Lung cancer was the leading cause of cancer death in men and the second leading cause in women worldwide in 2008. Although lung cancer incidence is slowly decreasing in developed countries, the number of lung cancer cases is still increasing in China and other developing countries . Over 75% of all lung cancer cases are NSCLC, which include adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma . Common treatments for NSCLC include surgery, chemotherapy, radiation therapy, and palliative care depending on the cancer type, stage, and other factors. Primary chemotherapy is also given for advanced and metastatic NSCLC. A combination of platinum chemotherapy compounds (cisplatin or carboplatin) with gemcitabine, vinorelbine, or taxanes (paclitaxel or docetaxel) is a widely used regimen for first-line treatment of stage IIIB or IV NSCLC . However, there is no standard regimen for local recurrence of NSCLC. In 2006, the National Comprehensive Cancer Network recommended pemetrexed as a single agent for second-line treatment of advanced NSCLC .
Pemetrexed is an antifolate drug that inhibits growth of a variety of tumor types by targeting the folate-dependent enzymes dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and thymidylate synthase (TS); but is most potent on TS [4, 5]. To date, three large phase III clinical trials have provided strong evidence for use of pemetrexed in control of NSCLC [5–8]. The data also showed that tumor histology was able to predict the sensitivity of pemetrexed therapy in lung cancer, and that expression of TS mRNA and TS protein differed between squamous cell lung cancer or NSCLC and lung adenocarcinoma . However, patients with similar histotype and disease stage might respond very differently to identical treatments, which suggests that TS genotypes contribute to these patients’ sensitivity to chemotherapeutic drugs. Therefore, clinical studies have begun to focus on developing personalized treatments based on both histotype and genotype to improve the efficacy of chemotherapy.
Indeed, it has been reported that the expression of TS was induced in various cancers, including gastric, colorectal, breast, and bladder cancers, compared with corresponding normal tissues [6, 7]. Functionally, TS generates thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair. TS is localized on chromosome 18, covering 16 kb, and with 7 exons that translates into a 72-kD protein and functions as a homodimer. A previous study showed that a 6-bp variation at 1494 bp of the TS 3'-UTR was associated with TS mRNA stability and reduced TS protein expression . Other studies showed that this polymorphism also affected sensitivity to anti-cancer drugs and prognoses of breast and gastrointestinal cancers [6, 9–11].
In the present study, we first detected expression of TS mRNA and TS protein in NSCLC tissue specimens, and then determined the genotype at the TS 3'-UTR at 1494del in 106 lung adenocarcinoma patients to investigate its association with sensitivity to pemetrexed.