RGD Reference Report - Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. - Rat Genome Database

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Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer.

Authors: Han, JY  Lim, HS  Yoo, YK  Shin, ES  Park, YH  Lee, SY  Lee, JE  Lee, DH  Kim, HT  Lee, JS 
Citation: Han JY, etal., Cancer. 2007 Jul 1;110(1):138-47.
RGD ID: 11080964
Pubmed: PMID:17534875   (View Abstract at PubMed)
DOI: DOI:10.1002/cncr.22760   (Journal Full-text)

BACKGROUND: The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and P = .048, [corrected] respectively) and longer progression-free survival (P = .010 and P = .019, [corrected] respectively), which was sustained in haplotype analysis. CONCLUSIONS: Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ABCB1HumanDrug-induced Neutropenia susceptibilityIAGP associated with Carcinoma more ...RGD 
Abcb1aMouseDrug-induced Neutropenia susceptibilityISOABCB1 (Homo sapiens)associated with Carcinoma more ...RGD 
Abcb1aRatDrug-induced Neutropenia susceptibilityISOABCB1 (Homo sapiens)associated with Carcinoma more ...RGD 
ABCB1Humanlung non-small cell carcinoma treatmentIAGP DNA:SNPs: :2677G>T and 3435C>T(human)RGD 
ABCC2Humanlung non-small cell carcinoma treatmentIAGP DNA:SNPs: :-24C>T and 3972C>T(human)RGD 
Abcb1aRatlung non-small cell carcinoma treatmentISOABCB1 (Homo sapiens)DNA:SNPs: :2677G>T and 3435C>T(human)RGD 
Abcb1aMouselung non-small cell carcinoma treatmentISOABCB1 (Homo sapiens)DNA:SNPs: :2677G>T and 3435C>T(human)RGD 
Abcc2Ratlung non-small cell carcinoma treatmentISOABCC2 (Homo sapiens)DNA:SNPs: :-24C>T and 3972C>T(human)RGD 
Abcc2Mouselung non-small cell carcinoma treatmentISOABCC2 (Homo sapiens)DNA:SNPs: :-24C>T and 3972C>T(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)
Abcc2  (ATP binding cassette subfamily C member 2)

Genes (Mus musculus)
Abcb1a  (ATP-binding cassette, sub-family B member 1A)
Abcc2  (ATP-binding cassette, sub-family member 2)

Genes (Homo sapiens)
ABCB1  (ATP binding cassette subfamily B member 1)
ABCC2  (ATP binding cassette subfamily C member 2)


Additional Information