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Combined treatment with histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma.

BACKGROUND
Histamine inhibits phagocyte-derived production of reactive oxygen species and improves the anti-tumour efficiency of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) 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-alpha 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-alpha 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 later randomized trials.