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Biomedical subjects

K Ishibiki

Publications and source records attributed to K Ishibiki.

At least 19 recordsLinked to original sources
PubMed1994

Synergistic antitumor activity of combination chemotherapy with mitomycin C and cisplatin against human gastric cancer xenografts in nude mice.

A new combined cancer chemotherapy regimen of mitomycin C (MMC) and cisplatin (DDP) showed synergistic antitumor activity against human gastric cancer xenografts St-40 and SC-1-NU in BALB/c nu/nu mice. The drugs were administered intraperitoneally at doses of 2 or 4 mg/kg for MMC and 3 or 6 mg/kg for DDP, respectively. To clarify the schedule-dependent antitumor activity of MMC and DDP against St-40 and SC-1-NU, different sequential therapies were conducted. Simultaneous administration of these agents showed the highest antitumor activity against SC1-NU among the three regimens used, whereas the sequence of MMC followed by DDP showed higher antitumor activity than the reverse sequence against St-40. The intratumoral concentration of platinum was significantly increased in St-40 treated with the sequence MMC to DDP, in comparison with the sequence DDP to MMC. The maximum tolerated dose (MTD) of this combination was 4 mg MMC plus 6 mg DDP per kg in all the combinations, and these MTDs were 2/3 of the corresponding values for their single use. Since this combination increased the antitumor activity of each single agent without any increase in their toxicity, it would appear to be useful clinically.

Adenocarcinoma↗
PubMed1994

Dose intensity of mitomycin C in adjuvant cancer chemotherapy for patients with gastric cancer.

Using a cohort of macroscopic curative resections of gastric cancer at stages II, III, and IV, a randomized controlled trial was performed to elucidate the dose efficacy of intensive adjuvant cancer chemotherapy with mitomycin C. Between June 1983 and December 1986, 336 patients with gastric cancer from 31 institutes were enrolled in the study. The cohort was stratified randomly by the telephone method into two arms. Group A received 20 mg and 10 mg of mitomycin C per body intravenously (IV) on postoperative days 0 and 1, respectively, and then tegafur at 600 mg/body daily perorally (PO) from postoperative week 2 for 1 year. Group B also received 0.2 mg of mitomycin C per kg IV at 3, 6, 9, and 12 months after surgery. The background factors in groups A and B were essentially identical, and the adverse effects were tolerable in both groups. The total administered doses of mitomycin C were significantly higher in group B than in group A, according to the protocol. Although no significant differences were observed in the actuarial overall survival rates between groups A and B at stages II, III, and IV, favorable survival was observed in group B, which received histologically absolute curative resection. This dose-intensive adjuvant cancer chemotherapy would be useful for gastric cancer patients treated by histologically curative surgery.

Chemotherapy, Adjuvant↗
PubMed1994

Combination chemotherapy with mitomycin C and cisplatin for advanced gastric cancer with multiple liver metastases.

A patient with advanced gastric cancer with multiple liver metastases was treated by reduction surgery at the primary site as well as by the intraarterial administration of mitomycin C (MMC) and cisplatin (CDDP) through a reservoir catheter inserted into the proper hepatic artery. After a palliative subtotal gastrectomy, MMC 8 mg/m2 was administered intraarterially (i.a.) followed by the administration of CDDP 80 or 40 mg/m2 i.a. with an interval of less than 1 week. After the completion of five courses of this regimen, a complete reduction of the hepatic tumors was achieved, while the level of serum carcinoembryonic antigen decreased to the normal range. The patient is currently alive with signs of disease recurrence at 17 months after initial diagnosis, while additional therapy with MMC + CDDP was continuously undergone until 17 months' after initial diagnosis with various interval. Although thrombocytopenia occurred during the treatment, it resolved within a few weeks after completing the combination chemotherapy without any specific treatment. The present case showed a better prognosis than we had expected, which suggested that combination chemotherapy with MMC and CDDP might thus be clinically useful because of its excellent antitumor activity and low toxicity.

Adenocarcinoma↗
PubMed1994

Improvement of therapeutic effect by using Fab' fragment in the treatment of carcinoembryonic antigen-positive human solid tumors with adriamycin-entrapped immunoliposomes.

To improve the therapeutic efficiency adriamycin entrapped in antibody-conjugated liposomes, Fab' fragment was used instead of the whole antibody molecule. The murine monoclonal antibody, 21B2, against human carcinoembryonic antigen (CEA) was digested with pepsin, and the thiol residue of intra-heavy chain produced by reduction of F(ab')2 with dithiothreitol was conjugated to liposomes containing adriamycin. The tissue distribution of adriamycin delivered with these liposomes was studied in BALB/c nu/nu female mice bearing CEA-positive human gastric cancer strain MKN-45. An increase in delivery of adriamycin to the tumor was observed in the mice given liposomes with Fab' fragment as compared to those given liposomes with whole antibody. However, the preferential distribution of adriamycin in liposomes to the reticuloendothelial cells remained the same regardless of the use of Fab' fragment. For investigation of in vivo therapeutic effect, three i.v. injections of free adriamycin or adriamycin in liposomes equivalent to 5 mg/kg were given, and adriamycin in Fab' fragment-conjugated liposomes was found most effective in the inhibition of tumor growth. This was confirmed in terms of actual tumor weights excised and CEA concentration in the blood, as well as by pathological observations. The advantages of using Fab' fragment instead of whole antibody are discussed.

Animals↗
PubMed1994

Single-cell suspension assay with an MTT end point is useful for evaluating the optimal adjuvant chemotherapy for advanced gastric cancer.

One hundred and forty-eight patients with gastric cancer admitted to Keio University Hospital between July 1988 and October 1992 underwent resection of the primary lesion, as well as single-cell suspension assay of fresh surgical materials with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay) for chemosensitivity evaluation. Fifty patients with histologically stage III or IV gastric cancer were enrolled in this study, among whom 10 received no chemotherapy after surgery while 40 received chemotherapy at equivalent dose levels after surgery. The patients given chemotherapy were divided into two groups consisting of an "Adapted" group treated with at least one agent identified as effective by the assay, and a "Non-adapted" group treated with agents to which the cells were not sensitive in the assay, in order to identify the optimal cut-off inhibition rate (IR) in MTT assay for evaluation of the appropriate adjuvant cancer chemotherapy after surgery. A cut-off IR of 30% was optimal for differentiating the survival rates between the "Adapted" and "Non-adapted" groups. Patients treated with drugs which showed more than 30% IR on their surgical specimens showed a better survival rate than patients treated with drugs which were ineffective in the assay.

Adult↗
PubMed1994

[Bacteria isolated from intraabdominal infection and their susceptibilities to antimicrobial agents].

Bacteria isolated from intraabdominal infections during the period from July 1982 to June 1993 were investigated with regard to their classifications according to a joint research by 9 university hospitals in Japan. The following results were obtained. 1. A total of 971 strains were isolated from 684 out of 597 patients with peritonitis, and 287 strains out of 971 were isolated from postoperative peritonitis. 2. The most predominant organism isolated from patients with acute peritonitis was Escherichia coli (28%), followed by Bacteroides fragilis group (17%), Gram-positive anaerobic cocci (16%), Enterococcus spp. (9%) and Klebsiella spp. (8%). 3. Against E. coli, cefmenoxime, cefuzonam, cefozopran, aztreonam and carumonam showed MIC50 less than 0.05 micrograms/ml. Against B. fragilis group, erthromycin, clindamycin, imipenem, lincomycin and latamoxef showed MIC50 less than 0.78 micrograms/ml. 4. The most predominant organism isolated from patients with postoperative peritonitis was Enterococcus spp. (20%) and followed by Pseudomonas spp. (14%), and Staphylococcus spp. (13%), E. coli (9%), Enterobacter spp. (8%) and Klebsiella spp. (8%). We suggest that cefazolin, cefmetazole, flomoxef, cefmenoxime, cefuzonam, and latamoxef are the first choice agents in empiric therapy for the treatment of acute peritonitis.

Aged↗
PubMed1994

[Year to year changes in isolation frequencies of different bacteria from postoperative infections].

Bacterial species isolated from postoperative infections during the period from July 1982 to June 1993 were studied regarding isolation frequencies of different species in different years in a joint research project involving nine (9) university hospitals in Japan. The obtained results are summarized as follows. (1) Altogether, 1,453 strains were isolated with 153 strains obtained during the most recent one year from July of 1992 through June of 1993. The most numerous source of isolation was postoperative intra-abdominal sepsis. (2) Gram-positive cocci were the most often isolated, among them methicillin-resistant Staphylococcus aureus was isolated in increasing frequencies until June, 1992. (3) In the last one year, Enterococcus spp. was isolated the most from postoperative infections followed by Staphylococcus spp. and Pseudomonas spp. Rates of isolation of anaerobic bacteria were relatively low with annual isolation frequencies ranging 8 to 15 per cent.

Digestive System Diseases↗
PubMed1993

A suitable model for experimental liver metastasis of human colon cancer xenografts using mice with severe combined immunodeficiency.

Studies on liver metastasis of human colon cancer are limited because of a lack of suitable animal models. In this study, the usefulness of mice with severe combined immunodeficiency (SCID), which congenitally lack functional T and B lymphocytes, was evaluated in comparison with currently available nude mice. Three human colon cancer xenografts transplantable into nude mice were disaggregated enzymatically to obtain tumor cell suspensions, and implanted intrasplenically into SCID and nude mice. The incidence of splenic tumorigenesis and of liver metastases were significantly greater in SCID mice for all xenografts, in comparison with nude mice. In total, 33 of 36 SCID mice and 17 of 43 nude mice developed liver metastases. On the basis of this result, we conclude that SCID mice would be a more suitable model than nude mice for studying liver metastasis of human colon cancer.

Adenocarcinoma↗
PubMed1993

Synergistic antitumor activity of mitomycin C and cisplatin against gastric cancer cells in vitro.

The synergistic antitumor activity of mitomycin C (MMC) and cisplatin (DDP) against the gastric cancer cell lines MKN-28 and MKN-45 was assessed in vitro using the MTT assay. The synergism of the two agents was evaluated in terms of the interaction index (I.I.). The sequence of MMC followed by DDP showed higher antitumor activity than the reverse sequence against MKN-28 and MKN-45, and the intracellular concentration of platinum was significantly increased in MKN-45 by preincubation with MMC, suggesting that MMC modulates cellular permeability to DDP or the ability of DDP to intercalate DNA. Since these two antitumor agents show different types of toxicity clinically, i.e., myelotoxicity by MMC and nephrotoxicity by DDP, this combination chemotherapy could be advantageous by providing synergistic antitumor activity without increased toxicity.

Adenocarcinoma↗
PubMed1993

Growth of human tumor xenografts in nude mice and mice with severe combined immunodeficiency (SCID).

Twenty-three fresh tumor specimens obtained at surgery and 5 serially transferable human tumor xenografts were implanted subcutaneously into nude mice and mice with severe combined immunodeficiency (SCID) to compare the take rates of the fresh surgical specimens and the growth rates of the transferable strains. The overall take rates were 65% for the SCID mice and 60% for the nude mice, without any significant difference, although colon carcinoma seemed to have higher acceptance in the SCID mice with a take rate of 6/8. All the serially transferable strains were successfully accepted in the SCID mice, their growth rates being essentially identical to those in the nude mice. These results indicate that the SCID mouse can be used as a human tumor xenograft-mouse system as well as the nude mouse.

Adenocarcinoma, Mucinous↗
PubMed1993

A metastatic model of human colon cancer constructed using cecal implantation of cancer tissue in nude mice.

COL-2-JCK, a human colon cancer xenograft line able to be transplanted into nude mice, was implanted in the subserosal layer of the cecum, either as cancer tissue or as a single cell suspension. When cancer tissue was used for the cecal implantation, 100% extensive local tumor growth and a high incidence of metastases to the regional lymph nodes, peritoneum, liver, and lung was observed. In contrast, when the cell suspension of this line was injected into the cecal wall, no metastases were observed, with significantly reduced local tumor growth. The use of cancer tissue maintaining the original cancer tissue structure is therefore considered imperative for allowing full expression of the biological characteristics of cancer cells. This nude mouse model using the cecal implantation of cancer tissue should thus prompt further study on the biology of human colon cancer.

Animals↗
PubMed1993

The modulation by L-leucovorin of 5-fluorouracil antitumor activity on human colon carcinoma cells in vitro and in vivo.

We investigated the modulating effect of L-leucovorin (LV) on the antitumor effect of 5-fluorouracil (5-FU) against human colon carcinoma cells (C-1) in vitro and human colon carcinoma xenografts (Co-4) in nude mice. The modulating effect of LV on 5-FU reached an optimal concentration of 40-80 micrograms/ml in vitro which was detected by a colorimetric MTT assay. An optimal dose of 200 mg/kg was also observed in the nude mouse system. The modulating effect of LV increased according to the increment of thymidylate synthetase inhibition in vivo. Since the pharmacokinetic pattern of LV in the nude mice administered LV at 200 mg/kg was similar to that in patients treated with LV at a dose of 100 mg/m2, this clinical method of administration was thought to be adequate for modulating the antitumor activity of 5-FU against clinical colon carcinomas.

Adenocarcinoma↗
PubMed1993

Enhancement of antitumor activity of cisplatin on human gastric cancer cells in vitro and in vivo by buthionine sulfoximine.

An attempt was made to evaluate the enhancement of the antitumor activity of cisplatin (DDP) by buthionine sulfoximine (BSO) in vitro and in vivo. In the in vitro study, pre-treatment with BSO (5, 10 and 25 mM) increased the antitumor activity of DDP against the gastric cancer cell lines MKN-28 and MKN-45, whereas BSO alone exhibited only slight antitumor activity (inhibition rate, 20-30%). In the in vivo study, the antitumor effects of DDP against human gastric cancer xenografts St-15 and SC-1-NU in BALB/c nu/nu mice were enhanced pretreatment with BSO, which was administered intraperitoneally at a dose of 500 mg/kg according to a schedule of qd x 3. BSO alone showed no antitumor effects against these tumors in nude mice. The side effects (assessed in terms of death rate and body weight loss) associated with the maximum tolerated dose of DDP (9 mg/kg) were not increased by BSO pretreatment. As BSO increased the antitumor activity of DDP without a corresponding increment of its toxicity, BSO appears to be a promising agent for further study.

Animals↗
PubMed1992

High in vitro-in vivo correlation of drug response using sponge-gel-supported three-dimensional histoculture and the MTT end point.

The in vitro sponge-gel-supported three-dimensional histoculture chemosensitivity assay (Hoffman assay) allows the in vivo-like culture of human tumors. In this study, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) end point was applied to the Hoffman assay in an attempt to increase in vitro-in vivo correlation. The chemosensitivities of 16 human tumor lines were determined in vitro by the histoculture assay, and retrospectively correlated to their in vivo chemosensitivity as xenografts in nude mice. The in vitro test was considered to be positive if tumor-cell MTT reduction activity was lowered by more than 50%. The cutoff drug concentrations to determine sensitivity in vitro were determined for mitomycin C, doxorubicin, 5-fluorouracil and cisplatin. Using these cutoff drug concentrations in vitro we found, as a function of time of exposure, a strong correlation between serum drug concentrations found in nude mice given maximum tolerated doses and drug concentrations found in the histoculture media in vitro, thereby establishing a relationship between the amounts of drugs to which tumors were exposed in vivo and in vitro. The overall correlation rate of the efficacy results of the drug-response assay to in vivo chemosensitivities was 89.8%, with 90.0% true-positive and 89.7% true-negative rates, 81.7% sensitivity and 94.6% specificity, thereby indicating potential clinical use for tumor histoculture with the MTT end point.

Animals↗
PubMed1992

Increased drug resistance of cultured human cancer cell lines in three-dimensional cellular growth assay using collagen gel matrix.

We have conducted a three-dimensional cellular growth assay using collagen gel matrix with an endpoint of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay, on four human gastric and colonic cancer cell lines. Three-dimensionally growing cells in collagen gel matrix were 2- to 180-fold more resistant to mitomycin C, doxorubicin, 5-fluorouracil, and cisplatin than those in monolayer culture, and these resistances were increased further when the cells increased their three-dimensionality. Furthermore, the influence of fibroblasts in the collagen gel matrix on the chemosensitivity of cancer cells was less than that in monolayer culture. Since this new assay using collagen gel matrix with an endpoint of the MTT assay was able to detect the increase of drug resistance of human cancer cell lines by three-dimensional cellular growth using a simple and convenient procedure, it was considered to be more useful than conventional monolayer cultures for evaluating the chemosensitivity of cancer cells.

Adenocarcinoma↗
PubMed1992

Targeting cancer chemotherapy using a monoclonal antibody (NCC-LU-243) conjugated with mitomycin C.

Two kinds of immunoconjugate (T-3M and T-11M) of murine monoclonal antibody with mitomycin C (MMC) were developed using spacers containing a disulfide (T-3M) or thiocarbamate (T-11M) bond. A murine monoclonal antibody (NCC-LU-243) raised against a human small cell lung carcinoma cell line, Lu-24, in nude mice, is an IgG2a monoclonal antibody that recognizes a 145-kDa protein on the cell surface membrane. T-3M and T-11M showed affinity for the LU-243 antigen-positive H-69 cell line but not for the antigen-negative Lu-65 cell line in vitro. In the in vitro MTT assay, the order of efficacy of these compounds was T-11M > T-3M > MMC against antigen positive H-69 and T-11M = MMC > T-3M against antigen-negative K562. When antigen-positive H-69 was transplanted into nude mice for in vivo assay, the maximum tolerated dose of T-3M was twice as high than that of the parent compound MMC. Furthermore, T-3M showed higher antitumor activity against antigen-positive H-69 than MMC conjugated with a non-specific rabbit IgG in vivo. When the maximum tolerated doses of T-3M and MMC were administered to H-69-bearing nude mice, the effect of T-3M was superior to that of MMC, whereas no differences were observed between the antitumor activity of T-3M and MMC against antigen- negative MX-1, a human breast carcinoma. These two immunoconjugates of monoclonal antibody with mitomycin C are thought to be useful for targeting cancer chemotherapy against human small cell lung carcinomas.

Animals↗