Systemic promoting action and leukemogenesis in SWR mice by phorbol and structurally related polyfunctional...

Area of Science:

• Toxicology
• Carcinogenesis
• Pharmacology

Background:

• Phorbol and related polyfunctional diterpenes are known for their biological activities.
• Understanding their carcinogenic and promoting potential is crucial for risk assessment.

Purpose of the Study:

• To evaluate the systemic promoting and leukemogenic activities of phorbol and related diterpenes in SWR mice.
• To investigate the influence of dimethylnitrosamine (DMN) initiation on these activities.

Main Methods:

• Systemic initiation using subcutaneous dimethylnitrosamine (DMN) in SWR mice.
• Intraperitoneal administration of phorbol and six related diterpenes, with or without prior DMN initiation.
• Assessment of liver adenoma induction (systemic promotion) and leukemogenesis.

Main Results:

• All tested diterpenes induced liver adenomas, indicating systemic promoting activity, with some being more potent than phorbol.
• Phorbol confirmed its leukemogenic effect in SWR mice; other diterpenes showed no significant leukemogenic activity.
• Prior DMN injection completely inhibited the leukemogenic action of phorbol.

Conclusions:

• The study demonstrates varied systemic promoting and leukemogenic potentials among tested diterpenes.
• A lack of correlation was observed between skin-promoting, systemic liver-promoting, and leukemogenic actions.
• DMN initiation significantly modulates the leukemogenic effects of phorbol.