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‐α 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-α) is able to modify the expression of these three proteins in different cell types. The effect of TNF-α 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-α and melphalan; 15 patients received additional interferon γ. 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 (≤ 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-α 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-α and melphalan does not induce MDR positive STS: a result with clinical importance when consecutive, adjuvant, doxorubicin-containing chemotherapy is considered. Cancer 2001;91:1940–8. © 2001 American Cancer Society.