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Variations in the 5-Hydroxytryptamine Type 3B Receptor Gene as Predictors of the Efficacy of Antiemetic Treatment in Cancer Patients

Pierre-Benoit Tremblay, Rolf Kaiser, Orhan Sezer, Nadja Rösler, Claudia Schelenz, Kurt Possinger, Ivar Roots, Jürgen Brockmöller

From the Institute of Clinical Pharmacology and Department of Hematology and Oncology, University Medical Center Charité, Humboldt University of Berlin, Berlin; and Department of Clinical Pharmacology, University Medical Center of the Georg-August-University Göttingen, Göttingen, Germany.

Address reprint requests to Rolf Kaiser, MD, Abteilung für Klinische Pharmakologie, Universitätsklinikum der Georg-August Universität Göttingen, Robert Koch Str 40, D-37075 Göttingen; email: rolf.kaiser{at}med.uni-goettingen.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Serotonin (5-hydroxytryptamine type 3 [5-HT₃]) receptor antagonists have substantially reduced but not eliminated nausea and vomiting in patients undergoing cancer chemotherapy. They act through specific binding to the 5-HT_3A, 5-HT_3B receptor complex. The 5-HT_3B subunit seems to be most important for its functionality. We hypothesized that patients with genetic variations in the 5-HT_3B receptor gene might respond differently to antiemetic treatment.

Patients and Methods: We included 242 cancer patients on their first day of chemotherapy. Nausea and vomiting were documented before and twice during the chemotherapy using standardized interviews and visual analog scales. We sequenced the entire 5-HT_3B receptor gene, including the 5` flanking region and at least a 20–base pair intronic sequence of each intron-exon splice site of all patients.

Results: Approximately 30% of all patients suffered from nausea or vomiting. Sequencing of the 5-HT_3B receptor gene revealed 13 polymorphisms: two of them were amino acid exchanges (Tyr129Ser, Ala223Thr) and two were deletion variants. In both observation periods, patients homozygous for the -100_-102delAAG deletion variant of the promotor region experienced vomiting more frequently than did all the other patients.

Conclusion: A more efficient antiemetic treatment with 5-HT₃ receptor antagonists might be possible on a pharmacogenetic basis. However, only a small fraction of the therapeutic failure is explained by the -AAG deletion variant of the 5-HT_3B receptor gene. Additional clinical and biochemical studies are needed to confirm the association.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
NAUSEA AND vomiting remain problematic side effects of cytostatic cancer therapy and may even influence the success of the individual cancer therapy.¹ Three forms of vomiting or nausea induced by cancer chemotherapy can be distinguished: the acute emesis within the first 24 hours, delayed emesis after the first 24 hours up to 6 days, and the anticipatory type.² Specifically, acute emesis seems to be provoked by serotonin release and the consecutive activation of 5-hydroxytryptamine type 3 (5-HT₃) receptors on peripheral vagal fibers and central structures such as the area postrema and nucleus tractus solitarii.^3–5

The introduction of 5-HT₃ receptor antagonists such as ondansetron, tropisetron, granisetron, or dolasetron into the current family of antiemetic treatments resulted in significant therapeutic improvement of acute emesis compared with earlier medications.^6–8 However, approximately 20% to 30% of the patients still do not respond satisfactorily to 5-HT₃ receptor antagonists.^5,9

The 5-HT₃ receptor antagonists bind specifically to the 5-HT₃ receptor. This receptor belongs to the family of ligand-gated ion channels, which becomes permeable to monovalent cations such as Na⁺ and K⁺ after activation.^10,11 Two subunits of the 5-HT₃ receptor, the 5-HT_3A and 5-HT_3B subunits, have been identified and, in addition, two splice variants of the 5-HT_3A receptor have been identified.^12–16 The 5-HT_3B receptor gene resides on the long arm of chromosome 11 at band 23.1, has nine exons coding for 441-amino acid residues, and spans at least 55 kb of contiguous genomic sequence.¹⁴

