Treatment with para-chlorophenylalanine antagonises the emetic response and the serotonin-releasing actions of cisplatin in cancer patients

Alfieri, AB; Cubeddu, LX

doi:10.1038/bjc.1995.123

Cited by 29 publications

(23 citation statements)

References 14 publications

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“…The large number of pharmaceutical agents that block or stimulate 5-HT receptors is indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (De Ponti, 2004). Direct blockade of 5-HT synthesis through inhibition of TPH was also evaluated with a compound called para-chlorophenylalanine (pCPA) in humans (Koe and Weissman, 1966;Engelman et al, 1967;Alfieri and Cubeddu, 1995). The compound proved effective in treating diarrhea in patients with carcinoid syndrome and emesis induced by chemotherapy (Engelman et al, 1967;Alfieri and Cubeddu, 1995).…”

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confidence: 99%

“…Direct blockade of 5-HT synthesis through inhibition of TPH was also evaluated with a compound called para-chlorophenylalanine (pCPA) in humans (Koe and Weissman, 1966;Engelman et al, 1967;Alfieri and Cubeddu, 1995). The compound proved effective in treating diarrhea in patients with carcinoid syndrome and emesis induced by chemotherapy (Engelman et al, 1967;Alfieri and Cubeddu, 1995). However, pCPA treatments have also been linked to depression and other alterations in CNS function (Engelman et al, 1967;Sjoerdsma et al, 1970), precluding the development of this agent for therapeutic use.…”

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confidence: 99%

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Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract

Liu

Yang

Sun

et al. 2008

J Pharmacol Exp Ther

138

136

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5-Hydroxytryptamine (serotonin) (5-HT) is a neurotransmitter with both central and peripheral functions, including the modulation of mood, appetite, hemodynamics, gastrointestinal (GI) sensation, secretion, and motility. Its synthesis is initiated by the enzyme tryptophan hydroxylase (TPH). Two isoforms of TPH have been discovered: TPH1, primarily expressed in the enterochromaffin cells of the gastrointestinal tract, and TPH2, expressed exclusively in neuronal cells. Mice lacking Tph1 contain little to no 5-HT in the blood and GI tract while maintaining normal levels in the brain. Because GI 5-HT is known to play important roles in normal and pathophysiology, we set out to discover and characterize novel compounds that selectively inhibit biosynthesis of GI 5-HT. Here, we describe two of a series of these inhibitors that are potent for TPH activity both in biochemical and cell-based assays. This class of compounds has unique properties with respect to pharmacokinetic and pharmacodynamic effects on GI serotonin production. Similar to the Tph1 knockout results, these TPH inhibitors have the ability to selectively reduce 5-HT levels in the murine GI tract without affecting brain 5-HT levels. In addition, administration of these compounds in a ferret model of chemotherapy-induced emesis caused modest reductions of intestinal serotonin levels and a decreased emetic response. These findings suggest that GI-specific TPH inhibitors may provide novel treatments for various gastrointestinal disorders associated with dysregulation of the GI serotonergic system, such as chemotherapyinduced emesis and irritable bowel syndrome.5-Hydroxytryptamine (serotonin) (5-HT) is a neurotransmitter with both synaptic and paracrine activities that modulates central and peripheral functions through action on neurons, smooth muscle, and other cell types. It is synthesized from tryptophan by the sequential actions of tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase. Only one form of TPH was known to exist until Walther et al. (2003a) published a second distinct TPH-encoding gene. The originally identified isoform was renamed TPH1, and the newly discovered isoform was designated TPH2. The two enzymes share an overall identity of ϳ70%, and they are both ϳ50% identical to the other two members of the aromatic amino acid hydroxylase family, phenylalanine and tyrosine hydroxylases. Tph1 is primarily expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin (EC) cells of the gastrointestinal (GI) tract (Côté et al., 2003;Patel et al., 2004). In contrast, Tph2 is expressed exclusively in neuronal cells, such as the dorsal raphe and myenteric plexus (Côté et al., 2003;Walther et al., 2003a;Patel et al., 2004).5-HT is involved in the control and modulation of multiple physiological and psychological processes. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other Article, publication date, and citation information can be found at

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Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract

Liu

Yang

Sun

et al. 2008

J Pharmacol Exp Ther

138

136

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“…Compound-Mediated Toxicity: pCPA in the Mouse and Rat: pCPA has been studied in the clinic for treatment of carcinoid syndrome (Engelman, Lovenberg, and Sjoerdsma 1967) and as an antiemetic in cancer patients (Alfieri and Cubeddu 1995). Among its dose-limiting effects in animal models is an inhibition of pancreatic secretion (Bieger, Wacker, and Forssmann 1971) and an associated pancreatic toxicity (Furuse et al 1993;Chen et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Early Toxicology Signal Generation in the Mouse

et al. 2010

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The rat has been the preferred rodent toxicology species since before regulatory requirements have been in place, and there exists in the pharmaceutical industry and the regulatory agencies a significant amount of historical data for the rat. The resulting experience base with the rat makes the possibility of replacing it with the mouse for regulated toxicology studies untenable for all but the most extreme circumstances. However, toxicologists are very familiar with the mouse as a model for chronic carcinogenicity studies, and there exist multiple preclinical mouse models of disease. The authors evaluated the use of the mouse for early in vivo toxicology signal generation and prioritization of small molecule lead compounds prior to nomination of a development candidate. In five-day oral gavage studies with three test agents in the mouse, the authors were able to identify the same dose-limiting toxicities as those identified in the rat, including examples of compound-mediated hemolysis as well as microscopic lesions in the alimentary canal, kidney, and pancreas. Performing early signal generation studies in the mouse allows for earlier assessment of the safety liabilities of small molecules, requires significantly less compound, and allows evaluation of more compounds earlier in the project's life cycle.

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“…In response to radiation, serotonin is released from enterochromaffin cells in the gastrointestinal (GI) mucosa. [5][6][7] Serotonin interacts with the 5-HT 3 receptors on vagal afferent neurons and the chemoreceptor trigger zone, which elicits nausea and vomiting. 8 The specific emetogenic potential of TBI is difficult to evaluate because TBI is used often in combination with or after emetogenic chemotherapy and many different TBI regimens are used in clinical practice.…”

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confidence: 99%

Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation

Spitzer

Friedman

Bushnell

et al. 2000

Bone Marrow Transplant

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Summary:The efficacy and safety of granisetron and ondansetron for the prophylaxis of nausea and vomiting resulting from hyperfractionated total body irradiation (TBI) were assessed. Thirty-four patients randomly received double-blind, oral granisetron (2 mg, 1 h before first daily fraction of radiation) or ondansetron (8 mg, 1.5 h prior to each fraction of TBI). Ninety patients who received the same TBI regimen prior to bone marrow transplantation (BMT), but no 5-HT 3 -receptor antagonist, were identified and comprised the historical control group. By design, this study was only powered to show a difference between each of the active treatment groups and the historical control group. Significantly more patients given granisetron (33.3%) or ondansetron (26.7%) had zero emetic episodes over 4 days, the primary efficacy end point, than those in the historical control group (0%) (P Ͻ 0.01; intent-to-treat). Secondary efficacy end points were also evaluated. During the first 24 h, significantly more patients taking granisetron (61.1%) or ondansetron (46.7%) had zero emetic episodes than patients in the historical control group (6.7%) (P Ͻ 0.01). Complete emetic control (no emesis or rescue antiemetic) over 4 days was more frequent in patients taking granisetron (27.8%) or ondansetron (26.7%) compared with the historical control group (0%) (P Ͻ 0.01). Significantly fewer patients taking granisetron (18/18), but not those taking ondansetron (12/15), experienced more than five emetic episodes during the 4 days of the study compared with the historical control group (40/90; P Ͻ 0.01). Oral granisetron and ondansetron are safe and effective for the prevention of nausea and vomiting resulting from TBI. Bone Marrow Transplantation (2000) 26, 203-210.

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Treatment with para-chlorophenylalanine antagonises the emetic response and the serotonin-releasing actions of cisplatin in cancer patients

Abstract: S_q To test the role of serotonin in chemotherapy-induce nausea and emesis, ten cancer patets were pretreated with the seroton synthesis inhibitor para-chlorophenylalanine (PCPA)

Cited by 29 publications

References 14 publications

Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract

Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract

Early Toxicology Signal Generation in the Mouse

Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation

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