MDR1 single nucleotide polymorphisms predict response to vinorelbine-based chemotherapy in patients with non-small cell lung cancer.
BACKGROUND
The polymorphisms of genes participate in metabolism and transport, and therefore may have an impact on the response to vinorelbine.


OBJECTIVE
To investigate whether genotypes of CYP3A5, MDR1 and cyclooxygenase-2 (COX-2) are associated with the response to vinorelbine in non-small cell lung cancers (NSCLC).


METHODS
We determined the genotypes of CYP3A5(*3), MDR1 (2677G-->T at exon 21 and 3435C-->T at exon 26 and their haplotypes) and COX-2 (-1195G-->A) polymorphisms by PCR-RFLP and chemotherapy response in 69 Chinese Han patients with NSCLC who received a combination chemotherapy of vinorelbine-cisplatin (VC). The chi(2) test was used to investigate potential associations between genotypes and response to chemotherapy. Odds ratios and 95% confidence intervals were calculated.


RESULTS
The 3435 CC genotype was associated with a significantly better chemotherapy response compared with the combined 3435 CT and TT genotypes (p = 0.025). The 2677 GG genotype was also associated with a better chemotherapy response compared with the combined 2677 GT and TT genotype, although it was not statistically significant. Moreover, we analyzed the haplotypes of MDR1 3435-2677: patients harboring the 2677G-3435C haplotype had a statistically significantly better response to chemotherapy compared with those with the other haplotypes combined (p = 0.015). CYP3A5*3 is not likely to correlate with sensitivity to vinorelbine in NSCLC. COX-2 (-1195G) is likely to result in a better response to vinorelbine (nonsignificant).


CONCLUSIONS
Our findings suggest that MDR1 2677G-->T/A and 3435C-->T polymorphisms can be used to predict treatment response to VC chemotherapy in NSCLC patients.
Pan
Ji-hong
JH
Key Laboratory, Ministry of Public Health, Biotech-Drugs, Shandong Medicinal and Biotechnology Center, Shandong Academy of Medical Sciences, Jinan, China. pjh933@yahoo.com.cn
Han
Jin-xiang
JX
Wu
Jian-mei
JM
Sheng
Li-jun
LJ
Huang
Hai-nan
HN
Yu
Qing-zhong
QZ
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014747:Vinblastine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077235:Vinorelbine
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D002945:Cisplatin; D000077235:Vinorelbine