The 5-HT₃ receptor channel itself is an oligomeric complex of five of these subunits.^17,18 It has not been definitely clarified whether the 5-HT₃ receptor is homo- or heteropentameric in its native state.¹⁹ The in vitro expression of a homopentameric 5-HT_3A receptor leads to a functional ion channel, which displays—in contrast to neuronal 5-HT₃ receptors—only a low single-channel conductance.²⁰ However, heteropentameric 5-HT₃ receptors, which are composed of both subunits, assemble to functional 5-HT–gated channels with a similar high single-channel conductance, low permeability to calcium ions, and current voltage relationship as the native 5-HT₃ channel.^14,15 The 5-HT_3A and 5-HT_3B receptor subunits have been detected in anatomic structures that seem to be involved in chemotherapy-induced nausea, such as the area postrema, amygdala, hippocampus, and the small intestine and colon.^14,15

Our hypothesis was that acute vomiting may be explained by polymorphisms in the 5-HT_3B receptor gene, resulting in differential effects of endogenous serotonin or of the 5-HT₃ receptor antagonists. Therefore, we sequenced the 5-HT_3B receptor gene in a representative sample of patients treated with ondansetron or tropisetron within the first 24 hours after chemotherapy. If there would be an association between functional 5-HT_3B receptor gene polymorphisms and antiemetic efficacy, 5-HT_3B receptor genotyping before the chemotherapy is started might provide a substantial improvement in supportive cancer care.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
We conducted a prospective, noninterventional cohort study to analyze the impact of genetic polymorphisms on the antiemetic efficacy of the 5-HT₃ receptor antagonists tropisetron and ondansetron. From April 1998 to September 2000, 286 adult cancer patients scheduled to receive moderately to highly emetogenic chemotherapy either for the first time or for the first course of a chemotherapy after relapse were enrolled onto the study. For the analysis of the 5-HT_3B receptor gene, we included 242 patients (105 male patients, 137 female patients, 145 outpatients, and 97 inpatients) at the Universitätsklinikum Charité, Berlin, Germany, and the community hospital Krankenhaus Moabit, Berlin, Germany. Mean patient age was 53.3 years (range, 18 to 83 years; SD = 13.6). Of these patients, 32.0% suffered from breast cancer, 16.0% from lung cancer, 15.1% from non-Hodgkin’s lymphoma, 5.5% from Hodgkin’s disease, 4.6% from multiple myeloma, 4.1% from ovarian carcinoma, and 22.7% from miscellaneous other malignancies.

Patients who met one of the following criteria were excluded from participation: presence of nausea or vomiting within 24 hours before chemotherapy; the use of antiemetics, benzodiazepines, or neuroleptics or the application of radiation therapy within 24 hours before start of chemotherapy; use of opioids within the last 2 weeks; or use of inducers of cytochrome P450 3A4 (CYP3A4; eg, rifampcin) or inhibitors of CYP2D6 (eg, quinidine, fluoxetine, and haloperidol) that might modify the pharmacokinetics of the 5-HT₃ receptor antagonists. We also excluded all patients with concomitant diseases that might cause nausea or vomiting (eg, severe heart failure, ulcerations or obstructions of the upper gastrointestinal system, severe hepatic or renal dysfunction, and brain metastases), as well as patients with artificial stoma or pregnant patients.

From 286 patients primarily enrolled onto the study, 16 patients had to be excluded later for predefined reasons; for example, administration of antiemetics other than ondansetron or tropisetron, missing antiemetic drug treatment at day 1 of the chemotherapy regimen, or failure to complete all questionnaires. For 28 patients, the amount of DNA was insufficient to perform sequencing of the whole gene. Thus DNA sequencing analysis of the 5-HT_3B receptor gene could be performed in 242 patients. Nine patients delivered incomplete data; therefore, efficacy of the antiemetic treatment could be analyzed for 233 patients.

The emetogenic level of the chemotherapy was classified according to the scheme of Hesketh et al^21,22 (level 1, n = 1; level 2, n = 50; level 3, n = 17; level 4, n = 83; level 5, n = 91). Cyclophosphamide was administered to 91 patients (mean dosage, 1,554 mg) either alone or in combination with various other cytostatic drugs. Cisplatin (mean dosage, 88 mg) and carboplatin (mean dosage, 424 mg) were given to 25 patients and 27 patients, respectively. The other patients (n = 99) received miscellaneous chemotherapeutic drugs. Glucocorticoids were administered to 141 patients either as a part of the antineoplastic therapy or as an additional antiemetic treatment.

