Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists.
BACKGROUND
Resistance to antiemetic treatment with 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists is still a major problem resulting in patient discomfort and poor compliance to chemotherapy. We hypothesized that clinical resistance to 5-HT(3) antagonists is associated with the single-nucleotide polymorphism (3435C>T) in the gene that codes for the drug efflux transporter adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1).


METHODS
Patients with cancer (N = 216) treated with chemotherapeutic regimens composed of highly or moderately emetogenic agents were examined for their antiemetic responses to tropisetron, ondansetron, or granisetron. The efficacy of antiemetic treatment was documented by self-report charts for 5 days after chemotherapy. ABCB1 3435C>T genotype was determined to analyze its association with the antiemetic efficacy of 5-HT(3) antagonists.


RESULTS
Within the first 24 hours of chemotherapy, the complete control rate of nausea and vomiting was higher in subjects with the ABCB1 TT genotype (n = 49) as compared with those with the CC (n = 60) or CT (n = 107) genotype (P = .044). The type of 5-HT(3) antagonists influenced the effect of genotype on antiemetic responses. The complete control rates were 92.9% in TT subjects (n = 14) in comparison to homozygote (47.6%, n = 21, P = .009) or heterozygote (56.1%, n = 41, P = .02) carriers of the 3435 C allele in granisetron-treated patients. However, during the delayed phase of chemotherapy, the complete control rates did not differ across genotypes.


CONCLUSIONS
These results suggest that ABCB1 3435C>T polymorphism is associated with antiemetic treatment efficacy in patients with cancer treated with 5-HT(3) antagonists, particularly in granisetron-treated patients, during the short-term phase of chemotherapy.
Babaoglu
Melih O
MO
Department of Pharmacology, Hacettepe University Faculty of Medicine, 06100 Sihhiye, Ankara, Turkey. babaoglu@hacettepe.edu.tr
Bayar
Banu
B
Aynacioglu
A Sukru
AS
Kerb
Reinhold
R
Abali
Huseyin
H
Celik
Ismail
I
Bozkurt
Atila
A
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000932:Antiemetics / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D017829:Granisetron / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control; D009369:Neoplasms / Q000188:drug therapy; D017294:Ondansetron / Q000008:administration & dosage / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000077526:Tropisetron; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
D018528:ATP-Binding Cassette Transporters; D000932:Antiemetics; D017829:Granisetron; D007211:Indoles; D017294:Ondansetron; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D000077526:Tropisetron