Abstract
A new pharmacological method for screening potential immunosuppressive drugs, the local graft-versus-host reaction in rats, has been used to evaluate the efficacy of cyclophosphamide applied at varous times in the development of this reaction.
This drug was relatively ineffective when applied to the F1 hybrid recipient of the graft cells (splenic lymphocytes) prior to grafting, rather more effective when given only to the parental donor prior to harvesting the graft cells, and most effective when given to the recipient either immediately after the graft or after a delay of three days.
Biliary and hepatic metabolites of cyclophosphamide diminished the competence of parental lymphocytes to evoke the graft response. By contrast, cyclophosphamide itself was devoid of such activity in vitro. Non-enzymic decomposition (hydroxylation) of cyclophosphamide with the Udenfriend system (Fe++, ascorbate, EDTA) efficiently generated in vitro graft-deactivating agents.
Fortified liver preparations from normal female rats formed alkylating metabolites at a much slower rate, and adjuvant-arthritic male rats were less capable of generating graft deactivating cyclophosphamide metabolites in vitro, than liver preparations from normal male rats. However cyclophosphamide appeared to be no less effective in normal female or arthritic male rats in vivo, than in normal male rats, in controlling the graft-versus-host response. This lack of correlation between rates of hepatic cyclophosphamide metabolism and evident bioefficacy as an immunosuppressive drug is discussed, with special reference to similar findings by Sladek concerning rates of bioactivation and anti-tumor efficacy.
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Whitehouse, M.W., Levy, L. & Beck, F.J. Effect of cyclophosphamide on a local graft-versus-host reaction in the rat: Influence of sex, disease and different dosage regimens. Agents and Actions 3, 53–60 (1973). https://doi.org/10.1007/BF02023854
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DOI: https://doi.org/10.1007/BF02023854