INVOLVEMENT OF HISTAMINE IN GROWTH OF MOUSE AND RAT-TUMORS - ANTITUMORAL PROPERTIES OF MONOFLUOROMETHYLHISTIDINE, AN ENZYME-ACTIVATED IRREVERSIBLE INHIBITOR OF HISTIDINE-DECARBOXYLASE

Abstract

The present study suggests that newly synthesized histamine is involved in the development of some animal tumors (e.g., Lewis lung carcinoma in mice and Morris hepatoma in rats). A marked introduction of histidine decarboxylase (HDC) and an increase in the histamine concentration were observed in the tumors .apprx. 1 wk after inoculation, and there were parallel increases in ornithine decarboxylase activity and the concentrations of polyamines. The H2 receptor antagonist, cimetidine, significantly reduced tumor growth in the animal models while the H1 receptor antagonist, dexchlorpheniramine, had no effect, suggesting that histamine could act via H2 receptor sites. Extensive depletion of tumor histamine induced by local injection of Compound 48/80 did not result in a significant cytostatic effect. Monofluoromethylhistidine (MFMH), an enzyme-activated irreversible inhibitor of HDC, retarded the growth of hepatoma tissue culture cells grown in culture and i.m. in Buffalo rats. MFMH had pronounced antitumoral effects on EMT6 sarcomas and Lewis lung carcinomas in mice, which were associated with inhibition of HDC and depletion of the histamine content of the tumors. These cytostatic effects were clearly enhanced when MFMH was combined in therapy with the specific ornithine decarboxylase inhibitor, DL-.alpha.-difluoromethylornithine. The antitumoral effects of the combination were associated with marked decreases in the tumor histamine and putrescine contents. Nascent histamine, like newly synthesized putrescine and spermidine, may play a role in the rapid proliferation of animal tumors. Inhibition of HDC by essentially nontoxic drugs such as MFMH could represent a novel approach to the control of neoplastic growth.