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Antitumor activity of a new orally active organotin compound: a preliminary study in murine tumor models
Federica Barbieri1, Maurizio Viale, Fabio Sparatore
1Laboratory of Pharmacology and Neuroscience, National Institute for Cancer Research, 16132 Genoa, Italy.
Abstract:
The toxicity and antitumor activity of the novel organotin compound triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), administered by the oral route, have been evaluated against three transplantable murine tumor models: P388 lymphocytic leukemia, B16F10 melanoma and 3LL Lewis lung carcinoma. Mild and reversible signs of acute toxicity such as behavioral symptoms, weight loss and histological alterations were mainly reported at the highest single dose of 28 mg/kg. Conversely, lower concentrations of compound ranging from 7 to 21 mg/kg did not result in major toxic effects, even after repeated dosing. The antitumor activity studies showed that fractionation dosing, rather than single bolus administration, over 1 week, might prove more active and better tolerated by allowing the achievement of the highest therapeutic total dose of IST-FS 29 (42 mg/kg). Indeed, repeated administrations of IST-FS 29 resulted in marked significant improvement of antitumor activity against B16F10 (50% of tumor volume inhibition, p = 0.0003) and, to a greater extent, 3LL (90% of tumor volume inhibition, p = 0.0001) tumors. These results indicate that IST-FS 29 might be a suitable candidate as an orally administrable anticancer drug and support its further development in human tumor xenografts.
Insights
The novel organotin compound triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29) shows promise as an oral anticancer drug. It demonstrated significant antitumor activity against melanoma and lung carcinoma in mice with mild toxicity.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Organotin compounds are being explored for their potential therapeutic properties.
- There is a need for novel orally administrable anticancer agents.
Purpose of the Study:
- To evaluate the toxicity and antitumor activity of triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29).
- To assess IST-FS 29 against murine tumor models for potential as an oral anticancer drug.
Main Methods:
- Oral administration of IST-FS 29 in transplantable murine tumor models (P388, B16F10, 3LL).
- Toxicity assessment included behavioral, weight, and histological analyses.
- Antitumor activity was evaluated using fractionated dosing over one week.
Main Results:
- Mild, reversible toxicity observed at high single doses (28 mg/kg).
- Lower doses (7-21 mg/kg) showed minimal toxicity, even with repeated administration.
- Fractionated dosing achieved higher therapeutic doses (42 mg/kg) and enhanced efficacy.
- Significant tumor volume inhibition: 50% for B16F10 melanoma and 90% for 3LL Lewis lung carcinoma.
Conclusions:
- IST-FS 29 exhibits significant antitumor activity against B16F10 and 3LL tumors.
- Fractionated oral administration appears to be a well-tolerated and effective dosing strategy.
- IST-FS 29 is a promising candidate for an orally administrable anticancer drug, warranting further development.