Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The selective targeting of tumors by enzymes conjugated to monoclonal antibodies (mAb) may be an ideal approach to convert relatively nontoxic prodrugs into active agents at the tumour site. We used the anti-carcinoembryonic antigen mAb BW431/26 conjugated to alkaline phosphatase (AP) and phosphorylated etoposide (etoposide-P) as a prodrug to study the feasibility of this concept. Etoposide was phosphorylated with POCl3. Quantitative hydrolysis of etoposide-P to etoposide occurred within 10 min in the presence of AP. BW431/26 and AP were conjugated using a thioether bond. The AP conjugate retained 93% of its calculated activity. 125I-labelled AP conjugate did not show a reduction of immunoreactivity as determined by a cell-binding assay. SW1398 colon cancer cells were used to analyse the cytotoxicity of etoposide and etoposide-P. Etoposide (IC50 22 microM) was 100 times more toxic than etoposide-P (20% growth inhibition at 200 microM). