Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Abstract

Purpose:The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability.We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats. Experimental Design:The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and L-arginine. BTB permeability, defined by the unidirectional transport constant, K i , for [ 14 C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, L-citrulline, and cGMP in the tumor and normal brain tissue were measured. Results: Oral administration of L-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (K Ca ) channel that is a cGMP pathway effector.The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, L-citrulline, a byproduct of NO formation from L-arginine, and cGMP were enhanced in the tumor tissue by oral administration of L-arginine and/ or hydroxyurea. Conclusions: Oral administration of L-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.

Headache in essential thrombocythaemia

“…Given that patients with myeloproliferative neoplasms may have reduced plasma NO, increased NO levels resulting from HC treatment may result in vasodilation and may contribute to headache symptoms in these patients. Indeed, there is evidence from animal models that NO from HC affects cerebral vascular permeability (44). …”

Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells

“…The limitation in efficacy and safety underscores the urgent need to understand the biology of drug accumulation in cancer tissues and development of novel drug delivery strategies. It has been previously demonstrated that pharmacological modulation of a cyclic guanosine monophosphate (cGMP) pathway, which involves bradykinin (BK) (1–3), nitric oxide (NO) (4–6), cGMP (7, 8), and potassium channel agonists (9–11), can selectively increase delivery of compounds, including chemotherapeutic drugs, to brain tumors.…”

“…However, both BK and RMP-7 have a short disposition half-life in the body and cause the side-effect of hypotension (5, 13), which make their clinical use difficult. NO donor compounds, such as L-arginine and hydroxyurea, and potassium channel (K Ca and K ATP ) agonists, such as NS1619, NS1851, minoxidil sulfate, and diazoxide, are also capable of increasing brain tumor permeability for drugs (6, 9–11, 14), although their ability to enhance chemotherapeutic efficacy remains to be determined. PDE5 inhibitors, which increase intracellular cGMP levels via their inhibition on cGMP-specific PDE5 (15, 16), may be effective pharmacological modulators in the cGMP pathway.…”

K + Channels as Therapeutic Targets in Oncology

“…Since a competent BTB precludes the access of chemotherapeutic agents to the target tissue, an increase in permeability can improve the efficacy of drugs in the CNS. Such an effect has been observed with treatment with nitric oxide donors [122] and dexamethasone [123]; in both cases, a concomitant increased K Ca 1.1 activity has been reported. In fact, the channel activator NS-1619 co-infusion with temozolomide and trastuzumab resulted in enhanced drug delivery to brain tumor cells [124] future science group on proliferation, pharmacological inhibition of the channel led to conflicting results probably depending on tumor type; in some cases, it impaired proliferation [125,126] but in others it had no effect [29,127,128].…”