S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis. METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated. RESULTS: Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively. CONCLUSION: Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Enhancement of the therapeutic outcome of radio-immunotherapy by combination with whole-body mild hyperthermia.

To enhance the effect of radio-immunotherapy for solid cancers, whole-body mild hyperthermia was added, and its effects on the pharmacokinetics of radiolabelled antibody, outcome of radio-immunotherapy, and radiosensitivity of the tumour were investigated. Nude mice bearing human colon cancer xenografts were heated to 40 degrees C for 3 or 6 h. After heating, mice received intravenous (i.v.) injections of [131I]-labelled anti-carcinoembryonic antigen (CEA) monoclonal antibody. Although 6-h heating did not alter the biodistribution of the radiolabelled antibody, and alone did not show any therapeutic effect on tumour growth, when combined with radio-immunotherapy, the therapeutic effect on tumour growth was significantly enhanced. Three-hour heating also significantly enhanced the effect of radio-immunotherapy. Colony formation assay showed that the radiosensitivity of the tumour was significantly enhanced after heating, which was achieved by a reduction of the hypoxic fraction of the tumour. In conclusion, the addition of whole-body mild hyperthermia significantly enhanced the therapeutic effect of radio-immunotherapy by increasing the radiosensitivity of the tumour.

Radioimmunotherapy of human glioma xenografts in nude mice by indium-111 labelled internalising monoclonal antibody.

The potential of 111Indium (111In)-labelled internalising anti-integrin alpha 3 antibody GA17 in the radioimmunotherapy of human glioblastoma xenografts in nude mice was investigated. A radioisotope retention assay showed a rapid release of radioiodine from the glioblastoma cells after the binding of 125I-GA17, whilst 111In-GA17 was retained in the cells for a longer time period. The glioblastoma xenografts showed a high and prolonged uptake of 111In-GA17, and tumour uptake of 125I-GA17 was lower and decreased with time. In the mice which received two injections of 18.5 MBq of 111In-GA17, the growth of the subcutaneous tumour was significantly suppressed compared with the untreated group and mice injected with an 111In-labelled control antibody. These results indicate that GA17 was internalized into the glioblastoma cells and that 111In was retained within the cancer cells. The injection of a high-dose of 111In-GA17 can suppress the growth of tumour xenografts in nude mice.

Simultaneous determination of ephedrine, pseudoephedrine, norephedrine and methylephedrine in Kampo medicines by high-performance liquid chromatography.

A simultaneous high-performance liquid chromatographic method for the determination of ephedrine, pseudoephedrine, norephedrine and methylephedrine (ephedrine alkaloids) in Kampo medicines which contain Ephedrae Herba was established. The analysis can be accomplished within 25 min with a Wakosil-II 5C18 HG column by isocratic elution using a mixture of water, acetonitrile and sodium dodecyl sulfate (65:35:0.4) as the mobile phase at a flow-rate of 1.0 ml min(-1), and detection at 210 nm. The detection limits of ephedrine alkaloids are 0.37-1.06 microM per injection (5 microl). This method was applied to analyze the quantities in eight Kampo decoctions; Mao-to, Makyo-yokukan-to, Makyo-kanseki-to, Yokuinin-to, Sho-seiryu-to, Keima-kakuhan-to, Kakkon-to and Kakkon-to-ka-senkyu-sin'i. The concentration (per Ephedrae Herba gram) of ephedrine alkaloids was higher in the Makyo-kanseki-to decoction than in the others. Calcium sulfate from Gypsum Fibrosum raised ephedrine alkaloids dissolution in the Makyo-kanseki-to decoction.

Effect of administration route and dose of streptavidin or biotin on the tumor uptake of radioactivity in intraperitoneal tumor with multistep targeting.

