 3-fold resistance to cisplatin (n=5; p<0.05), and 2- to 5-fold cross resistance to etoposide, alkylating drugs, the Vinca drugs and radiation. Resistance was mediated primarily by changes in glutathione metabolism and was not associated with changes in MRP2 transport protein. Treatment with etoposide (500 ng/ml) produced cells with 2-fold resistance to etoposide (n=5; p<0.05). Cross-resistance was limited and mediated by decreased topoisomerase IIalpha. Treatment of both drug-resistant sublines with a maximal non-cytotoxic dose of paclitaxel sensitized them to other drugs and to radiation, although this treatment had no effect on the parental H69 or H82 cells. We conclude that paclitaxel may play an important role in the treatment of refractory SCLC.	en_US
dc.language	eng	en_US
dc.relation.ispartof	Anticancer Drugs	en_US
dc.relation.isbasedon	10.1097/00001813-200308000-00004	en_US
dc.subject.classification	Oncology & Carcinogenesis	en_US
dc.subject.mesh	Tumor Cells, Cultured	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Carcinoma, Small Cell	en_US
dc.subject.mesh	Lung Neoplasms	en_US
dc.subject.mesh	Cisplatin	en_US
dc.subject.mesh	Paclitaxel	en_US
dc.subject.mesh	Etoposide	en_US
dc.subject.mesh	Glutathione	en_US
dc.subject.mesh	Antineoplastic Agents, Phytogenic	en_US
dc.subject.mesh	Drug Resistance, Neoplasm	en_US
dc.title	Modulation of drug and radiation resistance in small cell lung cancer cells by paclitaxel.	en_US
dc.type	Journal Article
utslib.citation.volume	7	en_US
utslib.citation.volume	14	en_US
utslib.location.activity	England	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	1101 Medical Biochemistry and Metabolomics	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	closed_access
pubs.issue	7	en_US
pubs.publication-status	Published	en_US
pubs.volume	14	en_US

Abstract:

Small cell lung cancer (SCLC) responds to treatment with cisplatin and etoposide, but relapse is rapid and survival rates are low. Our aims were to determine the mechanisms of resistance and the potential for paclitaxel (Taxol) to overcome any drug or radiation resistance. To mimic clinical treatment, H69 SCLC cells, representative of the classic form of the disease, and H82 cells, with the phenotype of the more resistant variant disease, were treated intermittently with 100 ng/ml cisplatin or 500 ng/ml etoposide (approximate IC50 drug doses) to produce stable sublines. Drug and radiation resistance were determined using the MTT assay. Protein expression was determined by Western blot. The effect of paclitaxel on drug resistance was determined by cytotoxicity assays. Intermittent 4-day treatment with 100 ng/ml cisplatin caused 2- to 3-fold resistance to cisplatin (n=5; p<0.05), and 2- to 5-fold cross resistance to etoposide, alkylating drugs, the Vinca drugs and radiation. Resistance was mediated primarily by changes in glutathione metabolism and was not associated with changes in MRP2 transport protein. Treatment with etoposide (500 ng/ml) produced cells with 2-fold resistance to etoposide (n=5; p<0.05). Cross-resistance was limited and mediated by decreased topoisomerase IIalpha. Treatment of both drug-resistant sublines with a maximal non-cytotoxic dose of paclitaxel sensitized them to other drugs and to radiation, although this treatment had no effect on the parental H69 or H82 cells. We conclude that paclitaxel may play an important role in the treatment of refractory SCLC.

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