Analysis of gene mutations and clastogenicity following short-term treatment with azathioprine in Muta?Mouse

Smith, Catherine C.; Archer, Graeme; Forster, Emma J.; Lambert, T.; Rees, Robert W.; Lynch, Anthony M.

doi:10.1002/(sici)1098-2280(1999)34:2/3<131::aid-em12>3.0.co;2-k

Cited by 24 publications

(8 citation statements)

References 35 publications

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“…This suggests a causative role for long-term pharmacological immunosuppression. Azathioprine, a mutagen in mice (Smith et al , 1999), is designated a human carcinogen by the IARC (IARC, 1987). Its potential carcinogenicity is particularly important for organ transplant patients who may require decades-long immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation

Brem

Montaner

et al. 2010

Oncogene

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The frequency of squamous cell skin carcinoma in organ transplant patients is around 100-fold higher than normal. This dramatic example of therapy-related cancer reflects exposure to sunlight and to immunosuppressive drugs. Here we demonstrate that the interaction between low doses of UVA, the major ultraviolet component of incident sunlight, and 6-TG, a UVA chromophore that is introduced into DNA by one of the most widely-prescribed immunosuppressive drugs, causes DNA single- and double strand breaks (DSB). S phase cells are particularly vulnerable to this DNA breakage and cells defective in rejoining of S-phase DSB are hypersensitive to the combination of low dose UVA and DNA 6-TG. 6-TG/UVA-induced DNA lesions provoke canonical DNA damage responses involving activation of the ATM/Chk2 and ATR/Chk1 pathways and appropriate cell cycle checkpoints. Higher levels of photochemical DNA damage induce a proteasome-mediated degradation of Chk1 and checkpoint abrogation that is consistent with persistent unrepaired DNA damage. These findings indicate that the interaction between UVA and an immunosuppressant drug causes photochemical DNA lesions, including DNA breaks, and can compromise cell cycle checkpoints. These two properties could contribute to the high risk of sunlight-related skin cancer in long-term immunosuppressed patients.

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Section: Discussionmentioning

confidence: 99%

DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation

Brem

Montaner

et al. 2010

Oncogene

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“…(1973), AZA was given (100 mg/kg s.c.) to male and female 7‐week‐old C57BL mice twice a week for 2 weeks and then once a week for 7 months. Smith et al. (1999) used the transgenic lacZ mouse (males; age 4–6 weeks); animals were dosed with AZA at 10, 50 and 100 mg/kg p.o.…”

Section: Discussionmentioning

confidence: 99%

The haemotoxicity of azathioprine in repeat dose studies in the female CD‐1 mouse

Molyneux

Gibson

Chen

et al. 2008

Int J Experimental Path

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Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.

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“…For a malignancy to occur, the nascent clone must continue to accumulate transformed phenotypes so as to include the ability to invade, disseminate, and escape destruction outside its native milieu (ie, in the interstitial space, the lymphatic system, or the blood stream). Genotoxic carcinogens, for example, azathioprine 90 can mediate all 3 steps.…”

Section: Chemical Co-carcinogenesismentioning

confidence: 99%

Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia

Bugelski¹,

Volk²,

Walker³

et al. 2010

Int J Toxicol

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Many immunosuppressive drugs are associated with an increased risk of B-cell lymphoma, squamous cell carcinoma, and Kaposi sarcoma. Thirteen immunosuppressive drugs have been tested in 2-year carcinogenicity studies (abatacept; azathioprine; busulfan; cyclophosphamide; cyclosporine; dexamethasone; everolimus; leflunomide; methotrexate; mycophenolate mofetil; prednisone; sirolimus; and tacrolimus) and in additional models including neonatal and genetically modified mice; chemical, viral, ultraviolet, and ionizing radiation co-carcinogenesis, and in models with transplanted tumor cells. The purpose of this review is to outline the mechanisms by which immunosuppressive drugs can influence neoplasia, to summarize the available preclinical data on the 13 drugs, and to critically review the performance of the models. A combination of primary tumor and metastasis assays conducted with transplanted cells may provide the highest value for hazard identification and can be applied on a case-by-case basis. However, for both small molecules and therapeutic proteins, determining the relative risk to patients from preclinical data remains problematic. Classifying immunosuppressive drugs based on their mechanism of action and hazard identification from preclinical studies and a prospective pharmacovigilance program to monitor carcinogenic risk may be a feasible way to manage patient safety during the clinical development program and postmarketing.

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Analysis of gene mutations and clastogenicity following short-term treatment with azathioprine in Muta?Mouse

Cited by 24 publications

References 35 publications

DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation

DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation

The haemotoxicity of azathioprine in repeat dose studies in the female CD‐1 mouse

Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia

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