Saburo Sone

Thymidine phosphorylase (TP) is an angiogenic factor that plays a pivotal role in tumor angiogenesis. Various kinds of solid tumors express TP and high TP activity is correlated with microvessel density. We have previously reported that TP enhances interleukin-8 (IL-8) expression in KB human epidermoid carcinoma cells. In this study, TP was shown to be involved in enhanced expression of IL-8 in EJ human bladder cancer cells and Yumoto human cervical cancer cells as well as KB human epidermoid carcinoma cells. The enzymatic activity of TP was required for the enhanced expression of IL-8. A degradation product of thymidine was implicated in the enhanced expression of IL-8. TP augmented reactive oxygen species (ROS) generation in KB and Yumoto cells, and the enzymatic activity of TP was again required for the generation of ROS. An antioxidant, N-acetylcysteine (NAC), attenuated the generation of ROS and IL-8 mRNA expression in KB and Yumoto cells, and H2O2 increased IL-8 mRNA expression in Yumoto cells, suggesting that ROS generated by TP caused the increased expression of IL-8 mRNA. Since TP also reduced cellular glutathione levels and transcription of γ-GCS in KB cells, the TP-induced augmentation of ROS may be partially attributed to the decreased glutathione. Our findings suggest that thymidine-derived sugars enhanced ROS generation and consequently increased IL-8 expression.

Background and objective: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the mesothelium with high chemotherapeutic resistance. In this study, the preclinical therapeutic activity of the multiple tyrosine kinase inhibitor, SU6668, against MPM was examined. Methods: Two human MPM cell lines with different pro-angiogenic cytokine expression, Y-MESO-14 cells that express high levels of vascular endothelial growth factor (VEGF) and MSTO-211H cells that express high levels of basic fibroblast growth factor (bFGF), were orthotopically inoculated into the thoracic cavities of mice with severe combined immunodeficiency. The mice with MPM were treated or not treated with SU6668 (200 mg/kg/day). Results: SU6668 abrogated the proliferation of endothelial cells stimulated by VEGF or bFGF, but did not directly affect the growth of human MPM cells in vitro. In this orthotopic implantation model, treatment with SU6668 effectively reduced tumour weight and pleural effusion volumes, in association with inhibition of the growth of tumour vasculature. More importantly, treatment with SU6668 significantly prolonged survival time in mice with MPM. Conclusions: These findings suggest that SU6668 has a promising therapeutic effect on the progression of MPM in vivo through its anti-angiogenic effects.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic effects against non-small cell lung cancer (NSCLC) with EGFR activating mutations. However, 25% – 30% of EGFR mutant lung cancer patients show intrinsic resistance, and the responders almost invariably acquire resistance to EGFR-TKIs within several years. Three mechanisms — second-site point mutation that substitutes methionine for threonine at position 790 (T790M) in EGFR, amplification of MET protooncogene, and overexpression of hepatocyte growth factor (HGF, a ligand of MET) — have been reported to contribute to resistance to EGFR-TKIs. These three factors were detected simultaneously in a population of patients with acquired resistance to EGFR-TKIs. Further investigations to develop optimal therapy based on accurate diagnosis of resistant mechanism are warranted to improve the prognosis of EGFR mutant lung cancer.

S-1 is an oral anticancer fluoropyrimidine agent designed to elevate anticancer activity with a decrease in gastrointestinal toxicity. We conducted a phase II study to evaluate the efficacy and safety of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 administered orally at 40 mg/m2 twice a day for 21 consecutive days, and cisplatin (60 mg/m2) infused intravenously on day 8, repeated every 5 weeks. Of the 44 patients enrolled in the study, 40 were assessable for efficacy and safety. The median number of cycles administered was 3 (range 1–9 cycles). Among the 40 assessable patients, 7 partial responses were observed, with an overall response rate (RR) of 17.5% [95% confidence interval (CI), 5.2–29.8]. Patients with squamous cell carcinoma showed a significantly higher RR (55.5%) than those with adenocarcinoma (9.1%) or other types of NSCLC (0%). The median progression-free survival was 4.3 months (95% CI, 3.4–4.9), the median survival time was 17.9 months (95% CI, 15.0–20.8), and the 1- and 2-year survival rates were 63.3 and 27.3%, respectively. Major grade 3–4 hematologic toxicities were leukocytopenia (7.5%), neutropenia (5.0%), anemia (15.0%) and thrombocytopenia (2.5%). No grade 4 non-hematologic toxicity or treatment-related death occurred. These results suggest that combination chemotherapy with S-1 plus cisplatin is a promising therapeutic candidate for patients with advanced NSCLC, particularly squamous cell carcinoma.

