Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney.

Hyoung-Yun Han,Seokjoo Yoon,Sang-Kyum Kim,Mi-Sun Choi,Tae-Won Kim,Je-Won Ko

doi:10.3390/ijms222212201

Abstract

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.

Highlights

Severe multiple organ toxicity was reported in patients who experienced early renal toxicity, and repeated high-dose ifosfamide-induced one organ failure that led to subsequent organ failure [4,5]
Comprehensive ifosfamide toxicity in multiple organs was explored with different doses and exposure terms through the IP route in rats under the GLP
Ifosfamide can exert a bimodal antitumor action with cytotoxic and immunomodulatory effects combined with adoptive immunotherapy [12]

Summary

Introduction

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers, including sarcomas and lymphomas. Ifosfamide is a cell cycle nonspecific anticancer drug that interferes with DNA replication and RNA production [1]. Ifosfamide is relatively well tolerated compared to other toxic alkylating agents, it is known to be associated with numerous life-threatening adverse effects that limit its clinical use [2]. The major side effects of ifosfamide include severe renal injury resulting from reactive toxic species from ifosfamide, including acute kidney injury, interstitial nephritis, hemorrhagic cystitis, and Fanconi syndrome [3]. Severe multiple organ toxicity was reported in patients who experienced early renal toxicity, and repeated high-dose ifosfamide-induced one organ failure that led to subsequent organ failure [4,5]

Methods

Results

Conclusion