Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma.
OBJECTIVE
To evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies.


METHODS
In the basic study, the effect of DFX was investigated in three hepatoma cell lines (HepG2, Hep3B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity (according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced.


RESULTS
Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent mannerin vitro. In the murine model, DFX treatment significantly suppressed the development of liver tumors (P< 0.01), and significantly upregulated the mRNA expression levels of hepcidin (P< 0.05), transferrin receptor 1 (P< 0.05), and hypoxia inducible factor-1α (P< 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%.


CONCLUSIONS
We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Issei
I
Saeki
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Naoki
N
Yamamoto
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Takahiro
T
Yamasaki
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Taro
T
Takami
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Masaki
M
Maeda
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Koichi
K
Fujisawa
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Takuya
T
Iwamoto
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Toshihiko
T
Matsumoto
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Isao
I
Hidaka
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Tsuyoshi
T
Ishikawa
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Koichi
K
Uchida
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Kenji
K
Tani
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
Isao
I
Sakaida
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001565:Benzoates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D000077588:Deferasirox; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D014230:Triazoles / Q000627:therapeutic use*
D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D000077588:Deferasirox
Advanced stage; Deferasirox; Hepatocellular carcinoma; Iron-chelator; Liver tumor