Expression of P-glycoprotein, multidrug resistance-associated protein 1, and lung resistance-related protein in human soft tissue sarcomas before andafter hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan

BACKGROUND. Multidrug resistance (MDR) is associated with expression of P-g lycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and l ung resistance-related protein (LRP). Tumor necrosis factor (TNF-alpha) is able to modify the expression of these three proteins in different cell typ es. 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 underw ent hyperthermic isolated limb perfusion (HILP) with TNF-alpha and melphala n; 15 patients received additional interferon gamma, Clinical and histologi c responses were documented and used to define the overall response. Sample s before and after HILP were analyzed immunohistochemically for P-gp! MRP1, and LRP, Samples were scored as negative or positive (less than or equal t o 5% or > 5% positive tumor cells). RESULTS, Six patients had an overall complete response, 25 patients had a p artial response, and 4 patients with STS revealed no change; in 2 patients, the response remained unclear. The percentage STS samples that were positi ve 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 significan t 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 p ositive for P-gp than for MRP1, MDR status in patients with STS is not pred ictive for tumor response after HILP. Data from the current study suggest t hat the combination of TNF-alpha and melphalan does not induce MDR positive STS: a result with clinical importance when consecutive, adjuvant, doxorub icin-containing chemotherapy is considered. (C) 2001 American Cancer Societ y.