THERAPY WITH INTERLEUKIN-2 INDUCES THE SYSTEMIC RELEASE OF PHOSPHOLIPASE-A(2)

Therapy with interleukin-2 (IL-2) induces remissions in some forms of cancel. This treatment however, is accompanied by side-effects which, in part, may be mediated by the formation of eicosanoids and platelet- activating factor. We investigated the systemic release of phospholipa se A(2) (PLA(2)), a rate-limiting enzyme in the formation of these lip id mediators, in patients receiving IL-2. In a pilot study of 4 patien ts we observed an increase in PLA(2) activity in serial plasma samples obtained during the first day after a bolus infusion of IL-2, which i ncrease closely correlated with that of antigen levels of secretory ph ospholipase A(2) (sPLA(2)) as measured by enzyme-linked immunosorbent assay (r = 0.92; P < 0.001). In 20 patients, receiving 12 x 10(6)-18 x 10(6) IU IL-2/m(2), we then investigated the course of antigenic leve ls of sPLA(2) in relation to those of the cytokines tumour necrosis fa ctor alpha (TNF) and interleukin-6 (IL-6) (both cytokines may induce s PLA(2) in vivo). From 4 h on, sPLA(2) levels significantly increased, reaching a peak 24 h after the IL-2 infusion. Subsequent IL-2 infusion s even induced a further increase of sPLA(2). This increase of sPLA(2) was presumably not due to a direct effect of IL-2 on, for example, he patocytes, since this cytokine, in contrast to IL-1, IL-6, TNF and int erferon gamma, was not able to induce the synthesis of sPLA(2) by Hep G2 cells in vitro. Consistent with this, plasma levels of TNF and IL-6 in the patients rose, reaching peak levels before a zenith of sPLA(2) occurred, i.e. at 2 h and 4 h after the start of the IL-2 infusion re spectively. sPLA(2) levels significantly correlated with the developme nt of the side-effects increase in body weight (r = 0.49; P<0.0001) an d decrease in mean arterial blood pressure (r = 0.40; P<0.0001). Moreo ver, maximum sPLA(2) levels induced by IL-2 were higher in patients wh o had progressive disease after therapy than in patients who had stabl e disease or a partial response.