Multiple pulmonary nodular lesions were noted on a chest X-ray film of a 56-year-old man. Partial resection of the left lung via thoracoscopy was performed, yielding a pathological diagnosis of leiomyosarcoma. Positron emission tomography/computed tomography (PET/CT) and other examinations revealed that the lesions originated in the lung. Chemotherapy with adriamycin and ifosfamide was performed but was ineffective. It is reported that leiomyosarcoma with multiple pulmonary nodules often derives from a uterine primary lesion. Primary pulmonary leiomyosarcoma with multiple nodular lesions is rare, but it should be considered in the differential diagnosis in cases with multiple lung nodules.

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm. S-1 has been developed as a novel oral antineoplastic agent based on the modulation of 5-fluorouracil (5-FU) bioactivity. This study was conducted to investigate the preclinical therapeutic effect of S-1 on MPM. We used three human MPM cell lines, Y-MESO-14, NCI-H290 and MSTO-211H. In vitro proliferation of human MPM cells was determined by MTT assay. Human MPM cells were orthotopically implanted into thoracic cavity of SCID mice. Tumor-bearing mice were treated with S-1 or vehicle. The combination of 5-FU and 5-chloro-2,4-dihydroxypyridine (CDHP) was more effective than 5-FU alone in inhibiting MPM cell proliferation in vitro. This combination was most effective in Y-MESO-14 cells, which co-expressed high protein level of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP). In vivo data showed that treatment with S-1 significantly reduced thoracic tumors and pleural effusion produced by Y-MESO-14 cells. Moreover, treatment with S-1 prolonged the survival of Y-MESO-14 cell-bearing SCID mice. We demonstrated that S-1 was effective for inhibiting the proliferation of MPM cells, particularly with both DPD and TP expressions, suggesting that S-1 might be therapeutically effective for control of MPM.

Recently, discovery and identification of critical molecules responsible for cancer progression lead to development of specific target-directed therapies, including monoclonal antibodies and small molecular compounds. For the past 15 years, the advent of target-specific therapeutics has remarkably improved the clinical outcomes of certain patients with various malignancies, and it was followed by the understanding of mechanism of the drug resistance. Moreover, useful biomarkers were developed to further increase the power of patient selection for molecular-targeted therapy. From the historical point of view, we review the progress in developing new molecular-targeted drugs for personalized medicine.

We clinically reviewed 33 surgery patients and 15 non-surgery patients aged 80 years or older with primary lung cancer treated at our hospital. The surgery group consisted of 21 males and 12 females (82.0 +/- 1.9 years old). The surgical procedures were 1 pneumonectomy, 19 lobectomies (1 bronchoplasty), 4 segmentectomies and 9 partial resections. The cancer types were 17 adenocarcinomas, 14 squamous cell carcinomas and 2 others. The stagings were 24 in stage I, 4 in stage II and 5 in stage III. There were no direct surgical deaths within 30 days post operatively. There have been 9 other disease-related deaths to date (27%). The non-surgery group consisted of 9 males and 6 females (81.7 +/- 1.5 years old). Treatment procedures consisted of radiationtherapy in 11, chemotherapy in 2 and best supportive care in 3. The cancer types were 2 adenocarcinomas, 11 squamous cell carcinomas and 2 others. The stagings were 7 in stage I, 4 in stage II and 4 in stage III. There have been 3 other disease-related deaths to date (20%). We must carefully select the therapeutic approach for elderly lung cancer patients, because the other disease-related death rates of both groups were high. The 5-year survival rate of stage I patients in the surgical group was relatively good (60.2%). There were long-term survival (7 5-year survivors) in the surgical group. Since there were some cases of radiation pneumonia in the group receiving radiation therapy, it would be better to perform surgery for elderly patients with lung cancer, especially those with stage I disease. For elderly patients, it is important to consider quality of life as well as the survival rate.

Recent insights into the molecular mechanism of cancer progression have given rise to specific target-directed therapies, including monoclonal antibodies and small molecular compounds, and the advent of target-specific therapeutics has remarkably improved the outcomes of patients with various malignancies. Recent advance also lead to the identification of prognostic biomarkers as predictive factors in determining response to molecular targeted drugs. Future studies also need to develop biomarkers to further increase the power of patient selection for molecular targeted therapy. Here we review the recent progress in developing new molecular targeted drugs and the resistance to treatments as well as the importance of measuring the QOL by patient-reported outcome, for personalized therapy.