Combined Treatment with Histamine Dihydrochloride, Interleukin-2 and Interferon-α in Patients with Metastatic Melanoma

Abstract

Background: Histamine inhibits phagocyte-derived production of reactive oxygen species and improves the antitumour efficiency of interleukin-2 (IL-2) and interferon-alpha (IFN-α) in vitro and in tumour-bearing animals. Patients and Methods: In a phase-II study, twenty-seven patients with stage IV melanoma received subcutanous injections of histamine dihydrochloride (histamine) 1.0 mg and IL-2 2.4 MIU/m² twice daily (BID) days 1-5 and 8-12. IFN-α 3 MIU once daily was administered throughout a cycle (days 1-28; n=14). Alternatively, bolus doses of IL-2 10 MIU/m² BID days 1 and 2 and histamine days 1-28 (n=13) were administered. The aim was to study efficiency (survival and tumour response), toxicity and histamine pharmacokinetics. Results: The median survival time was 11.3 (2.5-45) months. One patient achieved a complete response and 3 patients had partial responses. The compounds were safely self-administered with low toxicity. Plasma histamine concentrations significantly increased after an injection of histamine over 10 minutes (3±1 vs. 63±27 nmol/l). Conclusion: Histamine, IL-2 and IFN-α treatment is safe, well-tolerated and tumour responses were observed. The putative efficiency of histamine as an adjunct to cytokine therapy in metastatic melanoma needs to be confirmed in larger randomized trials.