Expression of multidrug resistance genes MVP, MDR1, and MRP1 determined sequentially before, during, and after hyperthermic isolated limb perfusion of soft tissue sarcoma and melanoma patients

Item Type:	Article
Title:	Expression of multidrug resistance genes MVP, MDR1, and MRP1 determined sequentially before, during, and after hyperthermic isolated limb perfusion of soft tissue sarcoma and melanoma patients
Creators Name:	Stein, U. and Juerchott, K. and Schlafke, M. and Hohenberger, P.
Abstract:	Purpose: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor alpha and melphalan is a highly effective treatment for advanced soft tissue sarcoma (STS) and locoregional metastatic malignant melanoma. Multidrug resistance (MDR)-associated genes are known to be inducible by heat and drugs; expression levels of the major vault protein (MVP), MDR1, and MDR-associated protein 1 (MRP1) were determined sequentially before, during, and after ILP of patients. Patients and Methods: Twenty-one STS or malignant melanoma patients were treated by ILP. Tumor tissue temperatures were recorded continuously and ranged from 33.4°C initially to peak values of 40.4°C during ILP. Serial true-cut biopsy specimens from tumor tissues were routinely microdissected. Expression analyses for MDR genes were performed by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. Results: In 83% of the patients, MVP expression was induced during hyperthermic ILP. MVP-mRNA inductions often paralleled the increase in temperature during ILP. Increased MVP protein expressions either were observed simultaneously with the MVP-mRNA induction or were delayed until after the induction at the transcriptional level. Inductions of MDR1 and MRP1 were observed in only 13% and 27% of the specimens analyzed. Temperatures and drugs applied preferentially led to an induction of MVP and were not sufficient to induce MDR1 and MRP1 in the majority of tumors. Conclusion: This study is the first to analyze the expression of MDR-associated genes sequentially during ILP of patients and demonstrates that treatment might lead to increased levels of MVP, whereas enhanced levels of MDR1 and MRP1 remain rare events.
Keywords:	Antineoplastic Agents, Alkylating Antineoplastic Agents, Regional Perfusion Cancer Chemotherapy, Fungal Proteins, Immunohistochemistry, Induced Hyperthermia, MDR Genes, Melanoma, Melphalan, Multidrug Resistance-Associated Proteins, Nonparametric Statistics, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Saccharomyces cerevisiae Proteins, Sarcoma, Soft Tissue Neoplasms, Treatment Outcome, Tumor Necrosis Factor-Alpha, Vault Ribonucleoprotein Particles
Source:	Journal of Clinical Oncology
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Volume:	20
Number:	15
Page Range:	3282-3292
Date:	1 January 2002
Official Publication:	https://doi.org/10.1200/JCO.2002.01.003
PubMed:	View item in PubMed

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