Chikao Yasuda

Comparison of standard-dose and low-dose gemcitabine regimens in pancreatic adenocarcinoma patients: a prospective randomized trial.

BackgroundA prospective, randomized study was performed to determine whether gemcitabine infusion at a low dose (250 mg/m2) is comparable or superior to the standard-dose infusion (1000 mg/m2) in terms of the survival period, clinical benefit, and frequency of adverse effects in patients with advanced pancreatic adenocarcinoma.MethodsTwenty-five patients who were histologically proven to have locally advanced pancreatic cancer or pancreatic cancer with distant metastases were initially enrolled in the present study. They were treated with gemcitabine infusion at either a dose of 1000 mg/m2 over 30 min (the standard regimen) on days 1, 8, and 15 of every 4-week cycle or at a dose of 250 mg/m2 over 30 min every week. Survival time, response rate, time to treatment failure, clinical benefit response, and adverse effects were compared between the two groups.ResultsTwenty-one patients received gemcitabine for more than 1 month. The median survival period was 7.2 months for patients who received the low-dose infusion regimen, in contrast to 5.2 months for patients administered the standard-dose infusion regimen. The time to treatment failure was 5.6 months for patients in the low-dose infusion regimen, in contrast to 3.4 months for patients in the standard-dose infusion regimen. There were no significant differences in either survival time to time to treatment failure or clinical benefits between the two groups, but the incidence of adverse reactions in patients administered the low-dose therapy was significantly lower than that in patients receiving the standard-dose therapy (P < 0.05). In particular, patients in the standard infusion regimen group experienced more hematologic toxicity than those in the low-dose regimen.ConclusionsThese findings suggest that the low-dose gemcitabine infusion regimen can be continuously administered to patients with locally advanced and systemically spreading pancreatic cancer because of its reduced toxicity, resulting in better quality of life and an improved safety profile as compared to the standard infusion treatment regimen.

Preparation of poly-lactic acid microspheres containing the angiogenesis inhibitor TNP-470 with medium-chain triglyceride and the in vitro evaluation of release profiles

TNP-470 (AGM-1470, 6-0-(N-chloroacetylcarbamoyl)-fumagillol), a derivative of fumagillin, is a promising angiogenesis inhibitor. However, as TNP-470 is very unstable in in vitro and in vivo, it has been difficult to verify its pharmacological efficacy in the clinical medicine. The preparation of a drug delivery system (DDS) in a microsphere form was studied for the stable inclusion and controlled release of TNP-470. Medium-chain triglyceride (MCTG) as an effective stabilizer and poly-lactic acid (PLA) as a biodegradable carrier were used for this purpose. The release of TNP-470 from the MCTG containing DDS continued for approximately 2 weeks, while the release of TNP-470 from the one without MCTG stopped after only 5 days. It was proved that TNP-470 could be released much more stable for much longer period from the MCTG containing DDS compared to the one without DDS.

VALUE OF COMPUTED TOMOGRAPHY FOR EVALUATING THE INJECTION SITE IN ENDOSONOGRAPHY-GUIDED CELIAC PLEXUS NEUROLYSIS

Endosonography‐guided celiac plexus neurolysis (EUS‐CPN) safely and effectively relieves pain associated with intra‐abdominal malignancies when the neurolytic is accurately injected. We applied contrast medium to evaluate the ethanol injection sites in patients who received EUS‐CPN due to abdominal pain caused by malignancies. We injected, under the guidance of endoscopic ultrasonography (EUS), ethanol containing 10% contrast medium into the celiac plexus of patients with intra‐abdominal pain due to malignancies. Immediately after the endoscopic therapy, patients underwent computed tomography (CT) to confirm the injection site. Images of distribution of injected solutions were classified into three groups. Injected solution dispersed in unilateral and bilateral anterocrural space was defined as ‘unilateral injection’ or ‘bilateral injection’, respectively. Injected solution located out of the anterocrural space was defined as ‘inappropriate injection’. Pre‐ and postprocedure pain was assessed using a standard analog scale. Before and 2, 4, 8, 12, and 16 weeks after the procedure, pain scores were evaluated. From April 2003 to May 2005, 13 patients were enrolled in this study. Improvement of pain score in the ‘bilateral injection’ and ‘unilateral injection’ groups was significantly superior to the change in the ‘inappropriate injection’ group. Although EUS‐CPN was effective in eight of 13 patients (61.5%), additional EUS‐CPN to the ‘inappropriate injection group’ increased the response rate to 84.6%. Injection of ethanol to the anterocrural space by EUS‐CPN produced adequate pain relief. Immediate examination by CT for confirmation of injection sites after EUS‐CPN would increase the likelihood of induction of pain relief.

