Biomedical subjects
Publications and source records attributed to K Isono.
A patient with obstructive jaundice was found to have bile duct carcinoma and right hepatic lobe agenesis. The diagnosis was made by computed tomography (CT), cholangiography, and angiography. Right hepatic lobe agenesis is a rare anomaly and has never been previously reported with bile duct carcinoma. CT cholangiography was critical in diagnosing the morphologic anomalies of the bile duct in this case.
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Anabolism of 5-fluorouracil (5-FU) in the presence of uracil was examined using the cell-free extract of Ehrlich ascites tumor cells. FU-nucleoside formation from 5-FU with ribose 1-phosphate (R-1-P) or 2'-deoxyribose 1-phosphate was not readily inhibited even by the addition of uracil at 100 times higher concentration than 5-FU. FU-nucleotide formation from 5-FU with R-1-P and adenosine 5'-triphosphate or with 5-phosphoribosyl 1-pyrophosphate was slightly reduced as the concentration of uracil was increased. It was also found that 5-fluorouridine (5-FUR) was produced by "nucleoside N-ribosyltransferase," transferring a ribose moiety from uridine (UR) to 5-FU directly. This activity might play a role in the preferential formation of 5-FUR. However, 5-fluoro-2'-deoxyuridine was not produced by directly transferring a deoxyribose moiety. On the basis of several column chromatographies and characterization of kinetics, pH dependency, and response to inhibitors, the enzyme protein of the ribosyltransferase could not be distinguished from that of the phosphorylase.
We have investigated the antitumor effect of murine colon carcinoma cells developed to produce cytokines. Retrovirally transduced cells were inoculated into syngeneic mice, and their survivals were examined. Inoculation of interleukin-4 (IL-4)- or granulocyte macrophage-colony stimulating factor (GM-CSF)-producing cells alone did not affect the survival of the mice. In the tumors derived from an admixture of IL-4 and GM-CSF producers, however, regression developed spontaneously, and prolonged survival of the challenged mice was consequently observed. Histological examination revealed predominant infiltration of neutrophils around the tumor of a mixed population of IL-4 and GM-CSF producers.
In this study, an experiment was performed to investigate the optimal concentration of branched chain amino acid (BCAA) in hyperalimentation to be administered when protein catabolism is accelerated by sepsis or bodily injury. Amino acid solutions containing BCAA 25%, 30%, 40%, 45% and 50% were prepared and were administered iv for three days with other essential amino acid-containing nitrogen in the same volume into rats with peritonitis which had been developed by ligature and puncture at the cecum, and the results were compared. After observing for three days, the influence over nitrogen balance, improvement of 3-methyl-histidine/creatinine in urine, weight loss in muscles, and aminogram in serum and muscles indicated that the hyperalimentation under stress is utilized most effectively when amino acid contains 45% of branched-chain amino acid.
The significance of serum p53-Abs in patients with esophageal squamous cell carcinoma was determined. Examination of clinicopathological features and assessment of tumor marker sensitivities of carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag) and CYFRA21-1 were performed. Thirty-three (58%) of 57 patients were positive for serum p53-Abs, however, no relation with cancer progression existed. Fourteen of the 33 sero-positive patients revealed normal levels of all tumor markers tested. Thus, serum p53-Abs appears to be a useful marker for the detection of esophageal squamous cell carcinoma.
BACKGROUND: The anti-tumor effects of high-energy shock waves (HESW) in combination with cisplatin (CDDP) and ATX-70, as a photosensitizer, were investigated in vitro and in vivo. METHODS: Active oxygen generation by HESW was studied by means of electron spin resonance (ESR) system. The anti-tumor effects of HESW in combination with cisplatin (CDDP) and ATX-70 was investigated in vitro and in vivo. RESULTS: HESW exposure induced singlet oxygen or hydroxyl radical. Adding ATX-70 enhanced the cell damage induced by HESW dose-dependently. Ascorbic acid inhibited the combined effect of HESW and ATX-70. Adding CDDP did not enhanced cell damage by HESW. The combined therapy of HESW, CDDP and ATX-70 showed further inhibition of tumor growth in vivo. CONCLUSIONS: These results indicate that HESW activated ATX-70, and that the anti-tumor effect of HESW and ATX-70 was caused by active oxygen generation. HESW is able to be utilized with any other cancer treatment.
Induction of apoptosis with chemotherapeutic agents or radiation in tumours is frequently related to the status of those p53 gene of the tumours. To examine whether forced expression of the wild-type p53 gene in tumour cells can modulate their susceptibility to radiation and anti-cancer agents, we retrovirally transduced two types of human breast cancer cell lines, which respectively harboured a mutated p53 gene (OCUB-M) or wild-type p53 gene (YMB-1), with the wild-type p53 gene. Transduced cells which consistently expressed the wild-type p53 gene (OCUB-M/p53, YMB-1/p53) proliferated at the same rate as control cells which were transduced with the beta-galactosidase gene (OCUB-M/lacz, YMB-1/lacz). However, sensitivity to radiation was increased in OCUB-M/p53 cells but not in YMB-1/p53 cells. In vitro chemosensitivity to DNA-damaging anticancer agents such as cyclophosphamide and 5-fluorouracil was not influenced by the transduction of the wild-type p53 gene in either cells. Expression of the wild-type p53 gene in p53-mutated human breast cancer cells can therefore increase their sensitivity to radiation but not their chemosensitivity. Therapeutic effects following by the transduction of the wild-type p53 gene were not observed in breast cancer cells already bearing the wild-type p53 gene.
Mucoepidermoid carcinomas of the salivary gland comprising low (n = 6), intermediate (n = 11) and high grade malignant (n = 11) tumors were evaluated for immunohistochemical reactivity of cytokeratin (monoclonal antibody KL1, PKK1, K8.12), vimentin, involucrin and secretory proteins (lysozyme, LY; lactoferrin, LA; alpha 1-antitrypsin, alpha 1-AT and alpha 1-antichymotrypsin, alpha 1-Ach). Keratin expression was usually confined to intense staining in epidermoid tumor cells, but was negative in almost all mucous cells. Vimentin was coexpressed with keratin only in epidermoid tumor cells. Great heterogeneity of intermediate filament proteins was found in intermediate and epidermoid tumor cells. Involucrin in epidermoid tumor cells was particularly abundant in well keratinized cells but was lacking in intermediate and mucous forming cells. The frequency of occurrence of positive staining for LY, LA, alpha 1-AT and alpha 1-Ach was relatively low in mucoepidermoid carcinoma with positive immunohistochemical staining for these secretory proteins in mucous forming tumor cells, while varying expression was observed in epidermoid tumor cells.
A total of 14 cases of clear cell carcinoma of salivary glands were evaluated by immunohistochemical methods using monoclonal antibodies to cytokeratin (K1.1 and K8.12), vimentin, S-100 alpha and beta subunits, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), MAM-3 and MAM-6 antigens and proliferating cell nuclear antigen (PCNA), as well as polyclonal antibodies to lysozyme (Ly), lactoferrin (la) and Alpha-1-antichymotrypsin (alpha 1-Ach). Histopathologically, the carcinoma was characterized by round or polygonal tumor cells with cytoplasm that does not stain with hematoxylin and eosin, nuclei with little pleomorphism and few or no mitotic figures, and growing in solid sheets, small nests or cords with collagenous stroma. Cytokeratin KL1 and K8.12 was present in few tumor cells with almost negligible to strong reaction in all cases, vimentin in 6, GFAP in 5 cases with multiple-expression of cytokeratin K8.12, vimentin and GFAP in 5 cases. S-100 protein immunoreactivity was the most prominent feature with more intense reaction of S-100 beta than S-100 alpha subunit. NSE reactivity was seen in 6 cases. Ly, La, a1-ch, MAM-3 and MAM-6 antigens were localized in clear cells with various reaction intensities. The authors conclude that the clear tumor cells in clear cell carcinoma of salivary glands are not myoepithelial in origin but epithelial or neuroectodermal/neural crest in origin, showing ductal differentiation at the immunohistochemical level.
