Abstract 4950

Methotrexate (MTX), a folic acid antagonist, is widely used as a treatment for malignancies as well as in the treatment of various inflammatory and autoimmune disorders. Nephrotoxicity is an important side-effect of this drug. Prevention and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, Pentoxifylline(PTX) is an anti-inflammatory and anti-oxidant agent and we hypothesized that pentoxifylline may affords renal protection by down regulating TNF-α as well as by improving cellular anti-oxidant activity.

Forty five male wistar rats were assigned to 3 groups of 15 animals each: Group 1: control group (0.9% saline). Group 2: MTX; injected with 20mg/kg MTX intra peritoneal. Group 3: MTX+PA; injected intraperitoneally (i.p.) MTX (20 mg/kg) + PTX (50mg/kg) intraperitoneally. PTX was administered since 3 days before MTX administration and continued for 6 days. After 6 days rats were anesthetized and serum sampled and renal tissue removed for biochemical and histological evaluation.

Data showed that glutathione peroxidase (GPx), superoxide dismutase (SOD)activities were lower in PTX+NTX group comparing to MTX group significantly(p<0.05). Renal tissue injury index and percent of TUNEL positive cells, renal tissue malondialdehyde (MDA) levels and plasma BUN(Blood Urea Nitrogen) and creatinine (Cr) and Tumor necrosis factor- Alpha(TNF-α) levels were higher in MTX group comparing to MTX+PTX group significantly (p<0.05).

In conclusions, it has been suggested that PTX may be a promising drug against MTX-induced renal damage and oxidative renal stress. Further studies are warranted to define the exact mechanism of the protecting effect of PTX on MTX-induced nephrotoxicity and the optimum dosage of this compound. In addition, these data indicate that the activities of GPX and SOD enzymes content in rat kidneys may play a role in the pathogenesis of MTX-damage. In our study, the increased level of tissue MDA and serum TNF-α level together may be suggested that the underlying mechanism is related to direct toxicity of MTX rather than blockage in folate synthesis in rat kidneys. PTX administration also attenuated renal tissue injury and number of apoptic cells and suppressed elevation of BUN and Cr levels; however, further studies are essential to elucidate the exact mechanisms of MTX-induced renal toxicity, and protection and the effect of PTX.

Disclosures:

Kermani: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Employment, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hajipour: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Kermani: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Ahmadi Asl: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Roshanghar: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Khodadadi: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding.

Topics:
methotrexate, nephrotoxicity, blood urea nitrogen, tumor necrosis factors, antioxidants, pentoxifylline, toxic effect, adverse effects, anti-inflammatory agents, autoimmune diseases

Author notes

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Asterisk with author names denotes non-ASH members.

© 2010 by The American Society of Hematology
2010
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