Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients.
OBJECTIVE
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-HT3A, 5-HT3B receptor complex. The 5-HT3B subunit seems to be most important for its functionality. We hypothesized that patients with genetic variations in the 5-HT3B receptor gene might respond differently to antiemetic treatment.


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-HT3B 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-HT3B 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.


CONCLUSIONS
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-HT3B receptor gene. Additional clinical and biochemical studies are needed to confirm the association.
Tremblay
Pierre-Benoit
PB
Institute of Clinical Pharmacology and Department of Hematology and Oncology, University Medical Center Charité, Humboldt University of Berlin, Berlin, Germany.
Kaiser
Rolf
R
Sezer
Orhan
O
Rosler
Nadja
N
Schelenz
Claudia
C
Possinger
Kurt
K
Roots
Ivar
I
Brockmoller
Jurgen
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects; D005260:Female; D017353:Gene Deletion; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017294:Ondansetron / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics*; D018709:Statistics, Nonparametric; D000077526:Tropisetron; D014839:Vomiting / Q000139:chemically induced / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control*
D000932:Antiemetics; D000970:Antineoplastic Agents; D007211:Indoles; D011985:Receptors, Serotonin; D017294:Ondansetron; D000077526:Tropisetron