Biomedical subjects

M Baba

Publications and source records attributed to M Baba.

At least 91 records · Page 5Linked to original sources

PubMed1999

Does preoperative chemotherapy cause adverse effects on the perioperative course of patients undergoing esophagectomy for carcinoma?

The aim of this study was to clarify whether preoperative chemotherapy caused adverse effects on the perioperative course of patients undergoing esophagectomy. A total of 42 esophageal cancer patients were entered into a randomized trial and were analyzed. Twenty-one patients were assigned to immediate surgery (Surgery Group). The other 21 received two 5-day courses of chemotherapy comprising cisplatin (70 mg/m2) on day 1, and fluorouracil (700 mg/m2) and leucovorin (20 mg/m2) on each of days 1 to 5 (chemotherapy group). Hospital mortality comprised of one patient (2.3%) who had undergone an operation in the beginning of this series at 21 days after chemotherapy. Thereafter, the interval between the chemotherapy and operation was prolonged, with the average being 35 +/- 7 days. Preoperatively, both the lymphocyte counts and serum albumin levels were not increased in the chemotherapy group of patients even though their body weights increased. In the chemotherapy group, the operation time and the blood loss were increased and, on the 1st postoperative day, the development of systemic inflammatory response syndrome was high but the level of C-reactive protein was low. The incidence of positive microbial cultures of sputum and/or wound discharge within 8 postoperative days was higher in the chemotherapy group (42.9%) than in the surgery group (4.8%). The host defense damage caused by chemotherapy may be prolonged and may show adverse effects in patients undergoing esophagectomy in the early postoperative period. Minimally, a 4-week interval between the completion of chemotherapy and operation is recommended for preventing surgical mortality related to the preoperative chemotherapy.

Aged↗

PubMed1999

Antiangiogenic therapy for liver metastasis of gastrointestinal malignancies.

In about half of the patients with gastrointestinal carcinomas, surgical excision of the primary tumor is not curative because metastasis has already occurred. Recent investigations of metastasis have shown that angiogenesis plays an important role in this process. In solid tumors angiogenesis occurs continuously to provide a blood supply for the proliferating cancer cells. As a new and potent method to control metastasis, antiangiogenic therapy has attracted considerable interest. This therapy inhibits angiogenesis, inducing a dormant state in which tumors cannot grow; the prognosis may thus be remarkably improved. Antiangiogenic agents show a characteristic antitumor effect which is different from that of chemotherapy. Based on our experimental in-vivo data, we conclude that antiangiogenic agents should not be used only for achieving tumor shrinkage, like chemotherapy. These agents should be used to control micrometastases, as the therapeutic effect on such metastasis is excellent. In addition, antiangiogenic agents may be valuable for long-term administration to maintain tumor dormancy, because drug resistance does not develop and these agents have a sustained effect. Combinations with conventional anti-cancer treatments such as chemotherapy, radiotherapy, immunotherapy, or surgery may also be valuable.

Animals↗

PubMed1999

Acridone derivatives are selective inhibitors of HIV-1 replication in chronically infected cells.

In our extensive screening of anti-HIV-1 agents in chronically infected cell lines, we have found acridone derivatives to be selective inhibitors of HIV-1 replication. Among the acridone derivatives, 1-hydroxy-10-methyl-9,10-dihydroacrid-9-one (RD6-5071) suppressed tumor necrosis factor (TNF)-alpha-induced HIV-1 expression in the latently infected cell line OM-10.1, U1, and ACH-2. Its 50% effective concentration for HIV-1 p24 antigen production was 2.0 microg/ml in OM-10.1 cells, while its 50% cytotoxic concentration was 18 microg/ml. The compound also inhibited phorbol 12-myristate 13-acetate (PMA)-induced HIV-1 expression in these cell lines. Furthermore, RD6-5071 was inhibitory to HIV-1 replication in acutely infected U937 and peripheral blood mononuclear cells. The compound was found to suppress TNF-alpha-induced HIV-1 long terminal repeat-driven gene expression. An inhibition assay for protein kinase C (PKC) revealed that RD6-5071 could reduce the enzyme activity. Furthermore, the compound was a moderate inhibitor of PMA-induced nuclear factor kappaB (NF-kappaB) activation, as determined by a gel mobility shift analysis. These results suggest that the acridone derivatives suppress HIV-1 replication at the transcriptional level primarily through a mechanism of PKC inhibition.

Acridines↗

PubMed1999

Prognostic factors in surgical treatment of solitary brain metastasis after resection of non-small-cell lung cancer.

Patients with brain metastasis after resection of non-small-cell lung cancer usually have poor prognosis. A few such patients, however, survive for long periods after surgical resection of brain metastases. To evaluate the prognostic factors in resection of solitary brain metastasis from non-small-cell lung cancer, we reviewed 24 cases undergoing resection of solitary brain metastasis after resection of the primary site from 1977 to 1993. The patient population consisted of 20 men and four women ranging in age from 40 to 75 years old (average, 57.8 years old). None of the patients had systemic metastasis except in the brain at the time of brain surgery. The overall survival rates were 12.5% at 3 years and 8.3% at 5 years after brain surgery. The longest survival periods were 11.5 years after brain surgery and 15.4 years after lung surgery. The interval between lung and brain surgery (< or =360 days vs. >360 days), differentiation of primary cancer (poor vs. moderate), size of primary site (< or =5.0 cm vs. >5.0 cm), and operation of primary site (lobectomy vs. pneumonectomy) significantly affected survival as shown by univariate analysis (P<0.05). Other clinical factors (age, gender, histology, T- and N-status, 'resectability with curative intent' of the primary site, location of the brain metastasis and postoperative radiation therapy) did not affect survival. Multivariate analysis using Cox's proportional hazards model indicated that an interval of more than 360 days between the two surgical procedures (hazard ratio = 0.2351, P = 0.0136) and lobectomy (hazard ratio = 0.5274, P = 0.0416) were independent prognostic factors. In conclusion, patients with solitary brain metastasis from non-small-cell lung cancer without other organ metastasis, in whom relapse in the brain occurred more than 1 year after resection of the primary site and in whom lobectomy was performed, should be treated surgically to maximize the chance of prolonged survival.

Adenocarcinoma↗

PubMed1999

Fat emulsion administration in the early postoperative period in patients undergoing esophagectomy for carcinoma depresses arachidonic acid metabolism in neutrophils.

The aim of this study was to evaluate the effect of fat emulsion administration on neutrophil arachidonic acid and leukotriene B4 (LTB4) generation in surgically stressed patients. Total parenteral nutrition was administered to 17 patients for 2 wk after esophagectomy for carcinoma. Eight patients received fat with glucose (fat group, 30% of total calories) and 9 patients received glucose (glucose group) as a non-protein calorie source from the day of the operation to the seventh postoperative day (POD), and they gradually were converted to enteral nutrition during the second postoperative week. The arachidonic acid in the fat group decreased in the serum from POD 4 to 14. and in neutrophils from 12 h after the beginning of surgery to POD 14, compared to preoperative levels. LTB4 production by A23187-stimulated neutrophils was highest 6 h after the beginning of surgery, when neutrophil arachidonic acid concentration was decreasing, and then fell below the preoperative value from POD 4 to 14 in both groups. LTB4 production on POD 14 was lower in the fat group than in the glucose group. Biosynthesis of arachidonic acid from linoleic acid is inhibited in surgically stressed patients receiving fat emulsion, resulting in the diminished synthesis of LTB4 by neutrophils. The decrease in LTB4 may diminish chemotactic and chemokinetic signals to other leukocytes.

Aged↗

PubMed1999

Does hoarseness of voice from recurrent nerve paralysis after esophagectomy for carcinoma influence patient quality of life?

BACKGROUND: Recurrent laryngeal nerve injury caused by esophageal cancer surgery is worrisome but often temporary; it is unclear when and how the paralysis is resolved. Hoarseness of voice from vocal cord paralysis (VCP) can have detrimental effects on postoperative patients. The aims of this study were to clarify the progress of nerve paralysis related to difficulty in talking after surgery and to assess whether hoarseness influences patient quality of life. STUDY DESIGN: Between 1985 and 1996, 141 esophageal cancer patients undergoing a resection by the Akiyama procedure were cancer free 1 year after surgery. Among them, 51 patients with VCP on discharge from the hospital were retrospectively reviewed. Their VCPs, body weights, and pulmonary functions were examined yearly. They were given a questionnaire relating to the difficulty in talking 1 year after surgery. RESULTS: VCP on discharge spontaneously healed within 1 year of surgery in 21 patients (41.2%), with the mean duration of difficulty in talking 5.7 months. The remaining 30 patients had persistent VCP 1 year after surgery; 4 VCPs spontaneously healed approximately 2 years after surgery. Eleven of the 30 patients with persistent VCP, who complained of severe hoarseness at 1 year postoperatively from inability to close the glottis during exertion, showed debilitation in performance status, abilities to go up stairs, and swallowing. In the group of patients with severe hoarseness, the percentage of ideal body weight (90.6%+/-11.0%) preoperatively and pulmonary functions at 3 years postoperatively were deteriorated, resulting in 3 patients with repeated aspiration pneumonia. CONCLUSIONS: The inability to compensate for aspiration, presenting as severe hoarseness, may be dependent on the preoperative nutritional state of patients along with degree of vocal cord atrophy and a decrease in pulmonary support. Persistent nerve paralysis deteriorates quality of life until it is adequately treated.

Airway Obstruction↗

PubMed1999

Effects of aging on central conduction in somatosensory evoked potentials: evaluation of onset versus peak methods.

OBJECTIVES: To investigate effects of aging on peripheral and central somatosensory conduction, and evaluate onset-to-onset and peak-to-peak measurements of each component and central conduction time (CCT) in somatosensory evoked potentials (SEPs). METHODS: We recorded SEPs with non-cephalic reference from the Erb's point, the posterior (cv 6) and anterior neck, and scalp (Fz and P4) after left median nerve stimulation in 138 normal subjects aged between 20 and 78 years. We determined onset or peak latencies of the Erb's potential (N9), the spinal N13-P13 in cv 6-to-anterior neck montage and the N20-P20 in scalp leads. Onset CCT was defined as a transit time from N13-P13 onset to N20-P20 onset. In each subject, interpeak latencies of the 'N13' component in cv 6-to-Fz montage and the N20-P20 in P4-to-Fz montage were also defined as conventional peak CCT. RESULTS: Using multiregression analysis, we found that the onset or peak latencies of each SEP component were correlated with the subject's height and age. So were the onset CCTs: Onset CCT (in ms) = 2.549+2.041x(height in meters) + 0.005 x (age in years) (P<0.0001). The conventional peak CCTs as well as onset-to-peak durations of the N20-P20 were correlated with the subject's age but not height: Peak CCT(in ms) = 5.458+0.012x (age in years) (P<0.0005). CONCLUSION: Conductive function is affected by normal aging in the central as well as peripheral somatosensory pathways. The peak CCT is more affected by aging than the onset CCT. However, the onset-to-peak duration of the N20-P20 increased by 0.8 ms between the 4th and 7th decades, suggesting that the peak CCT increase in older people reflects the age-related changes in N20-P20 profile but not in the fastest central conduction. We therefore conclude that the onset CCT measurement is preferable to the peak CCT measurement when assessing the central somatosensory conduction.

Adult↗

PubMed1999

Attenuation by all-trans-retinoic acid of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of all-trans-retinoic acid (RA) on sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labelling and apoptotic indices and immunoreactivity of transforming growth factor (TGF) alpha in the gastric cancers was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats were given chow pellets containing 10% sodium chloride and subcutaneous injections of RA at doses of 0.75 or 1.5 mg kg(-1) body weight every other day. In week 52, oral supplementation with sodium chloride significantly increased the incidence of gastric cancers compared with the untreated controls. Long-term administration of RA at both doses significantly reduced the incidence of gastric cancers, which was enhanced by oral administration of sodium chloride. RA at both doses significantly decreased the labelling index and TGF-alpha immunoreactivity of gastric cancers, which were enhanced by administration of sodium chloride, and significantly increased the apoptotic index of cancers, which was lowered by administration of sodium chloride. These findings suggest that RA attenuates gastric carcinogenesis, enhanced by sodium chloride, by increasing apoptosis, decreasing DNA synthesis, and reducing TGF-alpha expression in gastric cancers.

Adenocarcinoma↗

PubMed1999

High prevalence of sensitization to cat allergen among Japanese children with asthma, living without cats.

BACKGROUND: Cat allergy is common among children with asthma. Many cat-allergic patients in Japan and elsewhere do not keep cats, but nonetheless become sensitized through environmental exposure to cat allergen. OBJECTIVE: To assess the frequency of cat allergy and cat-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) antibody responses in young Japanese patients with asthma in relation to self-reported cat exposure and Fel d 1 levels in dust samples. METHODS: Cat dander-specific IgE antibody was measured in sera from asthma patients using the CAP system. IgE and IgG antibody to Fel d 1 was measured by antigen binding radioimmunoassay and by chimeric enzyme immunoassay. Fel d 1 levels in dust samples from a subset of patients' homes were measured by monoclonal antibody-based enzyme immunoassay. RESULTS: Cat-specific IgE (CAP class>/=2) was found in sera from 70% of 44 patients who kept cats and 34% of 394 patients who had never kept cats. The prevalence of sensitization increased progressively to age 6 years (40%: positive), and then increased gradually to age 16 years (approximately 60%: positive) in patients who had never kept cats. There was an excellent correlation between cat CAP values and IgE levels to Fel d 1. The absolute amount of IgE antibody to Fel d 1 ranged from 0.01 to 15.6% of total IgE. Most patients who did not keep cats were exposed to Fel d 1 levels ranging from 0.07-8 microg/g dust. CONCLUSIONS: Sensitization to cat allergen is common among young asthmatic patients in Japan, even among patients who do not keep cats. Use of CAP and the chimeric enzyme-linked immunosorbent assay allows accurate diagnosis of cat allergy and quantification of specific IgE antibody levels.

Adolescent↗

PubMed1999

Reversible F-wave hyperexcitability associated with antibodies to potassium channels in Isaacs' syndrome.

We report a case of Isaacs' syndrome showing F-wave hyperexcitability which was reversible after either epidural block or plasmapheresis. A 14-year-old girl with progressive muscle cramp and myokymia in the legs showed high amplitude, long duration, polyphasic F-waves after either tibial nerve or peroneal nerve stimulation. Potassium current of PC-12 cell membrane was suppressed by her serum, IgM of which strongly reacted with proteins of approximately 50 kDa of the lysates of a PC-12 cell line. After an epidural nerve block with 1 per cent lidocaine 10 ml, the myokymia temporally improved, during which time the hyperexcitable F-waves became normalized. We treated her with double filtration plasmapheresis, which resulted in remarkable improvement of myokymia; simultaneously, the abnormal F-waves showed a decrease in amplitude, duration, and in the number of phases. We concluded that there was hyperexcitability of the proximal site of motor fibers in our patient, and possible immune mechanisms gave rise to the myokymia and unusual F-wave features.

Adolescent↗

PubMed1999

Anti-rheumatic compound aurothioglucose inhibits tumor necrosis factor-alpha-induced HIV-1 replication in latently infected OM10.1 and Ach2 cells.

NF-kappaB is a potent cellular activator of HIV-1 gene expression. Down-regulation of NF-kappaB activation is known to inhibit HIV replication from the latently infected cells. Gold compounds have been effectively used for many decades in the treatment of rheumatoid arthritis. We previously reported that gold compounds, especially aurothioglucose (AuTG) containing monovalent gold ion, inhibited the DNA-binding of NF-kappaB in vitro. In this report we have examined the efficacy of the gold compound AuTG as an inhibitor of HIV replication in latently infected OM10.1 and Ach2 cells. Tumor necrosis factor (TNF)-alpha-induced HIV-1 replication in OM10.1 or Ach2 cells was significantly inhibited by non-cytotoxic doses of AuTG (>10 microM in OM10.1 cells and >25 F.M in Ach2 cells), while 25 microM of the counter-anion thioglucose (TG) or gold compound containing divalent gold ion, HAuCl3, had no effect. The effect of AuTG on NF-kappaB-dependent gene expression was confirmed by a transient CAT assay. Specific staining as well as electron microscopic examinations revealed the accumulation of metal gold in the cells, supporting our previous hypothesis that gold ions could block NF-kappaB-DNA binding by a redox mechanism. These observations indicate that the monovalent gold compound AuTG is a potentially useful drug for the treatment of patients infected with HIV.

Anti-HIV Agents↗

PubMed1999

IgG1 production by sIgD+ splenic B cells and peritoneal B-1 cells in response to IL-5 and CD38 ligation.

CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induces proliferation, IL-5 receptor alpha chain expression and tyrosine phosphorylation of Bruton's tyrosine kinase. Furthermore, stimulation of splenic B cells with IL-5 together with CS/2 induces Blimp-1 expression and differentiation into Ig-producing cells. Here we examined the role of IL-5 in IgG1 and IgA production by B cells isolated from the spleen and peritoneal cavity. CD38 recognized by CS/2 was expressed in the follicular mantle B cells surrounding the germinal center, sIgD+ splenic B cells and peritoneal B cells. IL-5 induced IgG1 production in splenic sIgD+ B cells stimulated with CS/2, while it was ineffective to induce IgA production. Among the various cytokines tested, only IL-5 had a synergistic effect on IgG1 production with CS/2. IL-5 could induce the generation of S micro-Sgamma1 reciprocal recombination DNA products in CS/2-stimulated B cells. IL-4 was ineffective to induce either micro-gamma1 switch recombination or IgG1 secretion with CS/2, demonstrating that IL-5 promotes both micro-gamma1 switch recombination and IgG1 secretion in an IL-4-independent manner. The peritoneal B-2 cells exhibited both IgG1 and IgA production in response to IL-5 plus CS/2, while B-1 cells produced IgG1. These results imply that the pattern of differentiation to Ig-producing cells seen with peritoneal B cells is not identical to the pattern seen with splenic B cells and that peritoneal B-2 cells contain precursors of IgA-producing cells responding to IL-5 plus CS/2.

ADP-ribosyl Cyclase↗

PubMed1999

How the lymph node metastases toward cervico-upper mediastinal region affect the outcome of patients with carcinoma of the thoracic esophagus.

BACKGROUND: The aim of this study was to establish whether the site of lymph node metastasis influences the survival of patients with carcinoma of the thoracic esophagus. METHODS: A series of 159 patients with lymph node metastasis who underwent right transthoracic R0 esophagectomy was analyzed retrospectively. Sites of the nodal metastasis were divided into two regions; the neck and/or upper mediastinum above (upward metastasis) and the abdomen and/or lower mediastinum below (downward metastasis) the tracheal carina. RESULTS: Univariate analysis of prognostic factors revealed the tumor location, distant lymphatic metastasis, number of metastatic nodes and upward metastasis influenced survival, but downward metastasis did not. Multivariate analysis showed that the number of metastatic nodes and upward metastasis were also significant prognostic factors. Thirty-one (33.3%) of the 93 patients with, but only 6 (9.1%) without, upward metastasis had recurrences in the neck and/or upper mediastinum (P = 0.0002). Eighteen (60.0%) of the 30 patients with extranodal invasion in the neck and/or upper mediastinum had recurrence in these regions. CONCLUSIONS: Nodal metastasis in the neck and/or upper mediastinum was a significant risk factor for prognosis, the same as the number of metastatic nodes.

Esophageal Neoplasms↗

PubMed1999

Assessment of cervical lymph node metastasis in esophageal carcinoma using ultrasonography.

OBJECTIVE: To evaluate the efficacy of ultrasonography for the diagnosis of cervical lymph node metastasis in esophageal carcinoma. SUMMARY BACKGROUND DATA: Ultrasound (US) examination is useful for diagnosing lymph node metastasis. However, few reports have examined its role in the decision to perform cervical lymph node dissection in esophageal carcinoma. METHODS: Ultrasound examination was performed to evaluate cervical lymph node metastasis in 519 patients with esophageal carcinoma. The patients were divided into 5 groups according to treatment received: group 1, 153 patients who underwent curative resection of primary tumor by right thoracotomy and complete bilateral cervical lymphadenectomy; group 2, 112 patients who underwent curative resection of primary tumor by right thoracotomy but without cervical lymphadenectomy; group 3, 78 patients who underwent esophagectomy by left thoracotomy or blunt dissection with or without removal of cervical lymph nodes; group 4, 76 patients with palliative resection without cervical lymphadenectomy; and group 5, 100 patients without any surgical treatment. US diagnosis was compared with histologic findings or cervical lymph node recurrence. RESULTS: Lymph node metastasis was detected in 30.8% of patients (160/519). The sensitivity, specificity, and accuracy of US diagnosis in group 1 were 74.5%, 94.1%, and 87.6%, respectively. Cervical lymph node recurrence was seen in 7 patients (4.6%) in group 1, in 4 patients (3.6%) in group 2, and 3 patients (3.8%) in group 3. Although the incidence of cervical lymph node metastasis as determined by US examination was high in groups 4 and 5, almost none of the patients died of cervical lymph node metastasis. CONCLUSIONS: Ultrasound examination plays a useful role in the decision to perform cervical lymph node dissection in patients with esophageal carcinoma, particularly in those with potentially curative dissection.

Esophageal Neoplasms↗

PubMed1999

Significance of anaerobic preincubation of Helicobacter pylori for measuring metronidazole susceptibility by the Etest.

The Etest is widely used for measuring the susceptibility of Helicobacter pylori to metronidazole. By using 55 H. pylori isolates from 55 patients and a standard H. pylori strain, NCTC11637, we compared metronidazole susceptibility results obtained from the Etest with or without anaerobic preincubation to those obtained from the agar dilution method. Mueller Hinton agar plates supplemented with 5% horse blood were used for both methods. For the Etest, plates were incubated for 72 hr at 35 C under microaerophilic conditions after 0-, 4- or 24-hr periods of anaerobic preincubation. For the agar dilution method, the plates were incubated at the same microaerophilic conditions as those for the Etest. Without anaerobic preincubation for the Etest, 39 of the 56 (70%) H. pylori isolates were categorized as resistant to metronidazole (minimal inhibitory concentration>8 mg/liter), whereas only one of the 56 (1.8%) isolates was resistant according to the agar dilution method. The resistant and susceptible agreement rate was 32%. Four-hour anaerobic preincubation did not alter the readings of the Etest significantly. However, when the Etest was performed with 24-hr anaerobic preincubation, the number of isolates categorized as resistant was reduced to six (11%), improving the agreement rate to 91%. For measuring the metronidazole susceptibility of H. pylori by the Etest, 24-hr anaerobic preincubation is necessary to agree with the results obtained by the agar dilution test.

Anaerobiosis↗

PubMed1999

Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats.

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti-carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2-week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6-week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN-76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.

Aminobiphenyl Compounds↗

PubMed1999

Therapeutic effect of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) on liver metastasis of xenotransplanted human colon carcinoma.

S-1 [1 M tegafur (FT)-0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP)-1 M potassium oxonate (Oxo)], was developed as a new oral antineoplastic agent based on biochemical modulation of fluorouracil (5-FU) by CDHP and Oxo. The therapeutic effect of S-1 on human colon cancer xenografts (TK-13) with high metastatic potential to the liver was evaluated. Small pieces of TK-13 were sutured into the cecal wall of 52 nude mice, and the animals were randomly divided into 3 groups [control (n=17), UFT (combination of 1 M FT and 4 M uracil) (n=18) and S-1 (n=17)]. S-1 or UFT was administered orally at an equitoxic dose (S-1, 7.5 mg/kg; UFT, 17.5 mg/kg as FT) for 37 consecutive days beginning 10 days after the transplantation. S-1 showed higher tumor growth inhibition than UFT (P<0.05) and also showed a significant anti-metastatic effect on liver metastasis, while UFT did not. Liver metastasis developed in only 2 of the 17 mice (12%) in the S-1 group, whereas it developed in 9 of the 17 (53%) and 7 of the 18 (39%) in the control and UFT group, respectively. Analysis of AUC (area under the curve) revealed that S-1 yielded higher 5-FU levels in both tumor tissue (1.6 times) and plasma (2.5 times) than UFT. These results suggest that S-1 will show a higher clinical therapeutic effect against human colorectal cancer than UFT.

Animals↗

PubMed1999

Antitumor effect on human gastric cancer and induction of apoptosis by vascular endothelial growth factor neutralizing antibody.

Induction of apoptosis by antiangiogenic therapy has been suggested as a new anticancer strategy. To clarify the mechanism of the antitumor effect achieved by inhibition of vascular endothelial growth factor (VEGF), which is a major mediator of angiogenesis, we used an orthotopic transplantation model of human gastric carcinoma line (MT2) treated with a monoclonal VEGF neutralizing antibody (VEGF Ab). We histologically examined the microvessel density (MVD) and the apoptotic index (AI) in this model. Transplanted tumor growth was significantly inhibited by the VEGF Ab (P = 0.03), and there was a significant decrease in the number of mice with liver metastasis (P = 0.004). The MVD detected by immunohistochemical staining with ER-MP12 antibody was 33.6 +/- 8.0 in the control group and 21.1 +/- 5.4 in the treated group, and the difference was significant (P < 0.0001). The AI values of the control and treated groups were 4.73 +/- 1.11 and 7.26 +/- 1.62, respectively, and this difference is also significant (P < 0.0001). However, the expression of VEGF mRNA in transplanted tumors did not show a significant difference between the control and treated groups. These results suggest that the antitumor effect of the VEGF Ab on human gastric carcinoma is exerted by inducing mild hypoxia followed by apoptosis, which does not influence VEGF mRNA expression in the carcinoma.

Adenocarcinoma↗