Experimental Studies on Potentiation of the Antitumor Activity of 5‐Fluorouracil with 3′‐Azido‐3‐deoxythymidine for the Gastric Cancer Cell Line MKN28 in vivo

A new method of biochemical modulation of 5‐fluorouracil (5‐FU) with 3‐azido‐3′‐deoxythymidine (AZT)was studied experimentally. Nude mice transplanted with cells of the human gastric cancer cell line MKN28 were divided into 4 groups, i.e., control, 5‐FU, AZT, and 5‐FU plus AZT, and the antitumor activities were compared. Based on the assessment of tumor volume, significant suppression of tumor growth was observed in the 5‐FU and 5‐FU plus AZT groups (P<0.05, P<0.01, versus control, respectively). The thymidylate synthase (TS) inhibition rate, an index of inhibition of the de novo pathway, was significantly higher in the 5‐FU and 5‐FU plus AZT groups than in the control group (P<0.01), but it did not differ from the control in the AZT group. TS‐bound FdUMP tended to be higher in the 5‐FU pins AZT group than in the 5‐FU group. The activity of thymidine kinase (TK) and the uptake ratio of 5‐hromo‐2′‐deoxyuridine (BrdU), indices of salvage pathway activity, were significantly lower in the AZT and 5‐FU plus AZT groups than in the control group (TK, P<0.05, P< 0.01; uptake ratio of BrdU, P< 0.01, P< 0.05, respectively). There were slight losses of body weight in the 5‐FU and 5‐FU plus AZT groups compared with that in the control group, but no difference between the AZT and control groups in weight loss. These findings suggest that addition of AZT plays an important role in potentiating the antitumor activity of 5‐FU through both blockage of a compensatory increase of activity in the salvage pathway and also an increase in TS‐bound FdUMP, anid has no adverse effects. Thus, the combination of 5‐FU and AZT could be useful as a new modality in gastric cancer chemotherapy.

In vivo evaluation of microspheres containing the angiogenesis inhibitor, TNP-470, and the metastasis suppression with liver metastatic model implanted neuroblastoma

TNP-470 (AGM-1470, O-(chloroacetylcarbamoyl) fumagillol), which strongly inhibits the angiogenesis, is promising as a new drug for tumor dormancy therapy; however, TNP-470 is very unstable in vitro and in vivo. We previously prepared TNP-470 containing microspheres composed of poly (lactic acid) with medium-chain triglyceride, and demonstrated that the microspheres released TNP-470 over the long-term in vitro. The present study was undertaken to evaluate the release profile of TNP-470 in vivo and the inhibitory effect on hepatic metastasis of neuroblastoma. It was found that the microspheres could maintain high levels of TNP-470 in the blood plasma for over 4 weeks in vivo. In addition, hepatic metastasis of neuroblastoma was strongly inhibited at 2 weeks after intraperitoneal injection of the microspheres. Following 2 weeks of treatment, the liver weights of mice injected with TNP-DDS (TNP-DDS (H), and TNP-DDS (L) groups) and those injected with only physiological saline (C-1300 group) after implantation of neuroblastoma cells were 1.18+/-0.13g, 1.28+/-0.10g, and 2.54+/-0.97g, respectively (p<0.05; C-1300 group compared with the TNP-DDS (H) and the TNP-DDS (L) groups, respectively). It was evident that microspheres containing TNP-470 have an excellent potential for clinical application in tumor dormancy therapy.