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Cisplatin resistance
S28
Abstracts
(LRP) is currently assessed with regard to its clinical reieVance. Other resistance mechanisms include alterations in either target enzymes (e.g. topoisomerase II) or the ghttathione/glutathione-S-transferase system, enhanced DNA repair, and altered apoptosis. Alterations in the expression of oncogenes or tumor suppressor genes can affect response to chemotherapy. Reversal of clinical drug resistance by either resistance modifiers or p53 gene transfer is currently studied within clinical trials. MRP and LRP Scheper RJ. Department
of Pathology,
Free University
Hospital,
The Netherlands.
Tumor cells with the multidrug resistance (MDR) phenotype show cross-resistance to several structurally unrelated natural product drugs. The most prominent cause of in vitro MDR is a reduced intracellular concentration of drugs, caused by overexpression of members of the ATP-binding cassette (ARC)-superfamily of transmembrane transporter molecules, exemplified by P-glycoprotein (Pgp) and multidrug resistancerelated protein (MRP). MRP is particularly active as a carrier for transport of glutathione S-conjugated endo- and xeno-biotics. Alternative non-ARC transporter-related mechanisms may also play a role in reducing concentrations of cytostatic drugs at their target sites, e.g. by sequestering drugs into exocytotic vesicles. A role in such a mechanism has been suggested for recently discovered subcellular particles called ‘vaults’. Vaults are 13-MDa ribonucleoprotein particles composed largely of the (104 kDa) major vault protein, also known as Lung Resistance Protein (LRP), in addition to three (55/195/210 kDa) minor vault proteins and vault RNA. Vault particles are thought to contribute to exocytosis of various substrates. Non-Pgp MDR has been observed in tumor cell lines. Clinical interest in LRP expression relates to recent studies in which LRP was predictive for poor response to anticancer drugs including cisplatin. Results of clinico-pathological studies on the clinical relevance of MRP and LRP will be discussed. Cisplatin resistance Akiyama S, Chen ZS, Sumizawa T, Furukawa T, Kuwano M. Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Kagoshima, and First Department of Biochemistry, Faculty of Medicine, Kyushu University, Fukuoku, Japan.
Cisplatin is now one of the most widely used anticancer drugs. However, intrinsic or acquired resistance to cisplatin reduces efficacy of treatment. The mechanisms of cisplatin resistance were studied in the cisplatin-resistant human ceIvical adenocarcinoma cell line KCP-4. A cell-cell hybridization test showed that the cisplatin resistance and the accumulation defect of cisplatin behaved as codominant traits. Decreased accumulation of cisplatin, elevated GSH and metallothionein, and enhanced DNA repair seemed to confer only low-level cisplatin resistance in KCP4 cells. An active efflux system for cisplatin, antimony, CPT-11 and SN-38 existed in KCP-4 cells. Our data suggested that ATP-dependent glutathione S-conjugate export pump (GS-X pump) plays a role in the elimination of the GS-platinum complex from KCP-4 cells. Although
transfection experiments suggested that cMOAT, but not MRP, was involved in low-level cisplatin resistance, neither MRP nor cMOAT were involved in cisplatin resistance in KCP4 cells. Thus an unknown organic anion transporter seems to be involved in cisplatin resistance in KCP4 cells. Drug resistance mechanisms in lung cancer specimens Filipits M. Division of Oncology, Department of Internal Medicine
4 Vienna,
Austria.
Lung cancer lends itself as a model disease for the evaluation of clinical drug resistance mechanisms. Small-cell lung cancer (SCLC) is a chemosensitive disease that rapidly acquires drug resistance, whereas non-small-cell lung cancer (NSCLC) usually shows intrinsic drug resistance. Clinical drug resistance can be due to multidrug resistance mechanisms, cisplatin resistance, methotrexate resistance and resistance to alkylating agents. Drug resistance mechanisms in tumor specimens can be determined by several methods at RNA level, protein level or functional level. Expression of P-glycoprotein occurs with various degrees in lung cancer specimens and might affect clinical outcome in SCLC. Expression of the multidrug resistance protein was associated with poor response to chemotherapy in NSCLC. The expression of the lung resistance protein is currently studied. Mutations in the p53 tumor suppressor gene correlate with worse response to both induction and palliative chemotherapy of NSCLC. Exact knowledge of the drug resistant mechanisms in individual patients could lead to new treatment strategies that might improve outcome of chemotherapy in lung cancer patients. Drug resistance in lung cancer: future perspectives Huber H. Division of Oncology, Department of Internal Medicine lj Vienna, Austria.
Several drug resistance mechanisms active in lung cancer have been characterized. The MDRl/P-glycoprotein (P-gp) gene, the multidrug resistance (MRP) gene and the lung resistance protein (LRP) gene are expressed to various degrees in lung cancer specimens and might, at least partly, contribute to the clinical drug resistance. The quantitative contributions of each of these mechanisms to clinical drug resistance remains to be determined, and the results of these studies will help to devise ways to overcome drug resistance. Reversal of drug resistance might be achieved by several ways. Firstly, new drugs with improved efficacy are currently available and some of these drugs might show some activity toward drug-resistant tumors. Secondly, resistance modifiers of P-gp have been developed and are currently evaluated in clinical trials. Finally, gene transfer of wild-type ~53 or administration of antisense oligonucleotides might restore chemosensitivity of tumor cells, and corresponding phase I/II trials with these agents have already been initiated. These investigations on clinical drug resistance should eventually result in improved outcome of chemotherapy in lung cancer. Protoadjuvant chemotherapy prior to radiotherapy Gatzemeier U. Dept. of Zhoracic Oncology, Grosshansdorf/ Hbg.
