Takahiko Oyama

Prediction of anti-tumour effect of thermochemotherapy with in vitro thermochemosensitivity testing for non-small cell lung cancer

Purpose: We investigated whether it is possible to predict the antitumour effects of thermochemotherapy from the results of anticancer agent sensitivity testing. Materials and Methods: We produced a nude mouse cancer model using 4 lung cancer cell lines. Animals were divided into 4 groups: Thermotherapy (HT group), chemotherapy (CT group), thermochemotherapy (HT+CT group), and no therapy (NT group). Comparison of in vivo and in vitro effects were performed using cisplatin (CDDP), doxorubicin (ADR) and vinorelbine (NVB). In vivo thermotherapy was performed using the Thermotron RF IV, and radiofrequency (RF) capacitative hyperthermia device that induces a localised temperature of 42.0°C for 45 min. The collagen gel embedded culture drug sensitivity test (CD-DST) was used for in vitro chemosensitivity analysis of the anticancer agents. In vitro thermochemotherapy was performed using a modified CD-DST method, with the incubator set at 42.0° for the first hour of the 24 hours drug exposure period. Results: A good correlation was seen between in vivo and in vitro treated/control ratios (T/C%) in the HT group (R = 0.91, p = 0.09). Good correlations were also seen between in vivo and in vitro T/C in all cell lines in the CT group (R = 0.759, p = 0.09) and the HT+CT group (R = 0.65, p = 0.02). True positive rate was 87.5% (7/8), and true negative rate was 100% (4/4). Sensitivity, specificity and accuracy were 100% (7/7), 80% (4/5), and 91.7% (11/12) respectively. Conclusion: A modified CD-DST using an exposure temperature of 42°C can be used to predict the antitumour effect of thermochemotherapy.

Intratumoral gene expression of 5-fluorouracil pharmacokinetics-related enzymes in stage I and II non-small cell lung cancer patients treated with uracil-tegafur after surgery: A prospective multi-institutional study in Japan

OBJECTIVES This investigation was conducted to assess the use of the intratumoral mRNA expression levels of nucleic acid-metabolizing enzymes as biomarkers of adjuvant chemotherapy for non-small cell lung cancer (NSCLC) using uracil-tegafur in a multi-institutional prospective study. MATERIALS AND METHODS 236 patients with a completely resected NSCLC (adenocarcinoma and squamous cell carcinoma) of pathological stage IA (maximum tumor diameter of 2 cm or greater), IB, and II tumors were given a dose of 250 mg of uracil-tegafur per square meter of body surface area per day orally for two years after surgery. Intratumoral mRNA levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) genes relative to an internal standard, β-actin, were determined using laser-capture microdissection and fluorescence-based real time PCR detection systems. RESULTS AND CONCLUSION Among 5-FU target enzymes, TS was the only one that showed a significant difference in the level of gene expression between the high and low gene expression groups, for both disease-free survival (DFS) and overall survival (OS), when patients were divided according to median values; 5-year DFS rates in high/low TS gene expression were 60.4% and 72.6%, respectively (p=0.050), 5-year OS rates were 78.1% and 88.6%, respectively (p=0.011). Coxs proportional hazard model indicated that the pathological stage and TS gene expression level were independent values for predicting DFS. The TS gene expression level was shown to be an independent predictive factor for DFS in stage I and II NSCLC patients who were treated with uracil-tegafur following surgery.