Search PubMed⌕ Search

Biomedical subjects

D M Ota

Publications and source records attributed to D M Ota.

At least 55 records · Page 3Linked to original sources
PubMed1991

Current strategies in the management of locoregional and metastatic gastric carcinoma.

Gastric carcinoma remains a significant cause of death worldwide. A patient's prognosis depends on the degree of gastric wall penetration, presence of lymph node metastases, and location of the primary site. Metastatic gastric carcinoma is currently incurable. However, chemotherapy continues to evolve at a rapid pace. Active agents include 5-fluorouracil (5-FU), doxorubicin, cisplatin, methotrexate, mitomycin, and etoposide. Combination etoposide, doxorubicin, and cisplatin (EAP) has been reported to result in encouragingly high response rates, including a 10% complete response rate in patients with metastatic gastric carcinoma. Trials are now under way to confirm these results. Similarly, another etoposide-based combination, etoposide, leucovorin, and 5-FU (ELF), has resulted in an equally good response rate but less toxicity than EAP. The 5-FU, doxorubicin, and methotrexate (FAMTX) regimen, previously reported to have an excellent response rate, is also being investigated further. For patients with locoregional carcinoma, curative resection rate is often unsatisfactorily low; however, curative resection is consistently associated with improved survival (between 23 and 26 months). In patients with potentially resectable carcinoma, two significant problems must be recognized: (1) a low rate of curative resection and (2) the development of widespread carcinoma despite curative resection. Despite many attempts, the postoperative strategies of adjuvant chemotherapy have been ineffective. New strategies must be investigated aggressively. Combination etoposide, 5-FU, and cisplatin (EFP) has been administered preoperatively and postoperatively to patients with resectable gastric carcinoma, resulting in an encouraging curative resection rate (greater than 70%) and manageable toxicity. Based on promising results reported with EAP in patients with unresectable locoregional carcinoma of the stomach, a trial of preoperative and postoperative EAP in potentially resectable carcinoma of the stomach is now under way.

Antineoplastic Agents↗
PubMed1991

Increased content of an endogenous lactose-binding lectin in human colorectal carcinoma progressed to metastatic stages.

The quantity and localization of two lactose-binding lectins with molecular weights of 31,000 and 14,500 in human colorectal carcinoma tissue specimens obtained by surgical resection have been studied using specific polyclonal antibodies. Electrophoretic separation and blotting of detergent extracts of tumor tissues (48 specimens), followed by the binding of an antibody that recognizes both of these lectins, demonstrated that the contents of Mr 31,000 and 14,500 lectins vary from one specimen to another. The Mr 31,000 lectin content was higher in tumor specimens classified as Dukes' stage D than in those from other stages. A significant correlation was found between Mr 31,000 lectin levels and the levels of carcinoembryonic antigen in the patients' sera at the time of surgery. Immunohistochemical staining with antibodies specific for each lectin was performed with 20 colon carcinoma tissues and 5 colonic adenoma tissues. The results showed that the Mr 31,000 lectin localizes in the cytoplasm of colorectal carcinoma cells and normal epithelial cells, whereas antibody binding to Mr 14,500 lectin is observed in a limited number of carcinoma specimens and is mainly associated with luminal surfaces and secretory products. Adenoma cells were reactive with Mr 14,500 anti-lectin antibody at their luminal surfaces or cytoplasms, but they did not stain with Mr 31,000 anti-lectin antibody. These results suggest that a correlation exists among the level of the Mr 31,000 lectin, the serum level of carcinoembryonic antigen, and the stage of progression of colorectal carcinomas.

Analysis of Variance↗
PubMed1991

Colorectal ornithine decarboxylase activity in human mucosa and tumors: elevation of enzymatic activity in distal mucosa.

To examine the value of ornithine decarboxylase (ODC) assay as a biological marker of potential malignancy in large bowel, we harvested 43 colorectal carcinoma, 7 adenoma, 6 polyps, and 77 normal-appearing mucosa at surgery from patients with colorectal carcinoma. In addition, 13 normal rectal mucosa were obtained at biopsy from patients with benign diseases or diseases unrelated to colorectal carcinoma as normal control. ODC activity was significantly higher in polyps and adenocarcinomas than in normal-appearing mucosa from patients with colorectal carcinoma. ODC activity in normal-appearing mucosa varied throughout the large intestine, with significantly higher activities in the distal segment of the large bowel. The higher ODC activity detected in the sigmoid colon and rectum correlates with the larger incidence of tumor development in this region of the large bowel. This observation needs to be taken into consideration when ODC activities of the colorectal mucosa are measured as biological markers of potential malignancies.

