S100A10 protein expression is associated with oxaliplatin sensitivity in human colorectal cancer cells.

BACKGROUND: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. The objective of our study was to find candidate protein markers for tumor sensitivity to L-OHP from intracellular proteins of human colorectal cancer (CRC) cell lines. We performed expression difference mapping (EDM) analysis of whole cell lysates from 11 human CRC cell lines with different sensitivities to L-OHP by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), and identified a candidate protein by liquid chromatography/mass spectrometry ion trap time-of-flight (LCMS-IT-TOF). RESULTS: Of the qualified mass peaks obtained by EDM analysis, 41 proteins were differentially expressed in 11 human colorectal cancer cell lines. Among these proteins, the peak intensity of 11.1 kDa protein was strongly correlated with the L-OHP sensitivity (50% inhibitory concentrations) (P < 0.001, R2 = 0.80). We identified this protein as Protein S100-A10 (S100A10) by MS/MS ion search using LCMS-IT-TOF. We verified its differential expression and the correlation between S100A10 protein expression levels in drug-untreated CRC cells and their L-OHP sensitivities by Western blot analyses. In addition, S100A10 protein expression levels were not correlated with sensitivity to 5-fluorouracil, suggesting that S100A10 is more specific to L-OHP than to 5-fluorouracil in CRC cells. S100A10 was detected in cell culture supernatant, suggesting secretion out of cells. CONCLUSIONS: By proteomic approaches including SELDI technology, we have demonstrated that intracellular S100A10 protein expression levels in drug-untreated CRC cells differ according to cell lines and are significantly correlated with sensitivity of CRC cells to L-OHP exposure. Our findings provide a new clue to searching predictive markers of the response to L-OHP, suggesting that S100A10 is expected to be one of the candidate protein markers.

[Appropriate hemodialysis scheduling based on therapeutic drug monitoring of carboplatin in a patient with lung cancer and chronic renal failure].

A 69-year-old woman undergoing hemodialysis due to ANCA-associated nephritis and chronic renal failure developed lung adenocarcinoma and underwent radical surgery. Upon recurrence of her cancer, she received combination chemotherapy with carboplatin (CBDCA) 150 mg/m2 and docetaxel 35-70 mg/m2. Concentration of free CBDCA in serum was monitored for 6 days after drug administration. Hemodialysis was performed 1 hour after administration of CBDCA, and on day 4. Despite the lower maximum concentration, serum CBDCA levels 20-24 h after chemotherapy in this patient were 15 to 20 times higher than in subjects with normal renal function who received CBDCA at the area under the curve (AUC) of 5. She experienced moderate to severe nausea and vomiting which persisted for 12 days. During her second course of chemotherapy, hemodialysis was performed for 3 consecutive days after drug administration. The serum CBDCA levels on day 2 or later remained lower than in the first course, and the patient experienced fewer severe side effects. Based on the data from therapeutic drug monitoring of CBDCA, hemodialysis for 3 consecutive days after drug administration has been demonstrated to be useful for treatment of a patient with chronic renal failure receiving chemotherapy with CBDCA.

Novel application of ProteinChip technology exploring acute rejection markers of rat small bowel transplantation.

BACKGROUND: Because no biomarker that reflects small bowel allograft rejection is available, we applied surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to develop noninvasive markers required for routine diagnosis. METHODS: Heterotopic small bowel transplantation (SBT) was performed in rats, and they were divided into four experimental groups: sham-operated rats (sham), syngeneic transplants (syngeneic), allogeneic transplants (allogeneic), allogeneic transplants received FK506 (allo+FK). Plasma samples were analyzed with SELDI ProteinChip arrays to detect peaks that predominated in the allogeneic model. Possible biomarkers were identified in combination with SELDI retentate chromatography mass spectrometry (RCMS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The identified protein was further analyzed by immunohistochemistry. RESULTS: An increase in the level of a 14.8-kDa protein, identified as lysozyme, was observed specifically in the plasma of the allogeneic group; the levels of this protein remained unchanged in the plasma of the other groups. On the other hand, the levels of a 10.1-kDa and a 13.0-kDa protein, identified as migration inhibitory factor-related proteins (MRP), MRP-8 and MRP-14, respectively, began to increase from an early stage of acute rejection. We also observed that lysozyme-positive macrophages had strongly infiltrated the lamina propria during acute rejection. CONCLUSIONS: We identified three plasma proteins-MRP-8, MRP-14, and lysozyme-that increased during small bowel allograft rejection. The identified proteins appeared to be markers for inflammation associated with allograft rejection. This proteomic approach will be useful for the identification of candidate biomarkers.

Cancer pharmacogenomics: international trends.

It is well known that inter-individual variability exists in the responses to many drugs. Many nongenetic factors, such as age, sex, diet, and organ function, are known to affect the therapeutic effects of drugs. However, recent advances in pharmacogenomics have revealed that genetic polymorphisms also significantly influence both the efficacy and the toxicity of drugs. Mutations in the genes encoding drug-metabolizing enzymes, transporters, and target molecules may alter their expression, activity, or affinity to drugs, thereby influencing the drugs' pharmacokinetics and pharmacodynamics. Numerous studies have reported on the correlations between therapeutic outcomes and polymorphisms in drug-metabolizing enzymes, transporters, target molecules, and DNA repair enzymes. These pharmacogenomic discoveries are expected to be useful for the individualization and optimization of cancer chemotherapy.

[Variability in drug response caused by the genetic polymorphisms of receptors].

A greater deal of attention has been given to the genetic polymorphism of receptors and related variability in drug response. In recent years, studies on pharmacogenomics accomplished remarkable progress in this issue. These studies include, the relationships between beta 2-adrenegic receptor polymorphism and the pharmacological effect of blonchodilator, dopamine D2 or 5-HT2 receptor polymorphism and response to antipsychotic medication, vitamin D receptor variants and the active vitamin D therapy, PPAR gamma and the insulin resistance treatment and so on. However, some of them are still controversial, and it requires further investigation to apply these studies to the actual therapy.