FTY720, a synthetic analogue of
myriocin (ISP-1), is derived from culture filtrates of the fungus Isaria sinclairii. As a
sphingosine analogue,
FTY720 appears to undergo phosphorylation and thereby interact with specific
G-protein-linked receptors. In vivo,
FTY720 causes emigration of lymphocytes from peripheral blood to secondary lymphoid structures. Thus, the
drug is the archetype of a new class of agents that alter cellular homing patterns: the adhesion-migration paradigm. Since
FTY720 seems to spare nonspecific elements of host resistance, it may address the not infrequent complications of
infections associated with existing
therapies. In experimental rodent, canine and non-human primate models,
FTY720 produces
lymphopenia and immunosuppression, prolonging the survival of allografts. Because of synergistic interactions, it promotes the immunosuppressive effects not only of
calcineurin antagonists, but also of proliferation signal inhibitors. These interactions proffer the possibility of large reductions in exposure to and mitigated toxicity of existing drugs. In humans,
FTY720 causes dose-dependent peripheral blood
lymphopenia, a reduced incidence of acute rejection episodes and only one apparent adverse reaction - a negative chronotropic effect - particularly after the loading dose. While the clinical utility of
FTY720 is difficult to predict before completion of Phase III studies that elucidate its benefits versus unanticipated side effects, the initial data suggest several potential advantages: it does not produce hyperlipidaemia,
diabetes mellitus, nephrotoxicity, neurotoxicity or myelosuppression, which are characteristic of other
immunosuppressants. Furthermore, it displays high oral bioavailability and a low interindividual coefficient of variation. Clearly, structural analogues, as well as other agents that alter the balance of
chemokines or affect cellular adhesion to activated endothelium, will represent important components of future regimens.