The Carcinogenicity Of

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The use of immunosuppressive drugs bears intrinsically the risk of tumor formation with two basic mechanisms: a genetic one, consisting of a direct effect of the drug on DNA replication; and an epigenetic mechanism, including indirect effects on immunological, hormonal, metabolic control of multiple cellular regulatory events [16]. CyA does not seem to be geno-toxic [15]: several experimental data have excluded any mutagenic properties [17, 18]. The association of CyA to carcinogenesis is mainly related to its immunosuppressive capacity. It is well known that severe immunosuppression leads to an increased incidence of malignancy, especially virus-related: a minor immune surveillance for transformed cells is associated to the development of a microenviroment more permissive towards chronic oncogenic viral infection [19]. Viral infections are common among immunodeficient patients, first of all Epstein Barr virus (EBV), papilloma and herpes virus [20, 21], EBV induces B-cell proliferation and, actually, a wide spectrum of EB V-related lymphoproliferative disorders, ranging from infectious mononucleosis to malignant lymphoma, may arise in transplant recipients who have received immunosuppressive regimens containing CyA [22], The development of EBV-associated lymphoproliferative disorders has been also described in patients with rheumatoid arthritis (RA) treated with CyA [23, 24], CyA may have a role in allowing a lymphoproliferative disorder to develop as it can abrogates EBV-specific T-cell con1 trol [25, 26], However, at the low dose currently used, CyA, allowing the normal function of these T-cell clones, results in regression of EBV-induced B-cell lines [27], The disappearance of post-transplant EBV lymphproliferative lesions has been described after reduction or discontinuance of immunosuppression [28]. A similar observation has been reported in patients with autoimmune diseases [29].

Specific markers able to detect at the earliest possible time the development of a lymphoproliferative disorder (LPD) would have great value in clinical setting. Vogl et al. [30] have evaluated the efficacy of tissue polypeptide specific (TSP) antigen for the detection at an early stage of CyA-induced post-transplant LPD: they actually found it increased in serum before LPD diagnosis and decreased after the reduction of immunosuppression and the beginning of tumor regression. The authors concluded that continuous mon itoring of TSP antigen concentration leads to an early treatment and a better prognosis for patients who had developed a LPD. No information are available about the usefulness of measuring this marker in patients with autoimmune diseases under CyA therapy.

3.1. The Cancerogenicity of CyA: Experience from Transplantations

It is rather difficult to ascertain the responsibility of a single immunosuppressive drug in the increased incidence of cancer after transplantation as patient usually adopt a multiple therapy. Many studies have shown that the combined use of several potent immunosuppressive agents is more obviously associated with the development of malignancy [31, 32], In renal transplantation a clear difference in the postoperative course of patients treated with conventional immunosuppressive therapy (azathioprine or azathioprine plus steroids) and those treated with CyA is unlikely [33], even if some authors indicate that the development of lymphoproliferative disorders may occur earlier in subjects using CyA [34], A similar observation comes from Japan [35],

Gaya et al. [36] analyzed the incidence of de novo malignancy in 274 renal transplant recipients who had been followed for 2622 patient-years and found no evidence that CyA treated subjects have an higher risk of cancer in comparison to those treated with conventional immunosuppressive therapy (azathioprine plus steroids). On the contrary, Hiesse et al., comparing the risk of malignancy in a historical group of transplants treated with azathioprine-steroids and those more recently submitted to multiple CyA-based immunosuppressive protocols, found an increased risk of skin cancers in the latter [37]. Previous observations from European [38] and Canadian [39] studies ruled out that lymphoproliferative disorders could be diagnosed more frequently in transplant-recipients using lower-dose of CyA. More recently, it has been [19] demonstrated that low-dose CyA regimen reduces the risk of malignancy in transplant recipients. In this study the majority of cancers were skin carcinomas, and they were observed especially in those patients who had previously received high dose of azathioprine. Azathioprine metabolites are known to have photosensitizing activity in the skin, and in UV light exposed mice more tumors are induced by azathioprine than by CyA [40], Careful skin examination should be periodically performed in patients receiving CyA therapy in association with azathioprine.

3.2. The Cancerogenicity of CyA: Experience from Autoimmune Disease

The majority of data regarding the risk of neoplasms in patients treated with CyA derives from transplantation recipients while scarce information is available about this issue in patients with autoimmune disorders.

Autoimmune diseases have an increased risk of morbidity and mortality linked to the development of neoplasms [41—45]. Which mechanisms underlie this observation is unclear yet, but their knowledge is of outstanding interest to choose a correct therapeutic approach for these disorders. One of the most important target for the next few years is the understanding of the complex relationship between the type and severity of immunosuppression and clonal expansion as well as the link between immunosuppressants and the expression of gene related to cell proliferation, survival and transformation [46],

3.3. CyA in Rheumatoid Arthritis

It is well known that rheumatoid arthritis (RA) is associated with an increased risk of malignancy. In 1978, a large cohort study demonstrated an increased risk of leukemia, lymphoma, and multiple myeloma as well as a significantly increased risk of lung cancer in men, and a lesser risk of stomach and rectal cancer in women [47]. Subsequent studies have generally confirmed the higher incidence of lymphoproliferative and myeloproliferative malignancies in RA. Tennis et al. [48] studied the incidence of malignancy in 1210 patient with RA who resulted as having a 3.4- to 4-fold enhanced risk of developing myeloma or lymphoma. Gridley et al. [49] studied 906 men with a diagnosis of Felty syndrome, and discovered in this group a twofold increase in total cancer incidence and a 12.8fold risk for non-Hodgkin's lymphoma. The etiology of neoplasia in RA is poorly understood, the use of immunosuppressive drugs is believed to play a significant role even if not all RA patient who develop lymphoma are treated with cytotoxic agents. Azathioprine has been reported to be associated with an 8-to 10-fold increased risk of lymphoproliferative malignancies in RA patients. This risk was present also with cyclophosphamide as well as with methotrexate therapy, although for the latter the literature consists predominantly of case reports [50]. Furthermore, the risk of B-cell malignancy linked to immunosuppressive drugs seems to be greater in RA than in other disorders [51],

It has been proved that CyA delays the appearance of new erosions and thus slows the progression of joint damage in RA patients [52], Arellano and Krupp [53] examined more than 1000 RA patients who were treated with CyA in clinical trials. The investigators found the development of tumors in 17 patients; these malignant tumors consisted of 4 skin cancers (2 basal cell carcinomas, 2 malignant melanomas), B-cell lymphoma in 1 patient and a solid tumor in 12 patients (3 breast cancers, 2 lung cancers, 2 colon cancers, 1 carcinoid tumor, 1 cervix carcinoma, 1 glioma, 1 glioblastoma multiforme, 1 prostate carcinoma). All patients except one received daily dose of CyA not exceeding 5 mg/Kg. The estimation of the RR for all types of malignancies amounts to 3.6. Therefore, RA patients treated with CyA are at an increased risk as compared to those who do not receive this treatment, but in the range for patients receiving disease modifying activity rheumatic drugs. The development of EBV-associated lymphoproliferative disorders has been also described in patients with RA treated with CyA [23,24],

3.4. CyA in Systemic Sclerosis

The similarity between progressive systemic sclerosis (PSS) and chronic graft-vs-host disease and a growing body of evidence of T-cell activation in both tissues and blood of PSS patients prompted some trials of CyA for this disorder which have shown, in some cases, a partial improvement of skin manifestation [54-59], In these reports, some of which are isolated or small series of cases, no information are available on the appearance of cancer during or after CyA therapy. On the other hand, an increased risk of malignancy is intrinsically associated with PSS, especially in sites commonly affected by fibrosis like lung and skin [60, 61]. As the standardized incidence ratio (the ratio of observed to expected incidence) for PSS patient is rather high [42] for nonmelanoma skin cancers (i.e., squamous cell cancers) [61] a careful skin examination is advised for those using CyA. In 1990 Merot et al. described the development of cutaneous malignant melanoma in a single patient with systemic sclerosis treated with CyA [62] but, because of the high frequency of this kind of cancer among the general population, it is hard to evaluate CyA contribution to the onset of melanoma in this isolated case.

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