Immune stimulatory and anti-tumour properties of haemin

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Abstract
IL-2 induces tumour regression in some patients with metastatic disease, but the dose of IL-2 is limited by severe toxicity. Agents that increase the expression of IL-2 receptors in the effector cells could be used to improve the effectiveness of IL-2 in mediating its anti-tumour effect. We have reported that haemin increased the expression of IL-2 receptors in human peripheral blood mononuclear cells (PBMC) and synergized with IL-2 in the induction of mitogenicity, cytotoxicity and cytokine production. We now report on haemin-induced immune stimulation and tumour regression in mice. Haemin-induced mitogenicity in mouse splenocytes was potentiated up to twofold by IL-2. The combination of haemin and IL-2 was also effective in inducing cytotoxicity for natural killer (NK)-resistant target cells. Maximal induction of cytotoxicity was attained at an optimal concentration of haemin of 10 μm. Higher concentrations were less effective. Splenocytes isolated from mice that had been treated in vivo with haemin and IL-2 incorporated twice the amount of 3H-thymidine compared with splenocytes from mice treated with either haemin or IL-2 alone. Cytotoxicity of splenocytes for NK-rcsistant target cells was not increased following in vivo administration of haemin and IL-2 when fresh splenocytes were tested. Cytotoxicity was enhanced, however, up to five-fold following 48 h in vitro incubation with IL-2. Administration of haemin and IL-2 resulted in a significant decrease (40%) of established hepatic metastases in mice. Either IL-2 or haemin alone at the dose used were ineffective. The anti-tumour effect of haemin and IL-2 was enhanced (63% decrease in metastases) by administration of the thiol compound, N-acetylcysteine. Since haemin can safely be administered to patients, it may represent a new class of biologic response modifiers that could enhance IL-2-mediated anti-tumour effects.