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.


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).


CONCLUSIONS
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.
Department of Surgery, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
Per
P
Lindnér
Magnus
M
Rizell
Jan
J
Mattsson
Kristoffer
K
Hellstrand
Peter
P
Naredi
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006632:Histamine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000097:blood / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D011994:Recombinant Proteins
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D006632:Histamine