Cimetidine amplifies the anti-neoplastic effect of Trichinella spiralis in mice.

MAST-CELL MEDIATORS, including histamine, exert a variety of pharmacological effects, which can be explained by assuming two kinds of receptors, designated Hi and H2 (Rocklin et al., 1979). H2 receptors have been shown on e.g. T lymphocytes, their function being suppressed by histamine. In two recent papers (Osband et al., 1981; Gifford et al., 1981) cimetidine, an H2receptor antagonist, was shown to possess anti-neoplastic properties in mice. In the experimental tumour models used, the specific immunity, based on the presence of cytotoxic T cells, was probably enhanced by the pharmacological blocking effect of cimetidine on H2-receptor-bearing suppressor cells. Experimental infections with the parasitic nematode Trichinella spiralis exert an immunomodulating activity on responses to unrelated antigens, including pathogens and tumour cells. The immunomodulation was reported to be connected to the intestinal phase (Ljungstrom & Huldt, 1977). Furthermore, the intestinal phase (i.e. the adult worm) is accompanied by a marked intestinal mastocytosis (Ruitenberg & Elgersma, 1976). It has been suggested that mast-cell proliferation, IgE-triggered mediator release (including histamine) and the ensuing hypersensitivity reaction might play a role in the regulation of malignancies (Lynch et al., 1978). Consequently, we tested the possibility of the involvement of histamine in the anti-neoplastic effect of T. spiralis on the growth of a murine fibrosarcoma using an H2-receptor antagonist (cimetidine) and an H2-receptor agonist (tolazoline). The mice used were conventional inbred female BALB/c, 7-9 weeks of age, obtained from the Central Institute for the Breeding of Animals, TNO, Zeist, The Netherlands. The tumour was a fibrosarcoma originally induced by 3-methylcholanthrene in the same inbred strain. The tumour was non-immunogenic and non-metastasizing (Ruitenberg et al., 1978). The T. spiralis strain was maintained in our Institute (Ruitenberg et al., 1977). Tolazoline hydrochloride was obtained from Brocacef Ltd, Maarssen, The Netherlands. Cimetidine (Tagemet®) was obtained from Smith, Kline and French, Rijswijk, The Netherlands. Groups of 8-10 mice were orally infected with 200 T. spiralis larvae each, 8 days before s.c. inoculation in the hind foot pad of 5 x 105 tumour cells in 0 05 ml (Day 0). Cimetidine (50 mg/kg) or tolazoline HC1 0 5 mg/kg were administered i.p. at Days -8, -6, -4, -2, and 0. Dilutions were prepared in saline. Tumour growth was measured twice weekly. The number of larvae and the intervals to tumour inoculation were selected on the basis of preliminary experiments in which a reproducible regression was observed using this schedule (unpublished data).