Tropisetron (Navoban; Novartis, Basel, Switzerland) was given in a dosage of 5 mg once daily (n = 84), and ondansetron (Zofran; GlaxoSmithKline, Brentford, United Kingdom) was administered in a dosage of 8 mg twice daily (n = 158). The measurements of nausea and vomiting were performed immediately before administration of the chemotherapeutic agents, 4 hours after administration of chemotherapy (observation period 1), and then within the next 20 hours (5th to 24th hour, observation period 2) on day 1 of chemotherapy administration. The timing within the first 24 hours and number of retching and vomiting episodes were recorded by the patients on diary cards. The intensity of nausea was assessed with visual analog scales, which ranged from no nausea at 0 mm to most extensive nausea at 100 mm. An emetic episode was defined as a single vomit or retch or any number of continuous vomits or retches. Vomiting or retching episodes had to be absent for at least 1 minute to calculate different episodes of emesis.²³ Protection from nausea was regarded as incomplete when any emetic episodes occurred or when nausea intensity was 20% above the baseline level. The study was approved by the ethics committee of the Universitätsklinikum Charité (Humboldt-Universität zu Berlin), and all patients gave written informed consent.

Sequencing of the 5-HT_3B Receptor Gene
High-molecular-weight genomic DNA was prepared from venous blood using the standard phenol chloroform extraction. All laboratory staff members were blinded to the clinical observations. All sequencing analysis was performed with polymerase chain reaction (PCR) from genomic DNA amplification reactions. As shown in Fig 1, we first amplified exons 1 to 2, exons 3 to 6, and exons 7 to 9 separately. Reactions were performed in a total volume of 25 µL, containing 100 ng of DNA, 200 µmol/L deoxynucleoside triphosphate, 1 µmol/L of each primer, 10X buffer, and 2.8 units Taq-Pwo-mix DNA polymerases (Expand Long Template PCR system; Roche, Mannheim, Germany) using a GenAmp 9600 PCR machine (Applied Biosystems, Foster City, CA). The applied primers are listed in Table 1, and cycling conditions were as follows: for exons 1 to 2, primers 1.1 and 2.2, 10X buffer 2, initial denaturation at 94°C for 2 minutes, followed by 35 cycles at 94°C for 30 seconds, at 55°C for 20 seconds, at 72°C for 5 minutes, and a final extension period at 72°C for 7 minutes; for exons 3 to 6, primers 3.1 and 6.2, 10X buffer 2, initial denaturation at 94°C for 2 minutes, followed by 35 cycles at 94°C for 30 seconds, at 51°C for 20 seconds, at 72°C for 4 minutes, and a final extension period at 72°C for 7 minutes; and for exons 7 to 9, primers 7.1 and 9.2, 10X buffer 1, initial denaturation at 94°C for 2 minutes, followed by 10 cycles at 96°C for 10 seconds, at 63°C - 1°C/cycle for 20 seconds, at 68°C for 6 minutes, followed by 30 cycles at 96°C for 10 seconds, at 53°C for 20 seconds, at 68°C for 6 minutes, and a final extension period at 68°C for 7 minutes.

View larger version (17K): [in this window] [in a new window]   Fig 1. Genomic structure, sequencing strategy, and polymorphisms found of the 5-HT3B receptor gene. Exons 1 to 9 are represented by boxes. Coding sequence is shadowed. Transmembrane domains (TM 1 to 4) are indicated by black boxes. All polymorphisms are indicated with their respective genomic localization.

CYP2D6 genotyping was carried out as published previously.^9,24 By definition, poor metabolizers (PM) are carriers of two of the alleles *3, *4, *5, and *6 of CYP2D6; intermediate metabolizers have one active allele *1 (wild type); extensive metabolizers have two active alleles *1 or one defective allele and one duplication allele; and ultrarapid metabolizers have one active allele *1 and one duplication allele or even two duplication alleles.

Statistical Methods
Statistical analysis was performed with SPSS (Version 10; SPSS, Inc, Chicago, IL). Significance of frequency differences of the different genotypes was assessed by Pearson’s ² test or, if any cell count was less than five, by Fisher’s exact test. The limit of significance was set to .05. The mean number of vomiting episodes and the mean degree of nausea were compared with the Kruskal-Wallis test, which corresponds to the Mann-Whitney U test in the cases of two groups. Considering the small number in some groups, the exact and not the asymptomatic P value of the Mann-Whitney U test was calculated. Logistic regression analysis was carried out with vomiting as a dependent variable and age, sex, genotypes of CYP2D6, genotypes of the deletion variant of the 5-HT3B receptor gene, and treatment with glucocorticoids as independent variables.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A total of 242 unrelated subjects were screened for genomic DNA polymorphisms of the 5-HT_3B receptor gene by sequencing of the protein coding exons including the exon-intron junctions. This revealed an extensive genetic variation in the 5-HT_3B gene (Fig 1, Table 2). A total of 13 polymorphisms were found and confirmed by repeated analysis. Frequencies of these variations ranged from 0.4% to 47.6%. Two amino acid exchanges were located in exon five (Tyr129Ser) and in exon six (Ala223Thr). Moreover, a 3–base pair deletion variant in the promoter region (-100_-120delAAG deletion) and a 2–base pair deletion in intron 5 were found. The 26946A>G and the 27721_27722delCA insertion-deletion polymorphism were particularly frequent, with an allele frequency of the rare allele of 0.4. The Tyr129Ser polymorphism had a respective frequency of 0.3, the 28232A>G of 0.2, and the -100_-102AAG deletion allele of 0.1. In contrast, the variations Ala154Ala and Ala223Thr were less frequent and were not found in any subject in the homozygous combination.

As illustrated in Fig 2 and Tables 3 and 4, patients homozygous for the -100_-102AAG deletion variant showed significantly more episodes of vomiting than all other patients in the first observation period (mean value of episodes of vomiting of 1.0; SEM, 0.58 v 0.23; SEM, 0.07; P < .02; exact Mann-Whitney U test, two-sided). However, this was not significant after Bonferroni adjustment for multiple testing (13 polymorphisms tested). The same association could be observed in the second observation period (mean value of episodes of vomiting of 4.0; SEM, 2.3 v 0.83; SEM, 0.2; P < .04; exact Mann-Whitney U test, two-sided). The validity of this finding was supported by a gene-dose effect; that is, the intensity of vomiting of heterozygous carriers of the deletion variant was in between the intensity of vomiting observed in the homozygous mutant and the wild-type carriers. Mean number of episodes of vomiting over the entire observation period of 24 hours after chemotherapy administration is shown in Figure 3.

View larger version (19K): [in this window] [in a new window]   Fig 2. Mean number of episodes of vomiting with SEM in both observation periods after administration of chemotherapy as a function of the genotypes of the -100_-102AAG deletion variant. Abbreviations: wt, wild type; del, deletion; VAS, visual analogue scale.

View larger version (13K): [in this window] [in a new window]   Fig 3. Mean number of episodes of vomiting with SEM over the whole observation period of 24 hours after administration of chemotherapy.

The -100_-102AAG deletion variant effects were carefully scrutinized for possible confounding by genotypes of the drug metabolizing enzyme CYP2D6, antiemetic comedication, and the emetogenic level of the chemotherapy. CYP2D6 is a major enzyme metabolizing ondansetron and tropisetron. As shown in Table 5, the unsatisfactory antiemetic treatment in patients homozygous for the deletion variant of the 5-HT_3B receptor gene was not due to the CYP2D6 genotypes: independent of the genotype of the 5-HT_3B variant, extensive metabolizers for CYP2D6 with three active genes had the highest score of vomiting and nausea. In addition, patients with only one active gene for CYP2D6, who were not at higher risk for vomiting because of rapid metabolic elimination of the antiemetics,⁹ also suffered from higher intensities of vomiting and nausea if they were homozygous for the deletion variant.

A logistic regression analysis for the first observation period was performed with any occurrence of vomiting versus no occurrence of vomiting as the dependent variable and age, sex, glucocorticoid treatment, genotypes of the CYP2D6 enzyme, and the 5-HT_3B receptor gene as explanatory variables. This analysis confirmed the effects of both polymorphisms (Table 6).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Our results indicate that antiemetic treatment may be improved by identification of nonresponders on a pharmacogenetic basis. Patients homozygous for the -100_-102AAG deletion variant of the promotor region had the highest score of vomiting and nausea, whereas patients having the wild type showed the lowest score. Our prospective investigation was, however, an exploratory approach that requires confirmation in additional studies. However, this variant is not just any single nucleotide polymorphism but rather a deletion of several nucleotides within the promotor, which has a higher a priori likelihood to be functionally relevant than a single nucleotide polymorphism. Moreover, the -AAG polymorphism was linked with an amino acid exchange in the coding region, and the observations were also supported by patients who were heterozygous for the deletion variant with a frequency of approximately 20% in our sample. As shown in Table 3, the mean number of vomiting episodes of these patients was situated in between the mean number of vomiting of patients homozygous for the insertion variant or homozygous for the deletion variant.

