Expression of drug resistance related proteins in sarcomas of the pulmonary artery and poorly differentiated leiomyosarcomas of other origin.
Sarcomas are known to develop resistance to current chemotherapeutic strategies, displaying a multidrug-resistant phenotype. Mechanisms involved in drug resistance include reduced cellular drug accumulation, drug detoxification as well as alterations in drug target specificity. In seven sarcomas of the pulmonary artery (SPA) and ten leiomyosarcomas of other origin, we studied the immunohistochemical expression of P-glycoprotein (P-gp), multidrug-resistance protein (MRP), lung resistance protein (LRP), metallothionein (MT) and topoisomerase IIalpha. Upregulation was found in tumour cells for P-gp but not for MRP in SPA and other leiomyosarcomas. Topoisomerase IIalpha was expressed at high levels in tissue of primary tumours as well as recurrent tumours. Both P-gp and topoisomerase IIalpha were present in numerous tumour-associated vessels. LRP was expressed at high levels in SPA but to a lesser extent in the other leiomyosarcomas. MT was expressed at low levels but was markedly present at the border of necrosis. The overall survival and the relapse-free survival did not correlate with the expression of these factors. There was no significant relationship between treated and non-treated patients with respect to the expression of the examined molecules. P-gp, but not MRP, may play a role in the development of drug resistance. P-gp, LRP and topoisomerase IIalpha contribute to drug resistance through expression in tumour-associated vessels. Unique high levels of topisomerase IIalpha reflect the high proliferation rate of these tumours. MT seems to serve as a detoxifying agent of metabolites at the border of necrosis. Our findings underline the fact that multiple factors contribute to chemoresistance and that examination of a spectrum of relevant molecules is probably necessary to plan the best therapy.
Institute of Pathology, University Clinics Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany. andreas.gaumann@klinik.uni-regensburg.de
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A
Gaumann
D S
DS
Tews
T
T
Mentzel
P K
PK
Petrow
E
E
Mayer
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M
Otto
C J
CJ
Kirkpatrick
J
J
Kriegsmann
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009383:Neoplasms, Vascular Tissue / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology*; D015996:Survival Rate; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism; D000099187:Major Vault Protein
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D008668:Metallothionein; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein