Markers of Emesis Induced by Anti-Cancer Drugs:
Role of Central Mechanisms
by Parvez, S. H. , Minami, M., Caudy, P., Endo, T., Parvez,
S. Hirafuji, M., Hamaue, N., Akita, K., Saito, H., Yoshioka,
M., and Qureshi, G.
Emesis is an instinctive defense reaction caused by the somato-autonomic
nerve reflex, which is integrated in the medulla oblongata.
Neurochemical and neuronal mechanisms involved in the emetic
response and relevant receptors seem to be rather complicated
relative to emetic stimuli. It is well known that dopamine receptor
agonists and L-DOPA are effective drugs for the treatment of
Parkinson's disease. These drugs, however, frequently (approximately
30%) cause nausea and vomiting as unavoidable side effects by
stimulating dopamine receptors in peripheral and brain tissues.
The emetic action of dopamine agonists has generally been assumed
to be mediated by action on dopamme receptors located in the
chemoreceptor trigger zone (CTZ), the tract of the nucleus solitarius
(NTS), or the stomach vagus neurons, and to be well inhibited
by dopamine receptor antagonists such as metoclopramide and
domperidone (Finder et al., 1976; Andrews et al., 1990; Mitchelson,
1992; Andrews and Bhandari, 1993). The emetic effects of talipexole
have appeared to be triggered by stimulation of the above dopamine
receptors, because haloperidol (Hsu et al., 1986) and metoclopramide
dose-dependently .suppress the drug induced vomiting in dogs,
which were the animals with the most vigorous vomiting among
the examined animal species. Talipexole, an azepine-derivative
D2, receptor agonist, showed a greater effectiveness and fewer
emetic side effects when compared with bromocriptine, the most
widely used dopamine receptor agonist (Nakanishi et al., 1993).
Talipexole, in a dose sufficient to produce antiparkinsonian
activity, did not induce emesis to the extent found with bromocriptine
in cynomolgus monkeys (Kohno et al., 1996a). Recently, Nishio
et al. (1996) have found that talipexole has a weak serotonin
5-HT3 receptor blocking effect, while
bromocriptine lacks this effect.
1. A diagram
summarizing the pathways involved in emesis. Rache: Nucleus
Rache, AP: area postrema, IV: 4 th ventricle, 5-HT: 5-hydroxytryptamine
(serotonin), EC: enterochromaffin cell, GI: gastrointestinal.
number of studies indicate that 5-HT and 5-HT3
receptors are involved in the emetic response. Emetic compounds
elevate 5-HT release from intestinal enterochromaffin (EC) cells,
activate 5-HT3 receptors on abdominal
afferent vagal axons, and evoke an abnormal discharge in the
vagal fibers projecting to the area postrema, which in turn
cause the vomiting reflex by releasing 5-HT and stimulating
5-HT3 receptors in the area postrema (Fig.
1) (Andrews et al., 1990; Mitchelson, 1992; Andrews and Bhandari,
Emesis, a distress side effects of cancer chemotherapy, may
lead to a patient's refusal of therapy. We have previously reported
that cisplatin and copper sulfate increase abdominal afferent
vagal activity in a time course parallel to retching and vomiting
in ferrets (Endo et al., 1995), and the administration of 5-HT3
receptor antagonist suppress both vagal activity and emesis.
This chapter will discuss the identification of emesis as an
unavoidable side effect induced by centrally acting drugs and
anti-cancer drugs. This review may be summarized as follows:
1) Cytotoxic drugs or centrally acting emetic drugs have an
initial action within the gut that results in histological changes,
activation of the biosynthesis of 5-HT, and an increase in the
concentration of 5-HT in the gastrointestinal tract. 2) The
5-HT is released from the EC cells of the intestinal mucosa,
which in rurn stimulates 5- HT3 receptors
on the vagal afferent nerve fibers. 3) This stimulation of vagal
afferent fibers results in an increase in 5-HT in the vomiting
center rather than a direct action of emetic drugs at this level
and leads to emesis. 4) The 5-HT in circulation trapped by platelets
is metabolized to 5-hydroxyindole acetic acid (5-HIAA) in the
liver and 5-HIAA is excreted in the urine.