Summary
Background Tirapazamine’s (TPZ) tolerability after an intra-arterial (IA) injection remains unclear. We investigated TPZ’s safety and tolerability in rats by first injecting into the left hepatic artery and then performing a hepatic artery ligation, which recapitulates the transarterial embolization used clinically. Research design and methods: Forty-six rats in five groups were respectively injected with 0, 0.25, 0.50, 1.0, or more than 1.5 mL IA of TPZ (0.7 mg/mL) into the left hepatic artery and then subjected to hepatic artery ligation under laparotomy. Blood samples were collected four times daily up to day 15 after which the rats were euthanized and necropsied. The toxicity profile of IA injection of TPZ followed by hepatic artery ligation was then assessed. Results No significant changes to the rats’ body weight and serum total bilirubin were observed. Serum alanine aminotransferase (ALT) levels increased slightly but remained below 100 U/L one day after treatment for most rats. Three rats in Groups 3 and 4 exhibited an over two-fold transient elevation of ALT. All ALT recovered to the baseline at day 14. Liver tissues were collected on day 15 using H&E staining. One rat in Group 3 showed ischemic coagulative necrosis in its liver tissue. Other sporadic pathological changes not related to TPZ doses were observed in Groups 2, 3, 4, and 5. Conclusion TPZ by IA injection followed by embolization is tolerated up to 7 mg/kg. This finding supports the strategy of administering an IA injection of TPZ followed by trans-arterial embolization to the liver.
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Abbreviations
- ALT:
-
alanine aminotransferase
- HBx:
-
Hepatitis B virus X protein
- HCC:
-
Hepatocellular carcinoma
- IA:
-
Intra-arterial
- IV:
-
Intravenous
- MTD:
-
Maximum tolerated dose
- TPZ:
-
Tirapazamine
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Acknowledgements
We thank Dr. Ray Lee for helpful discussion and suggestions, and thank Cheery Pharma Co. Ltd. for providing tirapazamine and funding for the study.
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The work was supported by Cheery Pharma Co. Ltd.
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CHL and SMK conceived and designed research. SMK, HWG, and YJH conducted the experiments. SMK, HWG, and YJH analyzed data. CHL and SMK wrote the manuscript. All authors read and approved the manuscript.
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Figure 1
Changes of creatinine in the 5 groups (Normal range: Male: 0.43-0.68 mg/dL; Female: 0.5-0.7 mg/dL) (PNG 2911 kb)
Figure 2
Changes of glucose in the 5 groups (Normal range: Male: 148.8-231 mg/dL; Female: 141.6-209.8 mg/dL) (PNG 2718 kb)
Figure 3
Changes of potassium in the 5 groups (Normal range: Male: 4-5.2 mmol/L; Female: 3.6-5 mmol/L) (PNG 2983 kb)
Figure 4
Changes of sodium in the 5 groups (Normal range: Male: 139.2-147.8 mmol/L; Female: 139.4-146.8 mmol/L) (PNG 3457 kb)
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Liu, CH., Kuo, SM., Gao, HW. et al. A rat toxicological study of intra-arterial injection of Tirapazamine, a hypoxia-activating Cancer therapeutic agent, followed by hepatic artery ligation. Invest New Drugs 39, 747–755 (2021). https://doi.org/10.1007/s10637-020-01057-3
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DOI: https://doi.org/10.1007/s10637-020-01057-3