Effects of nitric oxide manipulation on the disposition of platinum in an experimental glioma model

Abstract

Rodents with striatal C6 glioma were given carboplatin (65 mg kg(-1) in a 10 mg ml(-1) solution, i.v.) after pretreatment with the NO modulating agents 3-morpholinosydnonimine (SIN-1), NG-nitro-L-arginine methyl ester (L-NAME), bradykinin or dexamethasone, to determine whether platinum disposition in the glioma and normal brain was altered. There was no significant change in mean glioma platinum disposition after 3 days of dexamethasone (32+/-9.7 microg/g). Treatment with SIN-1 (45.1+/-14.2 microg/g), L-NAME (42.9+/-4.9 microg/g) and bradykinin (45.7+/-11.3 microg/g) all resulted in increased tumour platinum concentration compared with controls (29+/-5.5 microg/g) but these results were not statistically significant. Dexamethasone significantly (p < 0.05) reduced the platinum concentration in normal brain but the other agents had no effect. Although glioma platinum concentration could be increased by some agents that alter tissue NO levels, the patterns of response were unpredictable and the magnitude (approximately 50%) of the increased platinum disposition is unlikely to be biologically significant.

Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system

“…Manipulation of NO can be achieved pharmacologically with NO donors or NOS inhibitors, or genetically such as in iNOS knockout mice . NO inhibition by selective or non‐selective NOS inhibitors can reduce tumour growth and have anti‐angiogenic effects . Moreover, the NOS inhibitor N ‐nitro‐ l ‐arginine (L‐NNA) elicited tumour anti‐vascular effects in a phase I clinical trial .…”

“…15 NO inhibition by selective or nonselective NOS inhibitors can reduce tumour growth and have anti-angiogenic effects. [16][17][18] Moreover, the NOS inhibitor Nnitro-L-arginine (L-NNA) elicited tumour anti-vascular effects in a phase I clinical trial. 19 However, pharmacological NOS inhibition could lead to adverse systemic effects, including hypertension, sinus bradycardia and palpitation.…”