Cyclosporin A
Cyclosporin A is an FDA-approved immunomodulator primarily used to prevent organ transplant rejection and manage autoimmune conditions. This short polypeptide, which consists of eleven amino acids, can be administered orally, intravenously, or topically. While it is effective in modifying immune responses by inhibiting T cell activation, Cyclosporin A has been associated with an increased risk of certain cancers, including lymphoma and skin cancer, particularly among transplant recipients. The drug's mechanism may contribute to cancer progression by impairing apoptosis and activating pathways linked to tumor growth. Despite the heightened cancer risk, Cyclosporin A has gained approval for various other conditions, such as psoriasis and rheumatoid arthritis, and is still widely used in clinical practice. Ongoing research is exploring its potential anti-tumor effects on specific cancers, although the underlying mechanisms remain incompletely understood. It is important for patients and healthcare providers to weigh the benefits and risks associated with Cyclosporin A therapy.
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Subject Terms
Cyclosporin A
ROC STATUS: Known human carcinogen since 1998
ALSO KNOWN AS: Cyclosporin, ciclosporin, cyclosporine, CsA, CYA, Sandimmune, Neoral, Restasis, Gengraf, Cicloral, Cequa, Verkazia, Vevye
RELATED CANCERS: Lymphoma, skin cancer
DEFINITION: Cyclosporin A is a drug approved by the US Food and Drug Administration for use as an immunomodulator. It is a short polypeptide with eleven amino acids, eight of which form a ring.
Exposure routes: Oral, intravenous, or topical administration
Where found: Commercially available in pharmacies
At risk: People given the drug for therapeutic immunosuppression
Etiology and symptoms of associated cancers: Cyclosporin A modifies the immune response by inhibiting calcineurin in lymphocytes, primarily T cells; calcineurin is then unable to normally activate transcription of interleukin-2. It also inhibits the release of the important pro-apoptotic factor cytochrome C from mitochondria. Although not important in modulating the immune response, the deficit of cytochrome C may slow or prevent normal apoptosis and act as a pro-survival factor for cells.
Another mechanism by which cyclosporin A promotes cancer progression is independent of immune-cell inhibition. This direct carcinogenicity involves the activation of transforming growth factor beta (TGF-β). Tumors in transplant recipients may arise from the recipient’s cells or cells brought in with the transplanted organ, whereby premalignant donor cells are no longer subject to the surveillance of an intact immune system. Various studies have also suggested that cyclosporin A aids skin carcinogenesis by inhibiting the production of proteins that repair DNA damage caused by ultraviolet radiation, such as the xeroderma pigmentosum group C (XPC) protein.
Symptoms of include fatigue, enlarged and possibly painful lymph nodes, and elevated white blood cell counts. Skin cancer is usually detected by visual inspection. In some patients, tumors become apparent within a few weeks of treatment initiation, and in some cases, discontinuation of the drug is followed by tumor remission.
History: As part of a drug discovery effort, soil samples from Norway were tested and found to have immunosuppressive activity in the early 1970s. The active component was found to be a small peptide produced by the fungus Tolypocladium inflatum. The drug was first administered to prevent transplanted organ rejection in 1980 and was approved for this indication in 1983. Transplant recipients were soon found through registry data to have a threefold to fivefold increased risk of cancer compared with the general population, with more aggressive malignancies and overall poorer prognosis. Despite the increased risk of cancer, cyclosporin A has since been approved for other indications, including prevention of graft-versus-host disease (GVHD), psoriasis, rheumatoid arthritis, nephrotic syndrome, and keratoconjunctivitis sicca (dry eyes). The drug continues to be widely used, and efforts to minimize posttransplant malignancies continue.
Further studies have shown that cyclosporin A may have antitumor effects on certain cancers, including prostate cancer and colorectal cancer. Combined with pseudomonas aeruginosa exotoxin A-based immunotoxins (PE-ITs), research continues to explore the efficacy of cyclosporin A in treating breast, cervical, and bladder cancers. However, the mechanism of this effect is not fully understood.
Bibliography
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Han, Weinong, et al. "Deregulation of XPC and CypA by Cyclosporin A: An Immunosuppression-Independent Mechanism of Skin Carcinogenesis." Cancer Prevention Research, vol. 5, no. 9, 2012, pp. 1155–62. doi:10.1158/1940-6207.CAPR-12-0185-T.
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