title: Expression of P-glycoprotein, multidrug resistance-associated protein 1, and lung resistance-related protein in human soft tissue sarcomas before and after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan.
abstract: BACKGROUND
  Multidrug resistance (MDR) is associated with expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and lung resistance-related protein (LRP). Tumor necrosis factor (TNF-alpha) is able to modify the expression of these three proteins in different cell types. The effect of TNF-alpha in the clinical situation on patients with soft tissue sarcomas (STS) is indeterminate.
  
  
  METHODS
  Thirty-seven patients with a locally advanced extremity STS underwent hyperthermic isolated limb perfusion (HILP) with TNF-alpha and melphalan; 15 patients received additional interferon gamma. Clinical and histologic responses were documented and used to define the overall response. Samples before and after HILP were analyzed immunohistochemically for P-gp, MRP1, and LRP. Samples were scored as negative or positive (< or = 5% or > 5% positive tumor cells).
  
  
  RESULTS
  Six patients had an overall complete response, 25 patients had a partial response, and 4 patients with STS revealed no change; in 2 patients, the response remained unclear. The percentage STS samples that were positive for all three proteins dropped from 92% before HILP to 85% after HILP. P-gp positive samples were encountered more often than MRP1 positive samples (P < 0.05). The percentage of samples that were negative for all three MDR proteins increased after HILP from 6% to 16%. MDR status had no significant correlation with tumor response.
  
  
  CONCLUSIONS
  HILP with TNF-alpha and melphalan results in excellent overall tumor response in patients with locally advanced STS. STS more often are positive for P-gp than for MRP1. MDR status in patients with STS is not predictive for tumor response after HILP. Data from the current study suggest that the combination of TNF-alpha and melphalan does not induce MDR positive STS: a result with clinical importance when consecutive, adjuvant, doxorubicin-containing chemotherapy is considered.
authors.affiliation: Division of Surgical Oncology, University Hospital Groningen, Groningen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Komdeur
authors.forename: B E
authors.initials: BE
authors.lastname: Plaat
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoekstra
authors.forename: W M
authors.initials: WM
authors.lastname: Molenaar
authors.forename: H
authors.initials: H
authors.lastname: Hollema
authors.forename: E
authors.initials: E
authors.lastname: van den Berg
authors.forename: M F
authors.initials: MF
authors.lastname: Mastik
authors.forename: W T
authors.initials: WT
authors.lastname: van der Graaf
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000627:therapeutic use; D008297:Male; D008558:Melphalan / Q000627:therapeutic use*; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D018906:Antineoplastic Agents, Alkylating; D007371:Interferon-gamma; D008558:Melphalan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein