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Published on: August 25, 2019
Norcantharidin toxicity profile: an in vivo murine study
Gabriel Martínez-Razo1, María Lilia Domínguez-López2, José M de la Rosa3
1Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Laboratorio de Toxicología Ambiental, Unidad Profesional Zacatenco, Av. Wilfrido Massieu s/n, CP 07738, Mexico City, Mexico.
Abstract:
Norcantharidin (NCTD) is the demethylated analog of cantharidin, with allegedly reduced toxicity. However, there is still limited information regarding its posology and potential risk in its use in cancer treatment. Healthy BDF1 mice were intraperitoneally administered with norcantharidin (0, 3, 6, 12, and 25 mg/kg) every 24 h for 6 days. Survivor mice were euthanized, and the brain, lungs, kidneys, spleen, and liver were procured for enzymatic and histopathological analysis in the liver and kidney. DL50 were 8.86 mg/kg for females and 11.77 mg/kg for males. The treatments with 3.0 mg/kg and 6.0 mg/kg significantly modified the phosphorylase, alanine transaminase, and γ-glutamyl transferase activities; however, an organ-specific response was detected. A significant dose-dependent decrease was observed in the kidney for ROS, while the liver had the opposite effect. Histopathological analysis revealed a significant elevation in hepatocytes' nuclei average size and total area (3 mg/kg), as well as centrilobular vein and adjacent sinusoidal capillaries showed a significant difference. The portal triad presented a significant difference in veins and capillarity count in 6 mg/kg. Renal samples showed cortex convoluted tubules' average size significantly augmented in both doses' groups, and tubule count was found augmented in 6 mg/kg. These physiological effects of NCTD can be exploited as treatment strategies if able to operate in an established posology and proper testing.
Insights
Norcantharidin (NCTD) exhibits organ-specific toxicity in mice, affecting liver enzymes and kidney structures. Establishing a safe dosage is crucial for its potential use in cancer treatment.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- Norcantharidin (NCTD), a demethylated analog of cantharidin, is proposed for cancer treatment due to potentially lower toxicity.
- Limited data exists on NCTD's posology and associated risks, necessitating further investigation.
Purpose of the Study:
- To evaluate the toxicity and physiological effects of Norcantharidin (NCTD) in a mouse model.
- To determine the median lethal dose (DL50) and assess organ-specific responses to NCTD administration.
Main Methods:
- Intraperitoneal administration of varying NCTD doses (0-25 mg/kg) to BDF1 mice over six days.
- Enzymatic and histopathological analyses of liver and kidney tissues from surviving mice.
- Determination of DL50 for both male and female mice.
Main Results:
- DL50 values were 8.86 mg/kg (females) and 11.77 mg/kg (males).
- NCTD (3 and 6 mg/kg) altered liver enzyme activities (phosphorylase, alanine transaminase, γ-glutamyl transferase) and induced organ-specific changes.
- Dose-dependent effects observed: decreased reactive oxygen species (ROS) in kidneys, increased ROS in the liver.
- Histopathology revealed enlarged hepatocytes, altered liver vasculature, and augmented renal tubules.
Conclusions:
- NCTD demonstrates significant, dose-dependent, and organ-specific physiological effects in mice.
- These findings highlight the need for precise posology and further testing to mitigate risks.
- Understanding NCTD's toxicological profile is essential for its potential therapeutic application in cancer treatment.
