<P> Like tacrolimus, ciclosporin (Novartis' Sandimmune) is a calcineurin inhibitor (CNI). It has been in use since 1983 and is one of the most widely used immunosuppressive drugs . It is a cyclic fungal peptide, composed of 11 amino acids . </P> <P> Ciclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T - lymphocytes . This complex of ciclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin - 2 . The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T - cells . </P> <P> Ciclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer, and less nephrotoxic, immunosuppressants . </P> <P> Calcineurin inhibitors and azathioprine have been linked with post-transplant malignancies and skin cancers in organ transplant recipients . Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality . The results of several studies suggest that calcineurin inhibitors have oncogenic properties mainly linked to the production of cytokines that promote tumor growth, metastasis and angiogenesis . </P>

Which of the following have been an effective immunosuppressant for use in transplantation