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Published on: March 24, 2017
Determinants of anti-vascular action by combretastatin A-4 phosphate: role of nitric oxide
C S Parkins1, A L Holder, S A Hill
1Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR, UK.
Abstract:
The anti-vascular action of the tubulin binding agent combretastatin A-4 phosphate (CA-4-P) has been quantified in two types of murine tumour, the breast adenocarcinoma CaNT and the round cell sarcoma SaS. The functional vascular volume, assessed using a fluorescent carbocyanine dye, was significantly reduced at 18 h after CA-4-P treatment in both tumour types, although the degree of reduction was very different in the two tumours. The SaS tumour, which has a higher nitric oxide synthase (NOS) activity than the CaNT tumour, showed approximately 10-fold greater resistance to vascular damage by CA-4-P. This is consistent with our previous findings, which showed that NO exerts a protective action against this drug. Simultaneous administration of CA-4-P with a NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA), resulted in enhanced vascular damage and cytotoxicity in both tumour types. Administration of diethylamine NO, an NO donor, conferred protection against the vascular damaging effects. Following treatment with CA-4-P, neutrophil infiltration into the tumours, measured by myeloperoxidase (MPO) activity, was significantly increased. Levels of MPO activity also correlated with the levels of vascular injury and cytotoxicity measured in both tumour types. Neutrophilic MPO generates free radicals and may therefore contribute to the vascular damage associated with CA-4-P treatment. MPO activity was significantly increased in the presence of L-NNA, suggesting that the protective effect of NO against CA-4-P-induced vascular injury may be, at least partially, mediated by limiting neutrophil infiltration. The data are consistent with the hypothesis that neutrophil action contributes to vascular injury by CA-4-P and that NO generation acts to protect the tumour vasculature against CA4-P-induced injury. The protective effect of NO is probably associated with an anti-neutrophil action.
Insights
Combretastatin A-4 phosphate (CA-4-P) causes vascular damage in tumors, but nitric oxide (NO) protects against this effect. Inhibiting NO enhances CA-4-P
Area of Science:
- Oncology
- Pharmacology
- Vascular Biology
Background:
- Combretastatin A-4 phosphate (CA-4-P) is a tubulin-binding agent with anti-vascular properties.
- Tumor vascular function and response to CA-4-P can vary significantly between tumor types.
- Nitric oxide (NO) has been implicated in modulating the response to anti-vascular agents.
Purpose of the Study:
- To quantify the anti-vascular action of CA-4-P in two distinct murine tumor models (CaNT adenocarcinoma and SaS sarcoma).
- To investigate the role of nitric oxide synthase (NOS) activity in mediating resistance or sensitivity to CA-4-P.
- To explore the combined effects of CA-4-P with NOS inhibitors and NO donors on tumor vascular damage and cytotoxicity.
Main Methods:
- Assessment of functional vascular volume using fluorescent carbocyanine dye.
- Quantification of nitric oxide synthase (NOS) activity in tumor tissues.
- Administration of CA-4-P alone, with a NOS inhibitor (N(omega)-nitro-L-arginine, L-NNA), or with an NO donor (diethylamine NO).
- Measurement of neutrophil infiltration using myeloperoxidase (MPO) activity.
Main Results:
- CA-4-P significantly reduced functional vascular volume in both CaNT and SaS tumors, with SaS tumors showing greater resistance.
- Higher NOS activity in SaS tumors correlated with increased resistance to CA-4-P's vascular damaging effects.
- Simultaneous administration of CA-4-P and L-NNA enhanced vascular damage and cytotoxicity in both tumor types.
- NO donor administration protected against CA-4-P-induced vascular damage.
- Neutrophil infiltration (MPO activity) increased after CA-4-P treatment and correlated with vascular injury and cytotoxicity.
- L-NNA treatment increased MPO activity, suggesting NO limits neutrophil infiltration.
Conclusions:
- Nitric oxide (NO) exerts a protective effect against the vascular damaging action of CA-4-P, potentially by inhibiting neutrophil infiltration.
- Tumor NOS activity influences sensitivity to CA-4-P, with higher activity conferring resistance.
- Neutrophil myeloperoxidase (MPO) activity contributes to CA-4-P-induced vascular injury.
- Combined strategies involving CA-4-P and NOS inhibition may enhance anti-tumor vascular effects.
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