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Small-molecule cytokine inducers causing tumor necrosis
1Auckland Cancer Society Research Centre, The University of Auckland, New Zealand. b.baguley@auckland.ac.nz
Abstract:
The capillary networks of solid tumors are more permeable and less well organized than those of normal tissue. This review explores the hypothesis that these differences might be exploited as a selective antitumor strategy. Both high and low molecular weight compounds have been found to induce cytokines such as tumor necrosis factor (TNF) and to inhibit tumor blood flow in experimental tumors, with consequent induction of necrosis. Flavone acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are of particular interest. Accumulating evidence implicates the enzyme IkappaB kinase, which leads to the activation of the transcription factor, NFkappaB, as a target for these drugs. The downstream effects of FAA and DMXAA on the tumor microcirculation are complex, involving both direct and indirect effects on vascular endothelial cells. Induced changes in the shape and organization of vascular endothelial cells may lead to the activation of blood platelets and the release of 5-HT. Cytokines, 5-HT and nitric oxide (NO) released in response to FAA and DMXAA may induce a sustained increase in the permeability of tumor vascular cells, leading to cessation of blood flow and induction of tumor necrosis. Exploitation of this principle to clinical anticancer therapy represents an important challenge for the future.
Insights
Tumor blood vessels, altered by compounds like flavone acetic acid (FAA), can be targeted to inhibit blood flow and induce tumor necrosis. This strategy offers a potential selective antitumor approach by exploiting unique tumor vascular characteristics.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Tumor capillaries exhibit increased permeability and disorganization compared to normal tissue vasculature.
- These unique characteristics of tumor vasculature present a potential target for selective anticancer therapies.
Purpose of the Study:
- To explore the hypothesis that exploiting differences in tumor vasculature could serve as a selective antitumor strategy.
- To review the mechanisms by which certain compounds affect tumor blood flow and induce necrosis.
Main Methods:
- Review of existing literature on compounds affecting tumor microcirculation.
- Analysis of the molecular pathways involved, including IkappaB kinase and NFkappaB.
- Examination of the effects of compounds like flavone acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on tumor vascular endothelial cells.
Main Results:
- High and low molecular weight compounds can induce cytokines (e.g., tumor necrosis factor) and inhibit blood flow in experimental tumors, leading to necrosis.
- FAA and DMXAA are identified as key compounds, implicating IkappaB kinase and NFkappaB activation.
- These agents induce complex changes in tumor vascular endothelial cells, platelet activation, and release of mediators like 5-HT, ultimately increasing vascular permeability and halting blood flow.
Conclusions:
- The unique permeability of tumor vasculature can be exploited for selective antitumor effects.
- Compounds like FAA and DMXAA trigger a cascade of events leading to tumor necrosis via microcirculatory disruption.
- Further development is needed to translate this principle into effective clinical anticancer therapies.