Adenoma↗
PubMed1991

Amelioration of thrombocytopenia with concomitant ornithine in sarcoma-bearing rats receiving high dose difluoromethylornithine.

The dose limiting toxicity of difluoromethylornithine (DFMO), when administered by continuous infusion, is thrombocytopenia. DFMO-induced antitumor activity and thrombocytopenia were time- and dose-dependent up to 1700 mg/kg/d when administered continuously for 12 days. Concomitant ornithine administration (at selected molar ratios to DFMO) ameliorated thrombocytopenia induced by DFMO at a dose of 2000 mg/kg/day without adversely affecting its antitumor activity. The purpose of this study was to determine if ornithine could ameliorate the thrombocytopenia of higher DFMO doses and increase the efficacy of DFMO. Fischer 344 male rats with a transplantable sarcoma in the right flank were given 2000 and 3500 mg/kg/d DFMO alone or with ornithine at a molar ratio of 0.4 for 8 days by continuous infusion. Concomitant ornithine infusion overcame the thrombocytopenia that was induced by either dose of DFMO without reducing the antitumor activity against the sarcoma. The antitumor activity, tumor polyamine levels, and tumor S-adenosylmethionine decarboxylase activity did not consistently change with increasing doses of DFMO or with the addition of ornithine to the infusion regimen. These results demonstrate that the thrombocytopenia induced by doses of DFMO greater than 2000 mg/kg/d can be ameliorated without compromising the antitumor activity.

Animals↗
PubMed1991

Ectopic expression of mucins in colorectal cancer metastasis.

Cancer metastasis is an ectopic growth of malignant cells. In human colorectal cancer, it is hypothesized that, during the progression of the disease to an advanced stage, highly malignant and metastatic tumor cells arise within primary tumors and become predominant. Based on this hypothesis, molecules associated with metastatic cells have been sought by the comparison of surgical specimens from patients at various clinical stages. Colorectal carcinomas with increased metastatic potential and with poor prognosis have been characterized by a loss of an organ-specific mucin determinant (sulfomucin), by an increased expression of non-intestinal sialomucins, and by an ectopic expression of adhesion ligands (sialyl-dimeric Lex antigens) on mucins.

Adenocarcinoma↗
PubMed1991

Histologic observations and P-glycoprotein expression in gastric and esophageal adenocarcinomas treated with preoperative chemotherapy.

To describe histologic changes associated with chemotherapy response, we reviewed biopsy and resection specimens from 52 patients with locally advanced esophageal or gastric adenocarcinoma who were treated with preoperative chemotherapy, followed by resection. P-Glycoprotein expression in the adenocarcinomas was also determined with the use of antibody C219. Significant changes in morphologic appearance of the tumor between prechemotherapy and postchemotherapy samples was noted in 17 tumors (32.7%). The most frequent changes observed in these 17 tumors were a decrease in tumor cellularity and an increase in dense fibrosis in comparison with the prechemotherapy specimen. In signet-ring cell carcinomas, the intracytoplasmic mucin vacuoles were often smaller after chemotherapy, making tumor cells more difficult to identify. Another finding observed in tumors that showed histologic alteration after chemotherapy was the formation of large mucin pools that contained lymphocytes and macrophages. The remaining 35 tumors showed similar histologic features in prechemotherapy and postchemotherapy specimens. P-Glycoprotein was identified in 15 (29.4%) of 51 specimens after chemotherapy. P-Glycoprotein content of the residual tumors did not correlate with stage, degree of differentiation, or clinically determined chemotherapy response. We concluded that chemotherapy-induced changes in morphology were frequent in patients with upper gastrointestinal tract adenocarcinomas treated with preoperative chemotherapy. These changes should be recognized as they may cause difficulties in both gross and histologic evaluation of the extent of tumor in postchemotherapy resection specimens. The response of adenocarcinomas to this chemotherapy protocol does not appear to be linked to P-glycoprotein expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Soluble factor in normal tissues that stimulates high-molecular-weight sialoglycoprotein production by human colon carcinoma cells.

