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Selective blood-tumor barrier disruption by leukotrienes
1Brain Research Institute, Jonsson Cancer Center, University of California Medical Center, Los Angeles.
Journal of Neurosurgery
|September 1, 1992
Summary
Leukotriene C4 selectively increases blood-tumor barrier permeability in RG-2 tumors in rats. Leukotriene E4 demonstrated the highest potency in increasing this permeability.
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- Previous research indicated leukotriene C4 (LTC4) selectively increases blood-tumor barrier (BTB) permeability in rat RG-2 tumors.
- This study further investigates the dose-dependent effects and duration of LTC4 on BTB permeability.
Purpose of the Study:
- To determine the dose-response relationship of intracarotid LTC4 infusions on BTB permeability.
- To assess the duration of increased BTB permeability following LTC4 administration.
- To compare the potency of various sulfidopeptide leukotrienes in altering BTB permeability.
Main Methods:
- Rats with RG-2 tumors received intracarotid infusions of LTC4 at varying concentrations (0.5–50.0 µg).
- Blood-tumor and blood-brain barrier permeability were quantified using 14C-aminoisobutyric acid and quantitative autoradiography to measure the transfer constant (Ki).
- The duration of increased permeability was assessed at 15, 30, and 60 minutes post-infusion. Potency of different leukotrienes (LTC4, LTD4, LTE4, LTF4) was compared.
Main Results:
- LTC4 doses of 2.5, 5.0, and 50.0 µg significantly increased tumor Ki twofold compared to vehicle control (p < 0.01).
- No significant increase in tumor permeability was observed at 0.5 µg LTC4.
- Increased BTB permeability was selective to the tumor; normal brain permeability was unaffected at any dose.
- Permeability remained elevated at 15 minutes post-infusion but decreased by 30 and 60 minutes.
- Leukotriene E4 (LTE4) was the most potent, increasing permeability 3.5-fold compared to vehicle control.
Conclusions:
- Intracarotid LTC4 selectively increases BTB permeability in RG-2 tumors in a dose-dependent manner.
- The effect of LTC4 on BTB permeability is transient, with significant reduction observed within 30-60 minutes post-infusion.
- LTE4 is more potent than other tested sulfidopeptide leukotrienes in increasing BTB permeability, suggesting potential therapeutic applications for drug delivery.