Biomedical subjects

M Kitajima

Publications and source records attributed to M Kitajima.

At least 451 records · Page 25Linked to original sources

PubMedDate not supplied

Similarity of serum-tumor pharmacokinetics of antitumor agents in man and nude mice.

A pharmacokinetic comparison was made between nude mice and human gastric cancer patients. This comparison is important in order to optimize the human tumor xenograft-nude mouse system as a screening panel for potential antitumor agents. In this report, mitomycin C (MMC), doxorubicin (DXR), 5-fluorouracil (5-FU) and cisplatin (DDP) were administered to nude mice bearing human tumor subcutaneous xenografts in maximum tolerated doses and to patients with gastric cancer at conventional doses. The concentrations of antitumor agents in serum and tumor were detected by bioassay for MMC and 5-FU, by high performance liquid chromatography for DXR, and by atomic absorption method for DDP. Peak drug concentrations in the serum (Cmax) the mice and humans correlated well with statistical significance (R = 0.999, P < 0.0001). When Cmax and drug concentrations in the tumor (T) the mice and human were compared with each other to evaluate the uptake of drugs into the tumor from the serum and calculated as T/Cmax, similar results were observed for the same agent with statistical significance (r = 0.990, p < 0.02). These results indicate that the human tumor xenograft-nude mouse system and humans are essentially similar pharmacodynamically, which further validates the uses of this system to evaluate potential antitumor agents.

Adult↗

PubMedDate not supplied

How to convert the rabbit gracilis muscle into a neoanal sphincter.

For reconstruction of anal function in fecally incontinent patients, transposition of the gracilis muscle around the anal canal, with electrical stimulation to maintain contraction, seems practical. But the fast-twitch gracilis muscle is incapable of prolonged contraction without fatigue. Furthermore, the muscle must keep some tension between each stimulus. When the pressure decreases even transiently between stimuli, the neoanus cannot maintain continence. To fulfill these criteria, the neoanal sphincter must be stimulated at a frequency that can induce sufficient summation. We demonstrated that conditioning with long-term electrical stimulation will induce such summation at low frequency. The nerve to the gracilis muscle of rabbits was continuously stimulated at 5 Hz and 10 Hz for 4 to 8 weeks. This conditioning reduced the frequency necessary for summation, and conditioning at 10 Hz for 6 or 8 weeks induced sufficient summation (fusion index [FI] > 90%) at 20 Hz. The muscles conditioned at 10 Hz for 8 weeks showed sufficient summation (FI = 81%) at 15 Hz, a frequency that produced muscle contraction without fatigue, since even unconditioned muscle will remain contracted at 10 Hz without fatigue for 8 weeks. It is concluded that conditioning at 10 Hz for longer than 6 weeks produces enough summation at a low frequency stimulation to permit prolonged contraction.

Anal Canal↗

PubMedDate not supplied

A hybrid artificial esophagus using cultured human esophageal epithelial cells.

It is important to cover an artificial esophagus with epithelium to prevent stenosis and reinforce the lumen. We examined the possibility of epithelialization of the surface of a latissimus dorsi muscle of athymic mice using cultured human esophageal epithelial cells. Normal human esophageal mucosa (0.5 cm2) was processed from specimens resected from patients with esophageal cancer, and epithelial cells were cultured on collagen gel in a culture dish (30 cm2) for about 10 days. The collagen sheets with cultured cells were transplanted onto the surface of latissimus dorsi muscles of 16 athymic mice. Four animals were killed 4, 8, 12, and 16 days after transplantation, and the transplanted collagen sheets were studied histologically. Cultured sheets had attached to the muscle in all 16 athymic mice. By 16 days, neovascularization in the collagen layer was observed and the epithelial cell layer was similar to normal human esophageal epithelium. This study suggests that epithelialization on latissimus dorsi muscle is possible using cultured human esophageal epithelial cells, and this could lead to the practical use of a hybrid artificial esophagus consisting of a latissimus dorsi muscle tube with its inner side epithelialized by cultured cells.

Animals↗

PubMedDate not supplied

Different chemo- and endocrino-sensitivity of MCF-7 cells with or without estradiol supplement in vitro.

The sensitivity of MCF-7 cells to tamoxifen (TAM) and mitomycin C (MMC) was assessed in rapidly and slowly growing cells with or without estradiol supplementation, respectively. The growth of MCF-7 was inhibited by MMC in a concentration-dependent manner with or without estradiol (E2) supplementation. Preincubation with MMC suppressed subsequent E2 stimulated growth of MCF-7. TAM inhibited the growth of MCF-7 supplemented with E2 and preincubation with TAM prevented subsequent E2 stimulated growth of MCF-7. However, TAM did not inhibit the growth of MCF-7 cells in E2 free medium. These results suggested that MMC may be more effective than TAM on breast cancer cells in the dormant or slow-growth phase.

Breast Neoplasms↗

PubMedDate not supplied

Site-specific chemosensitivity of human small-cell lung carcinoma growing orthotopically compared to subcutaneously in SCID mice: the importance of orthotopic models to obtain relevant drug evaluation data.

We have developed a novel in vivo model of human small-cell lung carcinoma (SCLC) using orthotopic reconstitution by injecting human SCLC in the tail vein of severe combined immunodeficient (SCID) mice whereby the SCLC grows in the lung and other organs. Cisplatin (DDP) had significant antitumor effects on the SCLC growing orthotopically in the lung whereas mitomycin C (MMC) did not, thereby reflecting the clinical situation. However, the opposite effects were found when the SCLC was growing subcutaneously, where the tumors responded to MMC and not to DDP. This suggests that the tumors growing orthotopically reflect the clinical effects of drugs on human SCLC more closely than the tumors growing subcutaneously. Therefore, this orthotopic reconstitution model of human SCLC in SCID mice is thought to be useful for studies on the treatment of human SCLC and emphasizes the need for orthotopic models for relevant cancer drug evaluation.

Animals↗

PubMedDate not supplied

Immunochemotherapy prevents human colon cancer metastasis after orthotopic onplantation of histologically-intact tumor tissue in nude mice.

A metastatic model of human colon cancer has been previously established using orthotopic onplantation of histologically intact in tissue nude mice. In this study, effects of immunochemotherapy using OK-432, 5-fluorouracil (5-FU) and mitomycin C (MMC) on Col-2-JCK, a human colon cancer xenograft, were evaluated using this model. When 5-FU and MMC were administered without OK-432, liver metastases were not reduced even at maximum tolerated doses of both drugs, although cecal tumor growth was significantly reduced. On the other hand, when combined with OK-432, both 5-FU and MMC reduced liver metastases with synergistic reduction of cecal tumor growth, demonstrating the potential of combining immunotherapy with chemotherapy against metastases.

Animals↗

PubMedDate not supplied

Early resection of primary orthotopically-growing human colon tumor in nude mouse prevents liver metastasis: further evidence for patient-like hematogenous metastatic route.

We have developed an orthotopic transplant model of human cancer to immunodeficient mice utilizing microsurgical techniques with intact tissue. The resulting transplanted human tumors grow locally and metastasize in a clinical-like pattern. However, there has been no definitive evidence in colon cancer that the human tumors metastasize via hematogenous route in nude mice. In the present study, in order to obtain definitive evidence of physiological spread of the human tumors, the primary tumors were resected 10 days after the initial orthotopic transplantation to the nude mice. The resection prevented metastases from forming, demonstrating that metastases of the human colon cancers occur after 10 days and by physiological and non-seeding mechanisms in the transplanted nude mice.

Animals↗

PubMedDate not supplied

Interferon beta increases antitumor activity of 5-fluorouracil against human colon carcinoma cells in vitro and in vivo.

The modulating effect of human fibroblast-derived interferon beta (IFN-beta) on the antitumor effect of 5-fluorouracil (5-FU) against human colon carcinoma cells in vitro and in vivo was investigated. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay was carried out in vitro using the cultured human colon cancer cell line C-1. IFN-beta at concentrations of 50, 500, 5,000 and 50,000 IU/ml was added to the cultured tumor cells with or without 5-FU at concentrations of 10, 50 and 500 micrograms/ml. The antitumor activity of 5-FU with or without IFN-beta was assessed using Co-4, a human colon carcinoma xenograft in nude mice, with reference to thymidylate synthetase inhibition. IFN-beta was administered subcutaneously daily for 14 days at doses of 6,000, 60,000 and 600,000 IU/mouse. The combined antitumor effect with 5-FU was evaluated by simultaneous intraperitoneal administration of 5-FU at doses of 10 and 20 mg/kg daily for 10 days. The antitumor activity of IFN-beta alone increased in a dose-dependent manner against Co-4 in nude mice, whereas its antitumor activity in vitro against C-1 was limited. The synergistic effect of 5-FU and IFN-beta was observed both in vitro and in vivo, and the in vivo synergism was obtained without any enhancement of thymidylate synthetase inhibition or side effects in terms of death rate and body weight loss. These results suggest that the mechanism of the combined effect of 5-FU and IFN-beta is not related to enhancement of thymidylate synthetase inhibition or the host immune system, since human fibroblastoid IFN-beta is species-specific to humans. The clinical usefulness of this combination method for the treatment of advanced colorectal carcinoma is expected.