The stimulation of high molecular weight sialoglycoprotein synthesis by a soluble factor derived from normal colon tissues was studied in vitro with human colon carcinoma cell lines, HT-29 P and a metastatic variant HT-29 LMM. The synthesis of all three high-molecular-weight sialoglycoproteins (approximate Mr 900,000, 740,000, and 450,000) by HT-29 P cells or HT-29 LMM cells growing in vitro was enhanced by supplementing the culture medium with a conditioned medium of fresh human colon organ culture. Changes were detected by polyacrylamide gel electrophoresis of lysates from [3H]glucosamine-labeled cells on 3% gels followed by fluorography, or by electrophoresis of lysates from unlabeled cells followed by incubation with 125I-labeled wheat germ agglutinin and autoradiography. No changes were detected in the major protein components or in glycoproteins at Mr less than 200,000 as revealed by polyacrylamide gel electrophoresis. The treated cells did not change their growth rate or morphology. The connective tissue portions of the colon tissues were apparently responsible for the production of this stimulatory substance. The stimulatory activity was preserved at 56 degrees C but was inactivated by heating at 100 degrees C. The substance was eluted from a Sephacryl S-200 column at a position between the elution positions of ovalbumin and trypsinogen. The colon carcinoma cells treated with the conditioned medium and producing increased amounts of high-molecular-weight sialoglycoproteins were less sensitive to the cytolytic effects of recombinant interleukin 2-activated human peripheral blood lymphocytes than untreated cells were. The treated colon carcinoma cells induced stronger platelet aggregation than their untreated counterparts did. Therefore, this substance may represent one of the normal host tissue factors that can influence and modulate malignant behavior of carcinoma cells growing in vivo.

Cell Division↗
PubMed1990

Metastatic potential of colon carcinoma. Expression of ABO/Lewis-related antigens.

Four monoclonal antibodies specific to various Lewisx-related antigens were tested for binding to monolayers and detergent extracts of the human colon carcinoma cell line HT-29 P and its metastatic variant HT-29 LMM. Only monoclonal antibody FH6 (antisialyl-dimeric Lex) bound more to the metastatic variant compared with HT-29 P. Detergent extracts of human tissues were then assayed for their FH6-binding activity. Normal colonic mucosa displayed less FH6 binding than either Dukes stage B or D primary colon carcinomas. Liver metastases from colorectal carcinoma demonstrated greater binding than stage B and stage D primary tumors, and more than normal liver. Expression of sialyl-dimeric Lex increases as the metastatic potential of colorectal carcinomas increases, and is related to the progression of colorectal cancer.

ABO Blood-Group System↗
PubMed1990

Evaluation of continuous-infusion alpha-difluoromethylornithine therapy for colorectal carcinoma.

A total of 32 evaluable patients with measurable advanced colorectal carcinoma were treated with continuous-infusion alpha-difluoromethylornithine (DFMO) at a median daily dose of 8 g/m2 (range, 6-14 g/m2). DFMO was infused over 24 h daily for 28 days, followed by a rest period of 7 days. Of the 32 patients, 14 had received no prior chemotherapy. A total of 65 courses was given, with the median being 2 (range, 1-9 courses). None of the patients achieved a partial or complete response; however, 3 patients achieved a minor response and 14 had stable disease. The frequent toxic effects of DFMO included thrombocytopenia (which was dose-limiting), malaise, nausea, vomiting, reversible hearing loss, and diarrhea. Our data suggest that continuous-infusion DFMO therapy is feasible and results in only mild gastrointestinal toxicity. Although DFMO proved to be ineffective as a single agent in this trial, it could probably best be used in combination with cytotoxic agents known to enhance its antitumor activity in a preclinical setting.

Carcinoma↗
PubMed1990

Sialyl-dimeric Lewis-X antigen expressed on mucin-like glycoproteins in colorectal cancer metastases.

