Treatment of malignant tumors with histamine. Clinical and experimental studies

Abstract

For metastatic melanoma there is no treatment to prolong life. Histamine has in experimental tumors shown tumor inhibiting effects. In vitro, histamine inhibit phagocyte-derived radical oxygen species to protect natural killer and cytotoxic T-lymphocytes. By exposing the tumor milieu to sufficient concentrations of histamine dihydrochloride, tumor rejection might be facilitated. Methods: Microdialysis was used to estimate interstitial histamine concentrations in tumor as well as normal tissues. The Internal Reference Technique was validated for histamine concentration estimates in the rat, and used to study the pharmacokinetics of histamine in tumor and normal tissue. In a rat Leydig cell sarcoma model, the effect of a subcutaneous bolus dose (0.5mg/kg), or continuous (0.5-20 mg/kg/24h) administration of histamine dihydrochloride was explored. Toxicity and efficiency of combined treatment with histamine dihydrochloride, IL-2 and IFN-a was investigated in patients with metastatic melanoma. Pharmacokinetics of subcutaneously administered histamine was explored.Results: Interstitial histamine concentrations in rat liver, subcutis and tumor could be estimated by microdialysis, using the Internal Reference Technique. A bolus dose of histamine dihydrochloride yielded significant differences in interstitial pharmacokinetic parameters. Maximum concentration and AUC were lower in subcutaneous tumor than in liver tumor.Histamine as monotherapy inhibited rat Leydig cell sarcoma growth in liver and subcutis, if administered subcutaneously as a bolus injection, but not as continuous infusion. The antitumor effect was H2-receptor mediated. In melanoma patients, histamine dihydrochloride, IL-2 and IFN-a was safely administered with moderate adverse events and tumor responses were observed. Histamine dihydrochloride injected over ten minutes significantly increased plasma histamine concentration.Conclusions: Interstitial changes in histamine concentration could be followed by microdialysis, with significantly lower exposure to tumors in subcutis than in liver after a histamine bolus injection. In rat, tumor growth was inhibited by a subcutaneous bolus injection but not continuous infusion of histamine. Histamine dihydrochloride could be administered safely to patients with metastatic melanoma.