Animals↗

PubMedDate not supplied

Methionine starvation modulates the efficacy of cisplatin on human breast cancer in nude mice.

There are few agents with activity against metastatic breast cancer. We therefore exploited the elevated methionine dependence of tumors to develop a selective and effective therapy against metastatic breast and other cancers. Methionine starvation leads to depleted methionine levels in cells, modifies methylation reactions, lowers glutathione levels and alters folate distribution and leads to a tumor-selective cell cycle arrest in late-S/G2. These effects present the opportunity for methionine depletion to modulate the efficacy of a number of different classes of chemotherapeutic drugs. This report demonstrates that methionine depletion can strongly modulate the efficacy of cisplatin against the MX-t human breast carcinoma cell line when grown in nude mice. The tumor-bearing nude mice were subjected to a methionine-free diet and were additionally treated with cisplatin i.p. at one mg/kg once a week for 3 weeks. The MX-t tumor was relatively resistant to both methionine starvation and cisplatin alone but was very sensitive to the combination of methionine starvation and cisplatin with a 32.1% T/C ratio. The intratumoral platinum concentration was higher in combination with methionine starvation than cisplatin alone, possibly accounting for at least part of the modulating effect of methionine depletion. Future studies will focus on methionine depletion via the enzyme methioninase to modulate cisplatin as well as other classes of chemotherapeutic agents in order to develop a new approach to the treatment of cancer.

Animals↗

PubMedDate not supplied

Interferons alpha-2a and beta increase the antitumor activity, detected by MTT assay, of 5-fluorouracil against experimental and clinical human gastrointestinal carcinomas.

In order to investigate the combined antitumor activity of 5-fluorouracil (5-FU), and recombinant human interferon alpha 2a (IFN alpha) or human fibroblastoid interferon beta (IFN beta), the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay was carried out using a cultured human colon cancer cell line (C-1) and fresh surgical specimens of gastric and colon carcinomas. IFNs did not show positive antitumor activity against C-1 cells, whereas 5-FU showed time- and concentration-dependent antitumor activity against C-1 cells. Furthermore, the antitumor activity of 5-FU on C-1 cells was augmented by IFN alpha or beta. When 5-FU (50 micrograms/ml) with IFN alpha (50 IU/ml). or IFN beta (50 IU/ml) was applied for the MTT assay with 48 hours incubation of fresh surgical specimens of gastric and colon carcinomas, the inhibition rates increased by 10% in 9 of 21 gastric specimens and in 18 of 36 colon carcinomas for IFN alpha (47.4% or 27/57), and in 8 of 15 gastric specimens and in 15 of 28 colon carcinomas for IFN beta (53.5% or 23/43). These results suggest that the chemosensitivity to 5-FU of human gastric and colon carcinomas is increased in the presence of IFNs, without involvement of the host-mediated immune system, and that this combined effect can be predicted by the MTT assay in vitro.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Slope analysis of CA19-9 and CEA for predicting recurrence in colorectal cancer patients.

CA19-9 and CEA are two serum tumor marker that are associated with gastrointestinal malignancy, including colorectal cancer. We measured the slopes of the serum CA19-9 and CEA concentrations in 264 patients with colorectal cancer. A positive CA19-9 slope was noted in 15.1% of the patients, and a positive CEA slope was noted in 19.5%. No clear-cut correlations were observed between the slopes of the two markers. The slopes of the CA19-9 and CEA correlated with both recurrence and survival. Measuring the slopes of the CA19-9 and CEA concentrations makes it possible to differentiate local from distant recurrences in patients with colorectal cancer. The combination of CA19-9 and CEA is more sensitive than either test alone for detecting recurrences. The assessment of both the serum CA19-9 and the serum CEA concentration is important in the clinical management of patients with colorectal cancer.

CA-19-9 Antigen↗

PubMedDate not supplied

Representation of the visual field in the striate cortex: comparison of MR findings with visual field deficits in organic mercury poisoning (Minamata disease).

PURPOSE: To compare MR imaging findings of the striate cortex with visual field deficits in patients with Minamata disease and to reestimate the classical Holmes retinotopic map by using the data obtained from comparing visual field abnormalities with degree of visual cortex atrophy. METHODS: MR imaging was performed in eight patients with Minamata disease who had been given a full neuroophthalmic examination, including Goldmann dynamic perimetry. The atrophic portions of the calcarine area were measured in the sagittal plane next to the midsagittal image and represented as a percentage of atrophy of the total length of the calcarine fissure. MR findings were compared with results of a visual field test. RESULTS: The visual field test revealed moderate to severe concentric constriction of the visual fields, with central vision ranging from 7 degrees to 42 degrees (mean, 19 degrees). The ventral portion of the calcarine sulcus was significantly dilated on MR images in all patients. A logarithmic correlation was found between the visual field defect and the extent of dilatation of the calcarine fissure. The central 10 degrees and 30 degrees of vision seemed to fill about 20% and 50% of the total surface area of the calcarine cortex, respectively. CONCLUSION: Visual field deficits in patients with Minamata disease correlated well with MR findings of the striate cortex. Our data were consistent with the classical Holmes retinotopic map.

Atrophy↗

PubMedDate not supplied

A streptococcal preparation (OK-432) enhances monoclonal antibody NCC-ST-421 cytotoxicity against human colon cancer.

The murine IgG3 monoclonal antibody NCC-ST-421 (ST-421), raised against human gastric cancer, shows strong reactivity with the Le(a)/Le(a) (al-fucosylated extended type 1 chain) antigen expressed on gastrointestinal (GI) cancer cells. ST-421 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) by human peripheral blood lymphocytes (PBL), and complement dependent cytotoxicity (CDC). We investigated combination immunotherapy with OK-432, a streptococcal preparation, and ST-421 in vitro and in vivo. ADCC against Colo 205 (a human colon cancer cell line) was enhanced 2 to 3 fold after preincubation of PBL with OK-432 in vitro. These effect's were strongest when PBL were preincubated with OK-432 at a concentration of 0.5 ng/ml for 24 hours. In vivo, a human colon cancer xenograft model exhibited significant growth suppression after combined treatment with ST-421 and OK-432. Such combination immunotherapy may therefore be clinically useful in GI cancer.

Adjuvants, Immunologic↗

PubMedDate not supplied

Mitomycin C and cisplatin increase survival in a human pancreatic cancer metastatic model.

Pancreatic cancer is one of the most intractable of all human cancers. We have previously developed a patient-like model of human pancreatic cancer by surgical orthotopic implantation (SOI). After SOI of the human tumor xenograft PAN-12-JCK into the tail of the nude mouse pancreas, mitomycin C (MMC) and cisplatin (DDP) were administered intraperitoneally at a dose of 4 and 6 mg/kg, respectively, on day-7. The mice were observed for 95 days. There was a statistically significant increase in disease-free and overall survival rates in the MMC- and MMC + DDP-treated groups. Local tumor growth was eliminated only in the group treated with MMC + DDP. Hepatic metastasis and peritoneal disseminations were completely inhibited by MMC but not DDP. This study demonstrates the usefulness of the SOI model of pancreatic cancer to study the differential efficacy of agents affecting primary tumor growth metastasis and survival, thus presenting an opportunity for the discovery of new agents for this highly resistant cancer.

Animals↗

PubMedDate not supplied

Methionine-depletion modulates the efficacy of 5-fluorouracil in human gastric cancer in nude mice.

Human tumors are generally methionine (MET)-dependent in that their growth is inhibited by MET-depletion down to levels that will still allow normal cell growth. The differential effect of methionine depletion on tumor and normal cells has suggested that methionine depletion may be able to modulate many and possibly all classes of cancer drugs. In this report, we determined if MET-depletion could modulate 5-fluorouracil (5-FU) efficacy on the human gastric cancer xenograft, SC-1-NU in nude mice. The tumor-bearing mice were treated with a MET-free diet and intraperitoneal administration of 5-FU at a dose of 30 mg/kg given for four cycles. MET depletion enhanced the antitumor activity of 5-FU by approximately two-fold with statistical significance of p < 0.05. The MET-free diet increased intratumoral thymidylate synthetase inhibition early after 5-FU administration; Therefore, MET-depletion was thought to increase the 5-FU antitumor activity by modulating intratumoral folate metabolism. The data in this report suggest the high clinical potential of methionine depletion, combined with 5-FU and leucovorin on refractory tumors such as stomach cancer.