The treatment of pts with irresectable disease has, for many
Abstracts
(LRP) is currently assessed with regard to its clinical reieVance. Other resistance mechanisms include alterations in either target enzymes (e.g. topoisomerase II) or the ghttathione/glutathione-S-transferase system, enhanced DNA repair, and altered apoptosis. Alterations in the expression of oncogenes or tumor suppressor genes can affect response to chemotherapy. Reversal of clinical drug resistance by either resistance modifiers or p53 gene transfer is currently studied within clinical trials. MRP and LRP Scheper RJ. Department
of Pathology,
Free University
Hospital,
The Netherlands.
Tumor cells with the multidrug resistance (MDR) phenotype show cross-resistance to several structurally unrelated natural product drugs. The most prominent cause of in vitro MDR is a reduced intracellular concentration of drugs, caused by overexpression of members of the ATP-binding cassette (ARC)-superfamily of transmembrane transporter molecules, exemplified by P-glycoprotein (Pgp) and multidrug resistancerelated protein (MRP). MRP is particularly active as a carrier for transport of glutathione S-conjugated endo- and xeno-biotics. Alternative non-ARC transporter-related mechanisms may also play a role in reducing concentrations of cytostatic drugs at their target sites, e.g. by sequestering drugs into exocytotic vesicles. A role in such a mechanism has been suggested for recently discovered subcellular particles called ‘vaults’. Vaults are 13-MDa ribonucleoprotein particles composed largely of the (104 kDa) major vault protein, also known as Lung Resistance Protein (LRP), in addition to three (55/195/210 kDa) minor vault proteins and vault RNA. Vault particles are thought to contribute to exocytosis of various substrates. Non-Pgp MDR has been observed in tumor cell lines. Clinical interest in LRP expression relates to recent studies in which LRP was predictive for poor response to anticancer drugs including cisplatin. Results of clinico-pathological studies on the clinical relevance of MRP and LRP will be discussed. Cisplatin resistance Akiyama S, Chen ZS, Sumizawa T, Furukawa T, Kuwano M. Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Kagoshima, and First Department of Biochemistry, Faculty of Medicine, Kyushu University, Fukuoku, Japan.
Cisplatin is now one of the most widely used anticancer drugs. However, intrinsic or acquired resistance to cisplatin reduces efficacy of treatment. The mechanisms of cisplatin resistance were studied in the cisplatin-resistant human ceIvical adenocarcinoma cell line KCP-4. A cell-cell hybridization test showed that the cisplatin resistance and the accumulation defect of cisplatin behaved as codominant traits. Decreased accumulation of cisplatin, elevated GSH and metallothionein, and enhanced DNA repair seemed to confer only low-level cisplatin resistance in KCP4 cells. An active efflux system for cisplatin, antimony, CPT-11 and SN-38 existed in KCP-4 cells. Our data suggested that ATP-dependent glutathione S-conjugate export pump (GS-X pump) plays a role in the elimination of the GS-platinum complex from KCP-4 cells. Although
transfection experiments suggested that cMOAT, but not MRP, was involved in low-level cisplatin resistance, neither MRP nor cMOAT were involved in cisplatin resistance in KCP4 cells. Thus an unknown organic anion transporter seems to be involved in cisplatin resistance in KCP4 cells. Drug resistance mechanisms in lung cancer specimens Filipits M. Division of Oncology, Department of Internal Medicine
4 Vienna,
Austria.
Lung cancer lends itself as a model disease for the evaluation of clinical drug resistance mechanisms. Small-cell lung cancer (SCLC) is a chemosensitive disease that rapidly acquires drug resistance, whereas non-small-cell lung cancer (NSCLC) usually shows intrinsic drug resistance. Clinical drug resistance can be due to multidrug resistance mechanisms, cisplatin resistance, methotrexate resistance and resistance to alkylating agents. Drug resistance mechanisms in tumor specimens can be determined by several methods at RNA level, protein level or functional level. Expression of P-glycoprotein occurs with various degrees in lung cancer specimens and might affect clinical outcome in SCLC. Expression of the multidrug resistance protein was associated with poor response to chemotherapy in NSCLC. The expression of the lung resistance protein is currently studied. Mutations in the p53 tumor suppressor gene correlate with worse response to both induction and palliative chemotherapy of NSCLC. Exact knowledge of the drug resistant mechanisms in individual patients could lead to new treatment strategies that might improve outcome of chemotherapy in lung cancer patients. Drug resistance in lung cancer: future perspectives Huber H. Division of Oncology, Department of Internal Medicine lj Vienna, Austria.
Several drug resistance mechanisms active in lung cancer have been characterized. The MDRl/P-glycoprotein (P-gp) gene, the multidrug resistance (MRP) gene and the lung resistance protein (LRP) gene are expressed to various degrees in lung cancer specimens and might, at least partly, contribute to the clinical drug resistance. The quantitative contributions of each of these mechanisms to clinical drug resistance remains to be determined, and the results of these studies will help to devise ways to overcome drug resistance. Reversal of drug resistance might be achieved by several ways. Firstly, new drugs with improved efficacy are currently available and some of these drugs might show some activity toward drug-resistant tumors. Secondly, resistance modifiers of P-gp have been developed and are currently evaluated in clinical trials. Finally, gene transfer of wild-type ~53 or administration of antisense oligonucleotides might restore chemosensitivity of tumor cells, and corresponding phase I/II trials with these agents have already been initiated. These investigations on clinical drug resistance should eventually result in improved outcome of chemotherapy in lung cancer. Protoadjuvant chemotherapy prior to radiotherapy Gatzemeier U. Dept. of Zhoracic Oncology, Grosshansdorf/ Hbg.
The treatment of pts with irresectable disease has, for many