Pentoxifylline-induced modulation of melanoma cell growth, adhesion and lymphokine activated killer cell-mediated lysis

Pentoxifylline (PX) is a phosphodiesterase inhibitor which effectively incr eases overall cAMP levels within the cell. This study analyses the ability of PX to alter growth, adhesion and lymphokine activated killer (LAK) cell- mediated lysis of the C8161 and Hs294T human melanoma cell lines, and inves tigates the role of intercellular adhesion molecule-1 (ICAM-1) in the tumou r/LAK cell interaction. We have demonstrated that 4 days' pretreatment with PX (100-250 mu g/ml) significantly reduces cell numbers in a dose- and tim e-dependent manner, with cell numbers decreasing by 67.5% in the C8161 cell line and by 65.4% in the Hs294T cell line with 250 mu g/ml PX. Adherence o f both cell lines to a range of extracellular matrix components is not affe cted by PX, with the exception of the C8161 cells, where 4 days' pretreatme nt with 250 mu g/ml PX causes a 24.2% reduction in adherence to fibronectin . Four days' pretreatment of the tumour cells with 250 mu g/ml PX leads to increased lysis of the C8161 cells and decreased lysis of the Hs294T cells. The addition of blocking ICAM-1 antibody (10 mu g/ml) to the C8161 cells a t an effector:tumour cell ratio of 40:1 causes a 2.3-fold reduction in lysi s of both control and PX-treated cells. Addition of blocking ICAM-1 antibod y (5 mu g/ml) to Hs294T cells reduces lysis of control cells 1.8-fold. In P X-treated Hs294T cells, 10 mu g/ml of blocking ICAM-1 antibody significantl y reduces lysis 1.5-fold. The more aggressive C8161 cells produce 5-fold gr eater levels of soluble ICAM-1 (slCAM-1) than the poorly metastatic Hs294T cells. PX (10-250 mu g/ml) causes a dose-dependent increase in slCAM-1 expr ession in both cell lines, with maximum increases of 4.7-fold and 4.3-fold in the Hs294T and C8161 cell lines, respectively, following 4 days' pretrea tment with 250 mu g/ml PX. Collectively, these data demonstrate the ability of PX to alter tumour cell growth, adhesion and LAK cell-mediated lysis an d also support a role for the involvement of ICAM-1 in the tumour/LAK cell interaction. (C) 1999 Lippincott Williams & Wilkins.