Cimetidine and a tamoxifen derivate reduce tumour formation in SCID mice xenotransplanted with a human melanoma cell line.
Histamine is produced by many cells expressing histidine decarboxylase (HDC), the enzyme responsible for the synthesis of histamine. Since melanoma cells and tissue contain relatively large amounts of histamine, the functional significance of histamine was examined using specific antihistamines in vitro and in vivo in the human melanoma cell line HT168 and severe combined immunodeficiency (SCID) mice. It was shown that the H2 receptor antagonist cimetidine when combined with N, N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl (DPPE), a tamoxifen derivate, inhibits the proliferation of HT168 cells. Furthermore, it is suggested that there is a factor(s) that interferes with the exponential growth of HT168 cells xenografted to immunodeficient mice, and cimetidine and DPPE together significantly influence this factor(s). This combination of antihistamines also increases the survival of human melanoma-grafted mice. These changes are accompanied by enhanced infiltration of interferon-gamma- producing mouse macrophages into the tumour tissue. These findings suggest that two different mechanisms are probably acting concordantly: direct inhibition of tumour cell proliferation by the H2 receptor antagonists, and activation of the local immune response characterized by interferon-gamma production. These findings may help to elucidate the possibility of a rationally designed antihistamine strategy in melanoma therapy.
Szincsák
N
N
Department of Dermatology, Debrecen University, Debrecen, Hungary.
Hegyesi
H
H
Hunyadi
J
J
Martin
G
G
Lázár-Molnár
E
E
Kovács
P
P
Rivera
E
E
Falus
A
A
Juhász
I
I
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019898:Autocrine Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002927:Cimetidine / Q000008:administration & dosage; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D006635:Histamine H2 Antagonists / Q000008:administration & dosage; D006640:Histidine Decarboxylase / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000201:enzymology / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D010647:Phenyl Ethers / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D006635:Histamine H2 Antagonists; D009363:Neoplasm Proteins; D010647:Phenyl Ethers; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011970:Receptors, Histamine H2; D002927:Cimetidine; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System; D006640:Histidine Decarboxylase; C043062:tesmilifene