Adverse and beneficial immunological effects of purine nucleoside analogues

Purine nucleoside analogues are a new class of drugs with activity against non-dividing lymphocytes. They should thus play a major role in the treatment of low grade lymphoid malignancies. These drugs have been shown to have strong effect in DNA synthesis on actively dividing cells, mainly through interference with DNA polymerases and ribonucleotide reductase. However, the cell cycle kinetics of low grade lymphocytic lymphomas is characterized by the presence of very low growth fractions. Hence, the action of these drugs in slowly progressing lymphoid malignancies cannot be accounted by the same mechanism observed in actively proliferating tumors and needs to be explained through activity against quiescent resting lymphocytes. Recent work has stressed the role of purine analogues in inducing programmed cell death of quiescent lymphocytes, which could be explained through the induction of accelerated DNA strand breaks. This process leads to consumption of NAD for poly(ADP-ribose) synthesis, which could induce critical depletion of ATP. As this action extends to normal resting lymphocytes deleterious effects related to their immunosuppressive action are also observed, i.e. prolonged lymphopenia predominating in T cells and especially in CD4 subset, increased frequency of opportunistic infections and perhaps increase in autoimmune complications like autoimmune hemolytic anemia. Nevertheless, beneficial effects of this immunosuppressive action have also been reported in the prevention of graft-versus-host disease, graft rejection and in some autoimmune diseases like multiple sclerosis. Work needs to be carried out to define better the mechanisms of action of these drugs on the different immunological effectors, as well as studies in animal models of transplantation and autoimmune diseases.