Investigation of the association between 5-HT3A receptor gene polymorphisms and efficiency of antiemetic treatment with 5-HT3 receptor antagonists.
OBJECTIVE
Acute cytostatic drug induced nausea and vomiting is provoked by a release of endogenous serotonin that mediates its effect by binding to the 5-hydroxytryptamine type 3 (5-HT3) receptors. The most effective antiemetic drugs are the 5-HT3 receptor antagonists. Nevertheless about 30% of the patients do not respond satisfactorily. Five 5-HT3 receptor genes (5-HT(3A-E)) with high sequence homology have been identified. Two subunits, the 5-HT3A and 5-HT3B are expressed in anatomical structures known to be involved in the mechanism of acute cytostatic drug induced emesis.


METHODS
We included 242 cancer patients at their first day of chemotherapy to investigate the influence of genetic polymorphisms of the 5-HT3A receptor gene on the intensity of nausea and vomiting which was documented using standardized interviews and visual analog scales.


RESULTS
Sequencing of the entire 5-HT3A receptor gene of all patients revealed 21 polymorphisms, two of them were amino acid substitutions (Ala33Thr, Met257Ile). Linkage disequilibrium analysis revealed that 15 polymorphisms of the 5-HT3A receptor gene are partially linked to each other. However, none of the haplotypes was significantly associated with the intensity of cytostatic induced nausea and vomiting.


CONCLUSIONS
Polymorphisms and haplotype analysis of the 5-HT3A receptor gene may not serve as a pharmacogenetic predictor of the antiemetic treatment with 5-HT3 receptor antagonists in cancer patients.
Kaiser
Rolf
R
Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, D-10098 Berlin, Germany. rolf.kaiser@med.uni-goettingen.de
Tremblay
Pierre-Benoit
PB
Sezer
Orhan
O
Possinger
Kurt
K
Roots
Ivar
I
Brockmöller
Jürgen
J
D000932:Antiemetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D011110:Polymorphism, Genetic; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics*; D012702:Serotonin Antagonists / Q000627:therapeutic use*
D000932:Antiemetics; D000970:Antineoplastic Agents; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists