The unique interaction with immunity of FCE 24517, an antitumor drug with a novel mode of action.
The present study was designed to characterize in mice the effects on the immune system of the antineoplastic agent FCE 24517, a benzoic acid mustard derivative of distamycin A with specificity for AT-rich base pair sequences of beta-DNA. At antitumorally therapeutic doses, single injections of FCE 24517 caused profound leukopenia and a decrease of spleen cell numbers. However, primary and secondary antibody production to the T-dependent antigen sheep red blood cells were markedly increased by FCE 24517 given before or together with antigen. Antibody production to the T-independent antigen type III pneumococcal polysaccharide was not appreciably affected by FCE 24517. The delayed type hypersensitivity response to sheep erythrocytes was only marginally decreased, whereas proliferation of spleen cells to mitogens was markedly depressed. The ability of natural killer cells and macrophages to mediate cytotoxicity was not affected by FCE 24517 treatment. The ability of carrier-primed cells from drug-treated mice to cooperate for anti-trinitrophenyl antibody production increased twofold over that of vehicle-injected controls, suggesting an increase in T-helper cell activity. Serum cytokine levels were studied in mice injected with bacterial lipopolysaccharide used as a model stimulus. Peak levels of TNF and IL-6 were not modified by FCE 24517, but at later times higher amounts of cytokines were found in drug-treated mice compared with the control, suggesting a longer exposure of immunocompetent cells to these factors. Two compounds (FCE 24561 and CC-1065), also capable of binding AT-rich sequences in the minor groove of beta-DNA and containing an alkylating moiety, had immunomodulatory activity similar to FCE 24517 in increasing primary anti-sheep erythrocytes response. It is concluded that FCE 24517 exhibits a unique interaction with the immune system, markedly different from that of alkylating agents and may be representative of a novel group of antiproliferative-immunomodulating agents.
Riganti
F
F
Laboratory of Immunology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Sironi
M
M
Kankova
M
M
D'Incalci
M
M
Spreafico
F
F
Mantovani
A
A
Vecchi
A
A
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004214:Distamycins / Q000494:pharmacology*; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D006968:Hypersensitivity, Delayed; D007107:Immune System / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000970:Antineoplastic Agents; D016207:Cytokines; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine