Effect of epidural analgesia on postoperative insulin resistance as evaluated by insulin clamp technique

The influence of epidural neural blockade on postoperative insulin resistance was studied using the euglycaemic insulin clamp technique. Eighteen patients undergoing elective upper abdominal surgery of moderate severity were allocated to two groups: group G patients underwent operation under general anaesthesia, and postoperative pain was relieved by systemic administration of analgesia; and group E patients received epidural analgesia during surgery and epidural morphine postoperatively. In each patient the euglycaemic insulin clamp test was performed twice: several days before surgery and on postoperative day 1. Peroperative catecholamine and cortisol responses were also measured to investigate possible endocrine mechanisms of the insulin resistance. Glucose disposal (M) decreased in both groups on postoperative day 1 at plasma insulin concentrations ranging from 1.2 to 10.0 milliunits ml-1, resulting in the downward shift of dose-response curves. However, this downward shift was significantly smaller in group E than in group G patients. Urinary adrenaline excretion increased markedly on the day of operation in group G, but was significantly inhibited in group E. Urinary noradrenaline excretion increased mainly on postoperative day 1 in group G, but was significantly inhibited in group E. Plasma cortisol response was lower in group E than in group G during and shortly after operation, and was significantly inhibited in group E on postoperative day 1. These results indicate that insulin resistance after elective abdominal surgery is due to a postreceptor deficit in glucose utilization, as indicated by the downward shift of the dose-response curves. This disturbance in glucose metabolism was reduced by epidural analgesia, the results being associated with inhibited catecholamine and cortisol responses.     

Systemic and local evidence of increased Fas-mediated apoptosis in ulcerative colitis

BACKGROUND AND AIMS: Recent studies suggest that Fas-mediated apoptosis is involved in the pathogenesis of inflammatory bowel disease (IBD). This study was conducted to clarify whether soluble forms of Fas (sFas) and Fas ligand (sFasL) are concerned with inflammation in IBD. METHODS AND PATIENTS: Concentration of serum sFas and sFasL was measured by enzyme-linked immunosorbent assay in 10 patients with ulcerative colitis (UC), 10 with Crohn's disease (CD) in both active and remission stages, and 20 controls. Expression of Fas and sFas in colonic mucosa was examined by western blot. Distribution of Fas and FasL in colonic mucosa was examined by immunohistochemistry in 20 UC, 20 CD, and 10 non-IBD colitis patients and in 10 controls. Apoptotic cells were examined by TUNEL. RESULTS: Concentration of systemic sFas was significantly lower in active UC than controls. The number of FasL-containing cells was significantly higher in active UC than in remission UC, non-IBD colitis, and controls. Apoptotic cells were increased in active UC. CONCLUSIONS: Our results demonstrate that systemic and local Fas-mediated apoptosis is promoted in UC, which might be involved in the pathogenesis in UC.     

Comparison of alternate-day versus consecutive-day treatment with S-1: assessment of tumor growth inhibition and toxicity reduction in gastric cancer cell lines in vitro and in vivo

Background  The toxic effects of S-1 can lead to discontinuation of treatment. Strategies for reducing toxicity without compromising therapeutic effectiveness are required. Methods  We used the human gastric cancer cell lines MKN28 and MKN45 to examine such strategies in vitro. The cell lines were treated with three different regimens, given on alternate days (alternate-day) or on consecutive days (consecutive-day). On consecutive days, treatment A provided the same total dose as the alternate-day treatment, and treatment B was given for the same number of days as the alternate-day treatment. A fourth group served as control. In vitro, the relative inhibition (RI) of tumor growth by 5-fluorouracil was calculated using the 2-(2-methyl-4-nitrophenyl)-3-(4-nitrophyl)-5-2, 4-disulfophenyl)-2H-tetrazolium (WST-8) method. We also carried out an in vivo experiment in which tumor-bearing nude mice (BALBc/nu-nu) were used to examine the antitumor activity of S-1. Leukocyte counts and gastrointestinal mucosal injury were compared in mice that received alternate-day and consecutive-day treatments. Results  In vitro, for MKN28, the RI was 22.9% for alternate-day, 34.1% for consecutive-day A, and 37.7% for consecutive-day B treatments. For MKN45, the RI was 51.1% for alternate-day, 52.2% for consecutive-day A, and 50.5% for consecutive-day B treatments. In vivo, for MKN28, the treated groups showed higher inhibition than the control, and inhibition of tumor growth was higher with alternate-day than with consecutive-day treatment. The RI was significantly higher with alternate-day (49.3%) than with consecutive-day treatment (16.2%; P < 0.05). For MKN45, the RI was greater than 50% in both treated groups. With consecutive-day treatment, 5 of the 14 mice used died during treatment. Leukocyte counts were lower in the mice with consecutive-day than with alternate-day treatment, or control. Atrophic changes and inflammatory cell infiltration of the small intestinal mucosa were severe after consecutive-day, but minimal after alternate-day treatment. Conclusion  Experimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.     

Changes in folate concentration in Yoshida sarcoma after administration of leucovorin or cisplatin

Both leucovorin (LV) and cisplatin ( cis-dichlorodiammine platinum II, CDDP) act as modulators of 5-fluorouracil (5-FUra) by increasing the intracellular concentration of reduced folate. We measured intracellular folate levels following the administration of LV or cisplatin in tumor-bearing rats to determine the optimal schedules for their use as 5-FUra modulators. Donryu rats were inoculated with Yoshida sarcoma cells on the right flank. Seven days after tumor inoculation, the animals were injected with LV or CDDP. The kinetic and dose-related changes in intracellular folate concentration were analyzed by means of a binding assay. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after administration of LV and remained significantly high until 8 h after administration. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after cisplatin administration, then decreased to a rather low level 8 h after, and to a significantly lower level than baseline 24 h after administration. The folate levels in the tumor tissue increased in proportion to the dose of LV, but did not increase when the dose of cisplatin was increased from 1 mg/kg to 8 mg/kg. Repeat high-dose administration of LV and repeat low-dose administration of cisplatin are advocated when they are used as modulators of 5-FUra.     

Variation in MT expression in early-stage depressed-type and polypoid-type colorectal tumours

Metallothionein (MT) expression is observed in various carcinomas, but its role is not fully understood. To clarify the clinicopathological significance of MT, 87 colorectal adenomas and 128 early-stage carcinomas were immunohistochemically analysed for MT expression. The degree of MT immunostaining of a specimen was graded according to the proportion of MT-positive cells; negative (<5%) and positive (focally 5-50%, diffusely >50%). MT expression significantly decreased with tumour development. For carcinomas, MT-positivity was significantly associated with depth of invasion (T1 60% versus T2 33%; P<0.01), vascular involvement (positive 35% versus negative 61%; P<0.01) and morphology (polypoid 62% versus depressed 26%; P<0.01). Regarding MT-positive distribution, the diffuse-positive rate in MT-positive polypoid lesions was 28%, while MT-positive depressed lesions were all diffusely stained (P<0.01). In conclusion, our results suggested that decreasing MT expression is an early event in colorectal carcinogenesis and may reflect local invasion. Furthermore, MT-positive distribution may reflect genetic differences between the polypoid and depressed-type.     

Low-dose cisplatin and UFT for hormone refractory prostate cancer

OBJECTIVES: Biochemical modulation (BM) was initially used to enhance the effect of 5-fluorouracil (5-FU) by modulating its pharmacological action with the addition of other drugs. BM with low-dose cisplatin and 5-FU or UFT has been examined in cases of advanced gastric or pancreas cancer and 30 to 40% response rates have been reported. In the present study, the effect of BM on hormone refractory prostate cancer (HRPC) patients was examined. METHODS: BM consisting of 5 mg/body of cisplatin 3 times per week and 300-450 mg of UFT/day was given to 30 HRPC patients (median and range of age: 66 and 52-72, respectively). The ECOG performance status was 0 to 1. Gleason score was 7 in 8 patients, 8 in 10 patients and 9 in 12 patients, respectively. The metastatic site was bone in 29 patients (extent of disease on bone scan [EOD] grade 1: 10, 2: 10, 3: 8, 4: 1), lymph node in 8 and liver in 1. RESULTS: Among the 29 patients assessable for bone metastasis, 5 (17%) obtained marked improvement on bone scan. One was EOD grade 4 (super bone scan) and 4 were EOD grade 1-3. Eight (28%) were stable and 16 (55%) progressed on bone scan. Among 8 patients with lymph node metastasis, 4 (50%) showed partial response and 4 (50%) progression. One patient with liver metastasis showed complete response. Fourteen (47%) out of 30 patients showed a PSA decline of 50% or greater. Their median response duration was 8 months (range; 2 to 44 months). Among the 25 patients assessable for bone pain, 7 (28%) improved, 12 (48%) remained stable and 6 (24%) progressed. A side effect of Grade II anemia was seen in one patient. CONCLUSION: BM is effective in almost half of hormone refractory prostate cancer patients.     

Conceptual changes in cancer chemotherapy--biochemical modulation of 5-FU

Recently, the demand for more useful therapies for cancer patients has increased. We describe in this paper a therapeutic modality based on a self-rescuing concept (SRC), and which features dual activity, i.e., an effect-enhancing activity and an adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: the oral fluoropyrimidine agent tegafur; a DPD inhibitor (CDHP) which is more potent than uracil, which is used in UFT; and an ORTC inhibitor (Oxo) which localizes in the gastrointestinal tract. S-1 is a combination drug with a molar ratio of 1:0.4:1 in FT, CDHP, and Oxo, respectively. A clinical pharmacology study was conducted to examine blood concentrations of 5-FU after twice-a-day administration of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were found to be 60 to 200 ng/ml in all twelve patients examined. The overall response rate was 44.6% (45/101). In addition, the incidence of adverse reactions judged to be grade 3 or higher was 10% or less. We have also reported a combination therapy with 5-FU (civ) (5-FU: 250 to 350 mg/body, 24-hour cvi, consecutive days) and low-dose cisplatin (CDDP: 3 to 5 mg/body, i.v., 5 days/week), in which CDDP was used as a modulator of 5-FU. Low-dose FP therapy provided response rates as high as 40 to 60% in 163 patients with various gastrointestinal cancers other than pancreas cancer. The incidence of the adverse reactions of nausea and vomiting which were judged to be grade 3 or higher was 2.5% (4/163). The incidences of other adverse reactions were 1% or less. In line with the theory and practice of combination therapy with 5-FU (cvi) 24 hr cvi; 5-FU: 750 to 1,000 mg/body/day on Monday, Wednesday, and Friday (withdrawal on Tuesday, Thursday, Saturday and Sunday) intermittent administration and low-dose CDDP (3 to 5 mg/body/day day 1-5/w) consecutive administration was utilized in which there was a difference in cell cycle between gastrointestinal mucosal cell and tumor cell, or between bone marrow cell and tumor cell. Few adverse reactions, e.g., diarrhea and stomatitis, were observed despite the overall response rate being as high as 52.4% (22/42). The incidence of adverse reaction judged to be grade 3 or higher was as low as 9.3% (5/54), with an incidence of 9.3% (5/54) in Grade 3 or higher myelotoxicity. We intend in the future to combine the abovementioned therapeutic modalities, which provoke fewer adverse reactions and are easy on patients with cancer in an effort to further increase their life expectancy.     

An in vitro examination of a 5-fluorouracil regimen involving continuous venous infusion using cultured cell lines derived from ovarian cancers

To examine the antitumor effectiveness of continuous venous infusion of 5-fluorouracil (5-FU), such a regimen was mimicked in vitro using cultured ovarian cancer cell lines. Two ovarian carcinoma cell lines, HRA and KK with cell doubling times (DT) of 16 h and 45 h, respectively, were grown under three incubation conditions with respect to 5-FU exposure, and the extent of growth inhibition was compared among the three conditions and between the two cell lines. Protocol I: 6 h-intermittent exposure to 5-FU, protocol II: 24 h-intermittent exposure to 5-FU, protocol III: uninterrupted exposure to 5-FU. The 50% growth inhibitory concentrations (IC50) of 5-FU obtained for KK cells grown under protocols I and II were both two times higher than that obtained under protocol III. Regarding HRA cells, IC50 obtained under protocol I was two times higher than that obtained under protocol III, while that obtained under protocol II was 3.7 times higher than that obtained under protocol III. Results obtained from the present in vitro examination suggested that the drug-free interval in the intermittent infusion of 5-FU should be shorter than the DT of the targeted tumor cells to obtain an efficacy corresponding to that obtained by uninterrupted exposure to the drug. In establishing an effective intermittent continuous infusion therapy with 5-FU with fewer side effects, the drug-free interval should be shorter than the DT of tumor cells, but longer than the DT of proliferating cells in normal tissues, including gastrointestinal mucosa cells assuming that these normal cells possess shorter DT than tumor cells.