Colorectal primary carcinomas and metastases from 20 Dukes' stage C or D patients were examined for the immunohistochemical localization and contents of various fucosylated N-acetyl-lactosamine oligomers by specific monoclonal antibodies (MAbs). MAbs used were SH1, specific for Lewis X antigen; FH4, specific for dimeric Lewis X antigen; FH6, specific for sialyl-dimeric Lewis X antigen; and KH1, specific for Lewis Y-Lewis X antigen. The distribution of the carbohydrate antigens identified by these MAbs was heterogeneous within the primary tumor as well as within the metastatic lesion. Examinations of serial sections indicated that areas within an individual tumor which were stained with one MAb were not always reactive with the other MAbs, although these four MAbs identify closely related structures. The degree of MAb reactivity with carcinoma sections was classified by percentage positive carcinoma cells, and primary tumors and metastases from the same patients were compared. An equivalent or higher proportion of carcinoma cells in the metastatic lesions were reactive with MAb FH6 than in the primary colon carcinomas, but each correlation was not seen with the other MAbs. Electrophoretic separation of tumor tissue extracts followed by staining with these MAbs revealed that a component having an approximate molecular weight of 1,000,000 is the major site for the binding of MAbs, FH6, FH4, and KH1. The electrophoretic mobility of the antigenic molecule on polyacrylamide gels as shown by direct MAb bindings was slightly different from that of a major sialomucin revealed by wheat germ agglutinin in the same tissues. MAb FH6 binding to a high molecular weight component was eliminated by prior treatment of the glycoprotein with mild acid or sialidase to remove sialic acid. Simultaneously, binding of MAb SH2, specific for dimeric Lex antigen, to this component increased. An extract was prepared from a liver metastasis, and high molecular weight components were isolated by gel filtration and then fractionated by DEAE-cellulose ion exchange chromatography. A fraction eluted from DEAE-cellulose between 0.10-0.25 M sodium chloride contained most of the MAb FH6 reactivity, as shown by antibody affinity chromatography. These results support a hypothesis that high molecular weight glycoproteins produced by colorectal carcinoma tissues are heterogeneous with regard to their carbohydrate chains and their antigenic structures may change during tumor progression.

Adult↗
PubMed1989

Increased expression of sialyl-dimeric LeX antigen in liver metastases of human colorectal carcinoma.

We collected a total of 78 tissue specimens, including primary colorectal carcinoma, normal colonic mucosa, and liver metastases of colon carcinoma, to examine whether the extracts of these tissues inhibited the binding of a monoclonal antibody FH6, specific for sialyl-dimeric LeX antigen. The results of inhibition assays demonstrated that: (a) contents of FH6-reactive molecules were greater in carcinoma tissues than in normal colonic mucosa; (b) metastatic foci in livers contained more FH6-reactive molecules than primary tumors; (c) primary tumors from Dukes' stage B1 patients contained less FH6-reactive molecules than primary tumors from Dukes' stage D patients. The inhibitory activity of these tumor tissue extracts against the binding of a monoclonal antibody FH6 to cultured colon carcinoma cells was eliminated by prior treatment of the extracts with sialidase, confirming that the FH6-reactive materials were sialyl-dimeric LeX antigen. Electrophoretic separation of tumor tissue extracts on 3% polyacrylamide gels followed by direct staining with monoclonal antibody FH6 revealed that very high molecular weight glycoproteins, presumably mucins, contained sialyl-dimeric LeX antigen.

Antibodies, Monoclonal↗
PubMed1989

Alterations in polyamine metabolism during continuous intravenous infusion of alpha-difluoromethylornithine showing correlation of thrombocytopenia with alpha-difluoromethylornithine plasma levels.

Polyamine biosynthesis is important for cell proliferation and growth. The purpose of this study was to determine the biochemical and pharmacological parameters associated with host toxicity from a continuous infusion of alpha-difluoromethylornithine (DFMO). Twenty-five patients with metastatic carcinoma of the colon or rectum received continuous infusion of DFMO at a median dose of 8 g/m2/day (range, 6-14) for 28 days. DFMO plasma levels, RBC, plasma putrescine, spermidine, and spermine levels, and patient toxicities were evaluated. There was a significant decrease in RBC and plasma levels of putrescine, spermidine, and spermine following DFMO administration compared with the baseline RBC and plasma levels. Pearson correlation coefficient comparing nadir platelet count and steady-state DFMO level was statistically significant (n = 37; P less than 0.01; r = -0.53). Sustained suppression of circulating polyamine levels was also achieved with continuous DFMO infusion. The correlation between steady-state plasma DFMO levels and lowering of platelet count warrants prospective evaluation to determine its clinical usefulness.

Eflornithine↗
PubMed1989

Reduction of difluoromethylornithine-induced thrombocytopenia in rats with ornithine while maintaining antitumor activity.

The purpose of this study was to evaluate the effect of a concomitant infusion of ornithine on the difluoromethylornithine (DFMO)-induced thrombocytopenia and antitumor activity. Male Fischer 344 rats with either a transplantable fibrosarcoma or Ward colon tumor were given a 12-day continuous infusion of DFMO (2000 mg/kg/day) alone or with ornithine. The dose of ornithine was defined as the molar ratio to DFMO. A continuous infusion of DFMO significantly reduced circulating platelet counts to 5-16% of the control. Concomitant ornithine treatment at a molar ratio of 0.2-0.5 resulted in protection of the rat from thrombocytopenia while the antiproliferative activity of DFMO against the fibrosarcoma or Ward colon tumor was unaffected. At a higher ornithine: DFMO molar ratio (0.7), the DFMO-induced inhibition of tumor growth was blocked. Tissue polyamine levels suggest a different sensitivity of tumor and normal tissue to DFMO. Concomitant ornithine resulted in a greater increase in the polyamine levels of normal tissues, compared with the tumor. These results suggest that ornithine can selectively inhibit DFMO-induced thrombocytopenia while not affecting the antitumor activity.

Animals↗
PubMed1989

Monoclonal antibody against human colonic sulfomucin: immunochemical detection of its binding sites in colonic mucosa, colorectal primary carcinoma, and metastases.

Previous studies using metabolic labeling of fresh colonic mucosa and colorectal carcinoma with [35S]sulfate followed by biochemical analysis demonstrated that the amount of a sulfated high-molecular-weight glycoprotein expressed in primary colorectal carcinoma was lower than that in normal mucosa, and that the amount further decreased in liver metastases. This suggested that this sulfated molecule represented a sulfomucin previously defined by histochemical reactivity with a cationic dye. We have extracted and partially purified this high-molecular-weight sulfated glycoprotein from normal human colonic mucosa. We immunized mice with the partially purified sulfomucin and generated hybridomas. One cloned hybridoma, designated as 91.9H, produced a monoclonal antibody strongly reactive with a component which migrated at an identical position as the metabolically [35S]sulfate-labeled high-molecular-weight glycoprotein after polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The reactive molecules appeared to have a polydisperse nature with a molecular weight ranging between 400,000 and 900,000. The [35S]sulfate-labeled high-molecular-weight glycoprotein was bound to Staphylococcus Protein A-agarose coated with this monoclonal antibody but did not bind to unconjugated Protein A-agarose. The immunoprecipitated substance also migrated at an apparent molecular weight range of 400,000 to 900,000. The reactivity of monoclonal antibody 91.9H with the extracts of normal mucosa, colorectal primary carcinoma, and metastasis was compared by dot blot assay on a nitrocellulose membrane. This antibody was more reactive with the extracts of mucosa adjacent to carcinoma tissues than with the carcinoma extracts. Primary tumors showed higher reactivity than metastases in most of the cases. These results strongly suggest that this antibody is specific to colonic sulfomucins or at least to mucins closely related to colonic mucins previously identified by metabolic labeling with [35S]sulfate.

Antibodies, Monoclonal↗
PubMed1989

Prospective phase I trial of conservative management of low rectal lesions.

The purpose of this study was to assess and function and to compare the morbidity of local excision and postoperative radiotherapy for rectal adenocarcinoma with the morbidity of abdominoperineal resection. A posterior parasacral approach was used for local excision. All patients had negative margins, and all but one were continent after completion of radiotherapy. Seven patients (29%) had either a wound infection or a fistula in the local excision group. No local failures occurred, although follow-up was only 13 months. Thirteen (50%) of the 26 patients who underwent an abdominoperineal resection developed at least one complication. Combined treatment that spares the rectal sphincters may be preferable in selected patients with low rectal cancer, if long-term disease-free survival is maintained.