We have examined the effects of irradiation on the cytokine secretion from genetically modified human esophageal and gastric carcinomas. Both cell lines were transduced retrovirally to secrete interleukin-2, interleukin-6 and granulocyte-macrophage colony-stimulating factor, respectively. The metabolism of all the transduced cells was partially inhibited by 6 Gy, and greatly inhibited by 20 Gy irradiation. Cytokine productions, however, was not affected by 6 Gy in many cases, and continued to be detected even after 60 Gy irradiation. The analysis of the dose and time of irradiation in each cytokine producer is useful for the designing of tumor vaccine using cytokine gene transfer.
We examined the correlation between the amount of exogenous protein secreted and that of its viral transcript from PA317 packaging cells transduced with a cytokine gene. Amphotropic packaging cells for the retrovirus expressing murine interleukin-15 (IL-15) gene were cloned, and we examined 22 clones for both the amount of IL-15 secreted with enzyme-linked immunosorbent assay and the IL-15 transcript released as infectious virions by slot blot-hybridization analysis. The study revealed that there was no statistical correlation between them, and suggests that the integrated transcript is used discordantly. Thus, the examination of secreted protein from packaging cells cannot be substituted for laborious assays to determine the amount of virion transcripts when isolating high titer packaging cells.
We examined the antitumor effect of low and high interleukin-2 (IL-2) producers of murine colon carcinoma cells (Colon 26) which were generated by transduction with IL-2 gene in an experimental lung metastasis model using syngeneic mice. Intravenous injection of the low IL-2 producer cells formed multiple lung metastatic foci and the survival of the mice was not different from that of the mice injected with wild-type cells. However, the mice administrated with the high producer cells survived significantly longer. Subcutaneous inoculation of the low producers, although it caused the development of local tumors at the inoculation sites in some of the mice tested, inhibited lung metastasis of wild-type cells subsequently inoculated and prolonged the survival of the mice rechallenged with Meth A cells, syngeneic fibrosarcoma cells. In contrast, inoculation of the high producers did not cause the development of subcutaneous tumors and inhibited the experimental metastasis of parental but not Meth A cells inoculated thereafter. Thus, the amount of secreted IL-2 from tumor cells differentially influences antitumor effects by inducing tumor specific and nonspecific immunity.
The inoculation of cytokine-producing tumor cells into syngeneic animals can produce antitumor effects. We previously reported that injection of a mixed population of murine colon carcinoma (Colon 26) cells transduced with interleukin-4 (IL-4) gene with granulocyte macrophage-colony stimulating factor (GM-CSF) gene developed subcutaneous tumors in syngeneic mice, but these tumors thereafter regressed spontaneously (Oncology 1997;54:69-73). In this study, we found the generation of tumor-specific acquired immunity in the mice which had rejected the tumors of a mixed population of IL-4 and GM-CSF producer cells, and that the immunity was mediated by mature T cells. Moreover, local secretion of both IL-4 and GM-CSF in the vicinity of tumors was found to be crucial for this rejection. These data suggest that enhanced host defense brought about by the combined expression of IL-4 and GM-CSF genes in tumor cells is a potential therapeutic strategy.
We have examined the antitumor effect of the retrovirally expressed interleukin-2 (IL-2) gene in murine colon carcinoma cells (Colon 26) on a disseminated model within the peritoneal cavity. Intraperitoneal injection of IL-2-producing Colon 26, but not wild-type cells, into syngeneic mice did not cause animal death and conferred T-cell-dependent, tumor-specific protective immunity on the inoculated mice. Direct administration of the retrovirus harboring IL-2 gene into the peritoneal cavity of the mice that had intraperitoneal tumor of wild-type cells significantly prolonged the survival of the mice compared with that of the mice that received control retrovirus. In the surviving mice treated with the retrovirus we also observed the induction of protective immunity with tumor specificity. Integrated retrovirus DNA was not detected in any organs examined. Thus, in vivo IL-2 gene transfer by retrovirus enabled tumor-bearing mice to generate antitumor immunity without unnecessary retroviral insertion into host genome.