Somatic mutations in epidermal growth factor receptor underlying complete responsiveness to gefitinib in a Taiwanese female patient with metastatic adenocarcinoma of lung.

A 61-year-old never-smoker female suffered from adenocarcinoma of the lung with chest wall invasion and peri-adrenal lymph node metastases. After palliative resection of all clinically detectable primary and metastatic adenocarcinoma, she received cisplatin and gemcitabine combination chemotherapy for a total of 3 cycles. New metastatic lesions were found in spleen and para-aortic lymph nodes. Her tumor tissue was subjected to mutation analysis for epidermal growth factor receptor (EGFR) and had been shown to have a T-->G missense mutation in nucleotide 2819 of EGFR full-length cDNA (accession no. NM_005228.3), within exon 21 of the EGFR gene, resulting in amino acid substitutions from leucine to arginine at codon 858 (L858R) as expected. She received oral gefitinib 250 mg/day after mutation analysis. She had a very good tumor response with more than 90% tumor reduction shown by abdominal computed tomographic scan, normalization of previously elevated carcinoembryonic antigen level, and complete resolution of previous uptake signals in spleen and para-aortic lymph nodes shown by positron emission tomographic scan. She has been kept in clinical complete remission for 11+ months after the initiation of gefitinib treatment. Our patient supports the proposition that somatic mutation L858R in exon 21 of the EGFR gene accounts for complete responsiveness to gefitinib in a Taiwanese female patient with metastatic adenocarcinoma of lung.

Down-regulation of thymidylate synthase expression and its steady-state mRNA by oxaliplatin in colon cancer cells.

Recently, evidence has accumulated that weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) with leucovorin (LV, folinic acid) biochemical modulation may improve the response rates compared with the bolus 5-FU regimens in colorectal cancer (CRC). Combining the infusional 5-FU/LV (iFL) regimens with oxaliplatin or irinotecan is widely adopted to further improve treatment efficacy. Either oxaliplatin-iFL or irinotecan-iFL may achieve an overall response rate of more than 50% in the first-line treatment. Intriguingly, in the salvage treatment for metastatic CRC patients who had failed iFL, only oxaliplatin-iFL may achieve a response rate of about 13-25%. In contrast, oxaliplatin alone or irinotecan-iFL had a very low response rate of 5% or less. To test if the oxaliplatin may reverse the iFL-related 5-FU resistance in CRC, we used DLD-1 colon adenocarcinoma cells as the in vitro study model. First, we revealed that oxaliplatin and 5-FU act synergistically on DLD-1 cells by MTT cytotoxicity assay and median drug effect analysis. Second, we treated the DLD-1 cells with serial concentrations of oxaliplatin (0.1-10 microM). Oxaliplatin treatment results in down-regulation of free thymidylate synthase (TS) protein expression by Western blotting. Further, we analyzed the TS mRNA level by reverse transcription and real-time quantitative polymerase chain reaction assay. Oxaliplatin treatment results in down-regulation of the TS mRNA level up to 40% (mean +/- SD of ratio to reference control = 0.60 +/- 0.21, range 0.42-0.84). In this study, our data provide important information explaining the reason why the combination of oxaliplatin and 5-FU results in a better objective response in 5-FU-resistant patients than oxaliplatin alone does. Our data also suggest that TS down-regulation happens at the transcriptional level. TS modulation and down-regulation had, thus, shed light on the useful potential strategy to achieve objective responses in 5-FU-resistant CRC patients.