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-? and melphalan

Abstract

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. 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). 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. 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.