To date, there are no in vitro data about the functional effects of the variations in the 5-HT_3B receptor gene. Moreover, although knowledge exists that the 5-HT_3B subunit seems to be a major determinant of serotonin receptor function, it has not yet been clarified which extent and kind of interaction exists between these two subunits in the pentameric structure of the native 5-HT₃ receptor.¹⁴ Therefore, we can only speculate about the functional impact of the -100_-102AGG deletion variant of the promotor region, which might affect the expression levels of the B subunit either by itself or, alternatively, because of linkage disequilibrium with other yet unknown functional variants.

In our analysis, we divided the observation period of acute emesis into two periods. As already illustrated in one of the first efficacy studies on 5-HT₃ receptor antagonists, the maximum peak of vomiting preventable by these drugs was at 4 hours.²⁵ Thus, differentiation into two periods might be more specific for 5-HT₃ receptor–mediated effects. In addition, the half-life of ondansetron is approximately 3 to 5 hours, and this may correspond roughly to the duration of drug action. Finally, in the later period, any genotype effect may be covered more than in the first period by additional individual dose adjustments according to the individual response to the antiemetic treatment. Indeed, the analysis of the efficacy of the antiemetic treatment for the whole 24 hours showed the same trend; however, the statistical significance was not as high as for the first observation period (P < .04).

In a previous study analyzing the relationship between the metabolizing enzyme CYP2D6 of 5-HT₃ receptor antagonists and the efficiency of the antiemetic treatment, ultrarapid metabolizers for CYP2D6 had the highest score of vomiting and nausea, whereas poor metabolizers showed the lowest score and significantly higher tropisetron blood concentrations.⁹ The effect observed in patients homozygous for the -100_-102AGG deletion variant was not the result of an extreme metabolizer status that led to an inefficient blood concentration of the antiemetic drug; all of the patients were classified as intermediate metabolizers.

Because of the low frequency (1.5% to 2%) of genetically defined ultrarapid metabolizers and of the homozygous -100_-102delAAG deletion polymorphism (1.3%), it would be necessary to genotype at least approximately 30 patients for CYP2D6 and the 5-HT_3B receptor variant to prevent one case of severe vomiting.

In conclusion, patients homozygous for the -100_-102AGG deletion variant of the 5-HT_3B receptor gene and ultrarapid metabolizers of ondansetron or tropisetron showed the highest intensity of vomiting and nausea after cancer chemotherapy when ondansetron or tropisetron were given as antiemetic treatment. In these patients, a different antiemetic approach may be helpful. However, frequency of the variant was low, thus our preliminary data regarding the medical effect of the -100_-102AAG deletion variant must be confirmed by additional clinical trials with larger sample sizes and by biochemical studies.

	ACKNOWLEDGMENTS

 
We thank all patients participating in this study. We thank Dr M. Schweigert, Dr E. Späth-Schwalbe, Dr A. Johne, A. Flögel, E. Pohling, and Th. Fiedler for their contribution to the clinical data collection and data management. Moreover, we thank Dr G. Laschinski for the careful revision of the manuscript. We express our appreciation to Prof Dr H. Hellriegel for supporting this study in his department.

	NOTES

 
Supported by the German Ministry for Education and Research, grant nos. 01EC9408 and 01ZZ9511, and the German Ministry for Research and Technology, Bonn, Germany, grant no. 01GG9845/5.

