metallothionein and Leiomyosarcoma

We investigated the expression of P-glycoprotein (P-GP) and metallothionein (MT) in a series of 92 GIST and 14 gastrointestinal leiomyosarcomas (GILMS) with the purpose to expand our knowledge on the biological bases of GIST chemo-resistance and to ascertain their significance in patients' prognosis. P-GP expression was more frequent in GIST than in GI-LMS (83.7% vs. 21.4%, p<0.001), with no difference between low- and high-risk GIST (p=1.000) or low- and high-grade GI-LMS (p=0.538). P-GP expression was unrelated to anatomic location (gastric vs. intestinal) in GIST (39/45 vs. 35/43, p=0.770) and in GI-LMS (0/2 vs. 2/6, p=1.000). MT expression was non-significantly higher in GI-LMS than in GIST (35.7% vs. 14.1%, p=0.060), with no difference between low- and high-risk GIST (p=1.000) or low- and high-grade GI-LMS (p=1.000). MT expression was unrelated to the anatomic location (gastric vs. intestinal) in GIST (7/45 vs. 6/43) and GI-LMS (0/2 vs. 1/6) (p=1.000 and p=0.1000, respectively). Overall tumor-specific survival (p< 0.001) and disease-free survival (p<0.001) were different in GIST as compared with GI-LMS, and the number of events was higher in GI-LMS. When the survival analysis took into consideration P-GP or MT expression, the overall survival in GIST was influenced by the expression of MT (p=0.021) but not by that of P-GP (p=0.638). However, in GI-LMS, P-GP expression influenced disease-free survival (p=0.050); in addition, it is important to recognize the limited value of these results because of the low number of cases involved in the study. Differential expression of P-GP and MT might explain the known variability in response to systemic chemotherapy in these tumors. Detection of P-GP and MT seems to add certain prognostic value in GIST (MT) or GI-LMS (P-GP).

Topics: Aged; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Neoplasm; Female; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Gene Expression Regulation, Neoplastic; Humans; Leiomyosarcoma; Male; Metallothionein; Middle Aged; Prognosis; Survival Analysis

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.

Topics: Adult; Aged; Antigens, Neoplasm; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; DNA Topoisomerases, Type II; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Humans; Leiomyosarcoma; Male; Metallothionein; Middle Aged; Neoplasm Proteins; Neoplasms, Vascular Tissue; Pulmonary Artery; Survival Rate; Vault Ribonucleoprotein Particles