No abstract

FCE 23762 (3' desamino-3'[2(s)methoxyl-4-morpholinyl]doxorubicin) is a new doxorubicin (Dx) derivative that has been selected for clinical testing for its favourable antitumor characteristics, which include efficacy on Dx-resistant tumors. Immunosuppression is an undesirable side-effect of anti-cancer chemotherapy and the therapeutic efficacy of Dx is probably also related to its low immunotoxicity. It was, thus, of interest to compare the effects of FCE 23762 and its parental drug on the immune responses. Both compounds were injected i.v. into healthy mice at equitoxic doses and according to different treatment schedules. Single doses of FCE 23762 and Dx, given concomitant or after the antigen, suppressed at the same degree and dose-dependently the primary anti-SRBC antibody response. Following a multiple treatment schedule after the antigen, FCE 23762 was less suppressive than Dx on both primary and secondary antibody production. Differently from Dx, that was completely inactive, FCE 23762 moderately inhibited DTH reaction to SRBC, only at the highest single dose tested or for repeated administrations given simultaneously or after priming. Both drugs were totally ineffective in delaying skin allograft rejection. Since spleen cellularity and ex vivo lymphocyte proliferation to Con A and LPS were similarly impaired by the two drugs, the differentiated immunodepressive activity of FCE 23762 and Dx cannot be merely associated to their cytotoxic and antiproliferative action. The hypothesis of a selective effect on different regulatory cell subsets and/or immune mechanisms is discussed.

FCE 20696 is a new synthetic immunomodulating agent, active on some manifestations of the autoimmune disease of NZB/WF1 mice, in which a disorder of T suppressor cells (SC) has been described to be of pathogenetic relevance. The ability of FCE 20969 to induce SC in NZB/WF1 mice, which are then able to specifically inhibit the production of anti autologous red blood cells antibodies (aRBC Ab), was investigated. NZB/WF1 mice were chronically treated with the compound starting from the ninth week of age, sacrificed at different times and their spleen cells transferred to 9 weeks old, syngeneic mice. In donor animals SC were induced by rat RBC, whereas in the recipients the suppressive activity of transferred cells was evaluated from the appearance of aRBC Ab induced by the same antigen. The results show that antigen specific SC were present in both FCE 20696 treated and control young animals. In older controls, SC couldn't be induced, whereas in treated animals SC were present and able to transfer suppression into the recipients. FCE 20696 was active at 1.5 mg/Kg.

No abstract

A preliminary characterization of the immunopharmacological profile of the new immunomodulating agent FCE20696 (6H,6[2-(dimethylamino)-ethoxycarbonyl]-dibenzo[b,d]pyran-HCl) was performed in mice. Single i.p. doses of this chemical, concomitantly given with the antigen, increased the antibody response and decreased the delayed hypersensitivity reaction to a suboptimal dose of SRBC, the active doses ranging from 6.25 to 50 mg/kg. No activity was observed using a full antigen dose. Macrophage cytotoxic activity was enhanced 2-4 days after a single i.p. treatment with 50 and 10 mg/kg. Spleen cell proliferation to T and B mitogens was inhibited by a single dose of 30 mg/kg given i.p. 6 days before the test, or by 10 mg/kg x 3 days ending one day before the test. Finally, generation of suppressor cells was enhanced by the compound, given p.o. biweekly for at least 7 weeks, at doses ranging from 0.1 to 10 mg/kg. Collectively taken, these data suggest that FCE20696 has a broad range of immunomodulating activities and that macrophages and suppressor cells are presumed to be the main targets of its pharmacological activity.