Animals↗

PubMedDate not supplied

MKT-077, localized lipophilic cation: antitumor activity against human tumor xenografts serially transplanted into nude mice.

BACKGROUND: In in vitro experiments, the localized lipophilic cation, MKT-077, demonstrated time- and concentration-dependent antitumor activity. In the present experiment, the in vivo antitumor activity of MKT-077 was evaluated using human tumor xenografts serially transplanted into nude mice. MATERIALS AND METHODS: The antitumor efficacy of MKT-077 against five xenografts inoculated subcutaneously into nude mice was studied. Treatment with MKT-077 was initiated when the tumors started exponential growth. The antitumor activity of MKT-077 was assessed by a) the lowest value of the relative mean tumor weight of the treated:control tumors (T/CRW), where relative weight (RW) represented the change from baseline weight; and by b) the unadjusted weight of treated tumors at the end of the experiment. RESULTS: When MKT-077 was administered continuously using the Osmotic Micropump, antitumor activity was positively correlated with exposure time and drug concentration from 7.5 to 40 mg/kg/day. The maximum tolerated dose was 20 mg/kg/day for 7 days. Co-4 (human colon cancer), St-4 (human gastric cancer), and CRL1420 (human pancreatic cancer) were evaluated as sensitive to MKT-077 in tested 5 strains. CONCLUSION: The antitumor activity of MKT-077 was confirmed using human tumor xenografts in nude mice.

Animals↗

PubMedDate not supplied

Chemosensitivity of human pancreatic cancer cell lines serially transplanted in nude mouse.

BACKGROUND: Pancreatic cancer frequently recurs or metastasizes even after apparently curative surgical resection. Because of a low, five-year survival rate after radical surgery, multi-modal adjuvant treatment must be used to prevent recurrence of systemic spread. MATERIALS AND METHODS: The effectiveness of the experimental cancer chemotherapy of mitomycin C (MMC), cisplatin (DDP), doxorubicin (DXR) and 5-fluorouracil (5-FU) was evaluated in three human pancreatic cancer xenografts serially transplanted in nude mice. RESULTS: When the effects of these agents were evaluated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay, only MMC and DDP were effective on PAN-3-JCK, a poorly differentiated adenocarcinoma. When PAN-12-JCK, a moderately differentiated adenocarcinoma, was used an in vitro assessment of combined chemotherapy of MMC and DDP, a synergistic combination effect was observed. Three xenografts were transplanted subcutaneously into nude mice and the maximum tolerated doses of these agents were administered intraperitoneally or intravenously (DXR). MMC showed positive antitumor activity on PAN-3-JCK and PAN-12-JCK, and 5-FU was effective on PAN-12-JCK. CONCLUSIONS: These results reflect the low sensitivity of clinical pancreatic cancer to conventionally available antitumor agents, and suggest the possible synergistic combination antitumor activity of MMC and DDP.

Animals↗

PubMedDate not supplied

Further evidence for the value of the chemosensitivity test in deciding appropriate chemotherapy for advanced gastric cancer.

BACKGROUND: The chemosensitivity test using the MTT endpoint is useful in predicting chemosensitivity. PATIENTS AND METHODS: One hundred twenty-eight patients with advanced gastric cancer were enrolled in the study, which mitomycin C (MMC), doxorubicin (DXR), 5-fluorouracil (5-FU), and cisplatin (DDP) were used. RESULTS: The corresponding efficacy rates were 12.5% for MMC, 6.3% for DXR, 5.4% for 5-FU and 13.4% for DDP. The overall predictive accuracy was 78% in the patients with measurable lesions. Among the patients without measurable lesions, 21 were treated with a curative operation, and 33 with a non-curative operation. In those patients undergoing curative surgery, the "adapted" group detected by MTT assay survived longer than "non-adapted" cases (p < 0.05). CONCLUSIONS: The present study provides further evidence that the chemosensitivity test may be useful for evaluating appropriate chemotherapy for advanced gastric cancer.

Aged↗