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

J Clin Oncol. 2002 Aug 1;20(15):3282-92. doi: 10.1200/JCO.2002.01.003.


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 degrees C initially to peak values of 40.4 degrees 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Chemotherapy, Cancer, Regional Perfusion / methods*
  • Child
  • Female
  • Fungal Proteins / genetics*
  • Genes, MDR / genetics*
  • Humans
  • Hyperthermia, Induced*
  • Immunohistochemistry
  • Male
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melphalan / therapeutic use
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics*
  • Repressor Proteins / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Saccharomyces cerevisiae Proteins*
  • Sarcoma / drug therapy*
  • Sarcoma / metabolism
  • Sarcoma / pathology
  • Soft Tissue Neoplasms / drug therapy*
  • Soft Tissue Neoplasms / metabolism
  • Soft Tissue Neoplasms / pathology
  • Statistics, Nonparametric
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / therapeutic use
  • Vault Ribonucleoprotein Particles / metabolism


  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Fungal Proteins
  • MVP1 protein, S cerevisiae
  • Multidrug Resistance-Associated Proteins
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Tumor Necrosis Factor-alpha
  • Vault Ribonucleoprotein Particles
  • Melphalan
  • multidrug resistance-associated protein 1