for those trying IT herceptin for leptomeningeal or brain mets--important article

[Lani]

even though this was done on rodents rather than humans, the oncologists involved in this might want to review this article and gather information on
ROS and nitric oxide concentrations in blood as well as blood pressure.

The her2 antagonist was given intracisteral rather than via an LP, but the results may be similar I would suppose as CSF circulates in continuity between the brain cisterns and areas bathing the spinal cord, particularly when mets may make the lining of the spinal cord or brain (pia, dura, theca) more permeable/discontinuous.

Since this doesn't seem to have been a problem so far, measuring these parameters may be a way to convince other MDs that it is safe. And if hypertension develops it may give them an indication of which way to go to treat it.

In this study the erbb2 antagonist given was not herceptin (probably too expensive) so it might indicate that IT herceptins effects may be due to ADCC rather than occupying the her2 receptor and causing endocytosis and downregulation of the receptor(s) or other proposed mechanisms. If so, that would be good to know, as it might alter ideas about dosage and frequency of administration as well as alter ideas as to what combinations of IT treatments might be optimal.

The entire article is open access.

Hope this helps!

Am J Hypertens. 2013 Jan;26(1):51-7. doi: 10.1093/ajh/hps005. Epub 2012 Dec 13.
Inhibition of Neuregulin-1/ErbB Signaling in the Rostral Ventrolateral Medulla Leads to Hypertension through Reduced Nitric Oxide Synthesis.
Matsukawa R, Hirooka Y, Ito K, Sunagawa K.
Source
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan;
Abstract
BACKGROUND We recently reported that activation of neuregulin-1 (NRG-1)/ErbB signaling in the rostral ventrolateral medulla (RVLM) of the brainstem elicits sympathoinhibition and depressor effects, and ErbB2-type ErbB receptors are involved in the neurogenic mechanisms of hypertension. Nitric oxide (NO) in the RVLM also elicits sympathoinhibition and depressor effects. NRG-1 enhances NO synthase (NOS) expression in several tissues. Here, we tested the hypothesis that ErbB2 inhibition in the RVLM contributes to increasing blood pressure via modulating the effects of NOS. METHODS We measured the effects of chronic intracisternal infusion of an ErbB2 antagonist and local ErbB2 inhibition in the RVLM using RNA interference (ErbB2 siRNA) on blood pressure (BP), heart rate (HR), norepinephrine excretion (uNE), and NOS expression in the RVLM. The central effects of the ErbB2 antagonist or NRG-1β were investigated with or without chronic and acute prior administration of a NOS inhibitor. RESULTS Intracisternal infusion of the ErbB2 antagonist and ErbB2 siRNA increased BP, HR, and uNE; and reduced neuronal and endothelial NOS expression in the RVLM. Further, prior systemic administration of a NOS inhibitor abolished the pressor response to intracisternal infusion of an ErbB2 antagonist in awake rats. Prior injection of a NOS inhibitor or γ-aminobutyric acid-A receptor antagonist into the RVLM attenuated the depressor response to NRG-1 in anesthetized rats. CONCLUSIONS These findings indicate that inhibition of ErbB2 expression in the RVLM leads to hypertension, at least in part, by reducing NO synthesis and inhibiting γ-aminobutyric acid activity. NRG-1/ErbB signaling in the RVLM might exist upstream of NO synthesis.
PMID: 23382327