The effect of the administration route and dose of streptavidin or biotin on the biodistribution of radioactivity in multistep targeting was studied in nude mice bearing intraperitoneal (IP) colon cancer xenograft. The multistep targeting included a two-step method using biotinylated antibody and radiolabeled streptavidin and a three-step method with radiolabeled biotin based on the two-step method. A monoclonal antibody, MLS128, which recognizes Tn antigen on mucin, was biotinylated and injected intravenously (i.v.) or i.p. in nude mice bearing human colon cancer LS180 IP xenografts for pretargeting. In the two-step method, i.p.-injected streptavidin showed a higher tumor uptake and tumor-to-nontumor ratios than i.v.-injected streptavidin regardless of administration route of pretargeting. The tumor uptake of radiolabeled streptavidin was increased with a high dose of biotinylated antibody pretargeting, but decreased with an increasing dose of streptavidin. In the three-step targeting, i.p. injection also gave a higher tumor uptake of radiolabeled biotin than i.v. injection. In conclusion, i.p. administration of radiolabeled streptavidin or biotin resulted in more efficient IP tumor targeting with the multistep methods.

Absorption and bioavailability of diclofenac after rectal administration of diclofenac-na gel preparation in rat and man.

In order to evaluate diclofenac-Na (DC-Na) micro-enema, DC-Na gel preparations were administered to rats and man. When DC-Na gel preparations were rectally administered at various pH (pH 5- 8) to rats, their bioavailability increased at higher pH. The bioavailability of DC-Na gel preparations (pH 8.0) in rats was significantly higher than that with conventional suppository bases, Witepsol H-15 and polyethylene glycol 1000 (PEG 1000). In man, the DC-Na gel preparation showed higher Cmax and higher bioavailability than commercial suppository made with an oily base. DC-Na gel preparations containing 10% v/v oleic acid showed a prolonged action. The irritative effect of DC-Na gel preparation on rectal mucosa in rats was weaker than that of PEG 1000, but similar to that of Witepsol H-15. Therefore, the present results suggest that gel preparation is a favorable form for rectal administration of diclofenac-Na.

Tobramycin inactivation by carbenicillin, ticarcillin, and piperacillin.

The in vitro and in vivo inactivation of tobramycin by carbenicillin, ticarcillin, or piperacillin was investigated by the enzyme immunoassay method in clinically employed dosages. After the addition of an 80-mg dose of tobramycin to 4- to 5-g doses of a penicillin in 100 ml of 0.9% saline or distilled water, the degradation profile of tobramycin appeared to follow a biexponential pattern of decay. Remarkable losses (30 to 40%) of tobramycin combined with carbenicillin or ticarcillin were observed within 1 h, as compared with the later decline. The combination of tobramycin with piperacillin was least inactivating. When the admixture of tobramycin with carbenicillin or piperacillin used in the in vitro study was infused to six volunteers over 1 h, the observed maximum concentrations of tobramycin were on the average 66 and 74% for carbenicillin and piperacillin, respectively, of that observed after tobramycin alone was given. In contrast, the value obtained for tobramycin in combination with piperacillin was close to 90% of the control value. The elimination half-lives of tobramycin combined with the penicillins were slightly shorter than those of tobramycin alone, indicating that the interaction occurs even in patients with normal renal function.

Distribution of cephalothin to the exudate in comparison with the plasma or lymph concentrations in croton oil-induced inflammatory rats.

The transport of cephalothin (CET) to the exudate was investigated in croton oil-induced inflammatory rats following the intramuscular administration of CET-aqueous solution, CEt-O/W emulsion, or CET-W/O emulsion. The lymphatic transport of CET was the highest following the administration of W/O emulsion. The exudate level of CET was in a decreasing order of W/O emulsion, O/W emulsion, and aqueous solution. In the rat whose blood vessels at femoral rectus, the site of administration, were ligated, the plasma level was decreased by the administration of aqueous solution, but not by W/O emulsion. The exudate level of CET was significantly higher in case of W/O emulsion. Possible mechanisms involved are discussed.