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Blood flow failure as a major determinant in the antitumor action of flavone acetic acid
L J Zwi1, B C Baguley, J B Gavin
1Department of Pathology, University of Auckland School of Medicine, New Zealand.
Abstract:
Some investigators have suggested that the marked activity of flavone acetic acid (FAA) against advanced solid tumors in mice results from an indirect effect. This study indicates that the critical effect of FAA is irreversible inhibition of tumor blood flow. Perfusion of sc Colon 38 tumors, assessed with H33342 as a fluorescent stain for functional blood vessels, was reduced to 50% of controls within 3 hours of an ip injection of 1.2 mmol of FAA/kg and was completely inhibited by 24 hours. A double-label fluorescence technique demonstrated a significant decrease in blood flow in both sc Colon 38 and im EMT-6/Ak tumors as early as 15 minutes after iv treatment with 1.2 mmol of FAA/kg, with progressively enlarging zones of perfusion failure. The rate of cell death in totally ischemic EMT-6 tumors was shown to be sufficiently rapid to represent a major component of the observed antitumor effect of FAA if the flavonoid acts via inhibition of blood flow. Further, avascular EMT-6/Ak multicellular spheroids growing in the mouse peritoneum are relatively resistant to killing by FAA administered iv or ip, despite extensive infiltration with host immune cells. These results indicate that inhibition of tumor blood flow by FAA is a necessary component of its antitumor activity against solid tumors.
Insights
Flavone acetic acid (FAA) irreversibly inhibits tumor blood flow, leading to tumor cell death. This crucial effect explains FAA's anti-cancer activity against solid tumors in mice.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- The anti-tumor activity of flavone acetic acid (FAA) against advanced solid tumors in mice has been observed.
- Previous hypotheses suggested indirect mechanisms for FAA's efficacy.
Purpose of the Study:
- To investigate the critical mechanism underlying the anti-tumor activity of flavone acetic acid (FAA).
- To determine if FAA's effect is primarily due to the inhibition of tumor blood flow.
Main Methods:
- Assessing tumor perfusion using H33342 fluorescent stain in sc Colon 38 tumors after FAA injection.
- Employing a double-label fluorescence technique to evaluate blood flow changes in sc Colon 38 and im EMT-6/Ak tumors post-treatment.
- Comparing the sensitivity of avascular EMT-6/Ak multicellular spheroids to FAA treatment.
Main Results:
- FAA administration (ip or iv) significantly reduced tumor blood flow in a time-dependent manner.
- Complete inhibition of tumor perfusion was observed within 24 hours of FAA treatment.
- Avascular tumor spheroids showed relative resistance to FAA, suggesting a role for blood flow disruption.
Conclusions:
- The primary anti-tumor effect of flavone acetic acid (FAA) against solid tumors in mice is the irreversible inhibition of tumor blood flow.
- FAA-induced tumor ischemia contributes significantly to tumor cell death and overall anti-cancer activity.
- Targeting tumor vasculature with FAA is a key component of its therapeutic action.