Pierre-Benoit Tremblay and Rolf Kaiser contributed equally to this work.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Stewart DJ: Cancer therapy, vomiting, and antiemetics. Can J Physiol Pharmacol 68:304–313, 1990[Medline]

2. Andrews PL, Davis CJ: The mechanism of emesis induced by anti-cancer therapies, in Andrews PL SG (ed): Emesis in Anti-Cancer Therapy. London, England, Chapman and Hall, 1993, pp 113–161

3. Tyers MB, Freeman AJ: Mechanism of the anti-emetic activity of 5-HT3 receptor antagonists. Oncology 49:263–268, 1992[CrossRef][Medline]

4. Miller AD, Leslie RA: The area postrema and vomiting. Front Neuroendocrinol 15:301–320, 1994[CrossRef][Medline]

5. Gregory RE, Ettinger DS: 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting: A comparison of their pharmacology and clinical efficacy. Drugs 55:173–189, 1998[CrossRef][Medline]

6. Cunningham D, Hawthorn J, Pople A, et al: Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist. Lancet 1:1461–1463, 1987[Medline]

7. Jantunen IT, Kataja VV, Muhonen TT: An overview of randomised studies comparing 5-HT3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting. Eur J Cancer 33:66–74, 1997[CrossRef][Medline]

8. Gralla RJ, Osoba D, Kris MG, et al: Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines—American Society of Clinical Oncology. J Clin Oncol 17:2971–2994, 1999[Free Full Text]

9. Kaiser R, Sezer O, Papies A, et al: Patient-tailored antiemetic treatment with 5-HT3 receptor antagonists according to CYP2D6 genotypes. J Clin Oncol 20:2805–2811, 2002[Abstract/Free Full Text]

10. Maricq AV, Peterson AS, Brake AJ, et al: Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254:432–437, 1991[Abstract/Free Full Text]

11. Jackson MB, Yakel JL: The 5-HT3 receptor channel. Annu Rev Physiol 57:447–468, 1995[CrossRef][Medline]

12. Miyake A, Mochizuki S, Takemoto Y, et al: Molecular cloning of human 5-hydroxytryptamine 3 receptor: Heterogeneity in distribution and function among species. Mol Pharmacol 48:407–416, 1995[Abstract]

13. Belelli D, Balcarek JM, Hope AG, et al: Cloning and functional expression of a human 5-hydroxytryptamine type 3AS receptor subunit. Mol Pharmacol 48:1054–1062, 1995[Abstract]

14. Davies PA, Pistis M, Hanna MC, et al: The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 397:359–363, 1999[CrossRef][Medline]

15. Dubin AE, Huvar R, D’Andrea MR, et al: The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit. J Biol Chem 274:30799–30810, 1999[Abstract/Free Full Text]

16. Bruss M, Göthert M, Hayer M, et al: Molecular cloning of alternatively spliced human 5-HT3 receptor cDNAs. Ann N Y Acad Sci 861:234–235, 1998[CrossRef][Medline]

17. Boess FG, Martin IL: Molecular biology of 5-HT receptors. Neuropharmacology 33:275–317, 1994[CrossRef][Medline]

18. Boess FG, Beroukhim R, Martin IL: Ultrastructure of the 5-hydroxytryptamine 3 receptor. J Neurochem 64:1401–1405, 1995[Medline]

19. Bruss M, Barann M, Hayer-Zillgen M, et al: Modified 5-HT3A receptor function by co-expression of alternatively spliced human 5-HT3A receptor isoforms. Naunyn Schmiedebergs Arch Pharmacol 362:392–401, 2000[CrossRef][Medline]

20. Fletcher S, Barnes NM: Desperately seeking subunits: Are native 5-HT3 receptors really homomeric complexes? Trends Pharmacol Sci 19:212–215, 1998[CrossRef][Medline]

21. Hesketh PJ, Kris MG, Grunberg SM, et al: Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 15:103–109, 1997[Abstract/Free Full Text]

22. Hesketh PJ: Defining the emetogenicity of cancer chemotherapy regimens: Relevance to clinical practice. Oncologist 4:191–196, 1999[Abstract/Free Full Text]

23. Italian Group for Antiemetic Research: Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis: Italian Group for Antiemetic Research. J Clin Oncol 16:2937–2942, 1998[Abstract/Free Full Text]

24. Sachse C, Brockmöller J, Bauer S, et al: Cytochrome P450 2D6 variants in a Caucasian population: Allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295, 1997[Medline]

25. Brown GW, Paes D, Bryson J, et al: The effectiveness of a single intravenous dose of ondansetron. Oncology 49:273–278, 1992[Medline]

Submitted May 23, 2002; accepted February 24, 2003.

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