ENHANCED CANCER GROWTH IN MICE ADMINISTERED DAILY HUMAN-EQUIVALENT DOSES OF SOME H-1-ANTIHISTAMINES - PREDICTIVE IN-VITRO CORRELATES

Backgronnd: Present studies of drug-induced tumor growth promotion hav e evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4- (phenylmethyl)phenoxy]ethanamine HCl, a tamoxifen de rivative which potently inhibits lymphocyte mitogenesis in vitro and s timulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (H-IC), some of which are on cytochr omes P450, may correlate with tumor growth-promoting activity. Purpose : We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H-1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine. Methods: Potency of each agent was ranked 1-5 in each of the following in vitro assays : 1) inhibition of [H-3]histamine binding to microsomal H-IC, 2) inhib ition of histamine binding to microsomal P450, 3) inhibition of the P4 50-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. TWO laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous i njection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C- 3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly ass igned to treatment groups, then received a single, daily intraperitone al injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being kille d. Tumors were surgically removed and wet weights compared statistical ly among groups. Results: The cumulative potency of each drug in affec ting tumor growth or growth mechanisms in the five in vitro assays ran ked as follows: Loratidine and astemizole ranked highest and were equa lly potent, followed in decreasing order by hydroxyzine, doxylamine, a nd cetirizine. A significant correlation (r =.97; P<.02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth vivo: Loratid ine and astemizole significantly (P<.001) promoted growth of both mela noma and fibrosarcoma, hydroxyzine significantly (P<.001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote t he growth of either tumor. Conclusion: Data demonstrate that the in vi tro assays predicted the propensity of each H-1-antihistamine to stimu late cancer growth in vivo. Implication: These in vitro tests may prov e valuable to screen potential tumor growth promoters.