Adenocarcinoma↗
PubMed1988

Polyamine-directed preferential nutritional repletion of normal tissues in tumor-bearing hosts.

Our previous study demonstrated that total parenteral nutrition (TPN) increases erythrocyte (RBC) polyamines selectively in cancer patients but not in non-cancer patients, suggesting that these changes may relate to tumor presence. We therefore studied the possible relationship between RBC polyamine levels and potential tumor growth induced by TPN. In addition, we attempted to control tumor growth during TPN with alpha-difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), in a fibrosarcoma-bearing rat model. Rats in a control group received chow ad libitum for 3 weeks and their tumors grew exponentially. A restricted intake (RI) tumor-bearing group received 8 g chow per day per rat; this produced malnourished rats in which tumor growth significantly slowed. The third group (RI----TPN) received the RI diet for 2 weeks and TPN for 1 week, which resulted in an increase in tumor growth. The last group (RI----TPN + DFMO) received a 2-week RI regimen and 1-week TPN plus DFMO regimen, which inhibited tumor growth to the level of the RI group due to the addition of DFMO (1 g/kg/day). Although the addition of TPN to the RI regimen markedly increased tumor ODC activity, as well as tumor putrescine and RBC putrescine levels, the addition of DFMO to the RI----TPN regimen entirely abolished these increases. Despite DFMO treatment, liver ODC activity in RI----TPN + DFMO group was unaffected. The plasma albumin level, an indicator of host nutrition, of the RI----TPN + DFMO group was significantly higher than that of the RI group. Liver, spleen, kidney and total body weights of the RI----TPN or RI----TPN + DFMO group were significantly higher than those of the RI group. These results indicate that TPN can enhance tumor growth in malnourished hosts and that the addition of DFMO to TPN can effectively control this TPN-enhanced tumor growth, leading to preferential nutritional repletion of the host.

Animals↗
PubMed1988

Differential expression of a sialoglycoprotein with an approximate molecular weight of 900,000 on metastatic human colon carcinoma cells growing in culture and in tumor tissues.

Wheat germ agglutinin (WGA)-binding cellular glycoproteins produced by HT-29 human colon carcinoma and its variant cells established from liver metastases in nude mice after intrasplenic injection were analyzed by polyacrylamide gel electrophoresis. On 5.5% polyacrylamide gels five major sialoglycoproteins (approximate Mr 115,000, 145,000, 190,000, 450,000, and 740,000) reactive with WGA were common to the parental and metastatic sublines. There was an additional component of Mr approximately 900,000 that was prominent in cells established from liver metastases. Specific removal of sialic acid from the glycoproteins eliminated WGA binding, indicating that all the WGA-binding glycoproteins including the Mr 900,000 component were sialoglycoproteins. Smith degradation following mild acid hydrolysis resulted in formation of WGA-binding carbohydrate chains on Mr 115,000, 145,000, 190,000, and 900,000 components, but not on Mr 450,000 and 740,000 components, which indicated that these two sialoglycoproteins bore different oligosaccharides from the other sialoglycoproteins. The Mr 900,000 component was more prominent with HT-29 cells growing in nude mice than those growing in vitro. WGA binding to the Mr 900,000 component of metastasis-derived HT-29 cells growing in a nude mouse was higher than that of parental cells growing in nude mice. The expression in liver metastases derived from parental as well as metastatic cells was higher than the primary tumor growing in the spleen of the same mouse, indicating that the levels of Mr 900,000 sialoglycoprotein (SGP = 900) were regulated by intrinsic and environmental factors. The influence of organ microenvironmental factors was confirmed by analyzing sialoglycoproteins of HT-29 cells growing in the liver of a nude mouse following intrahepatic injection. Analyses of human colorectal carcinoma tissues and liver metastases revealed a polydisperse WGA-reactive high-molecular-weight component similar to that seen in tumors growing in nude mice. The mean value of WGA binding to high-molecular-weight glycoproteins in the primary tumors of stage B1 patients was smaller than that of all other primary tumors. Comparison of primary tumors with liver metastases from the same patients indicated that the level of SGP-900-like high-molecular-weight glycoproteins in metastases was not always higher than those in primary tumors.

Adenocarcinoma↗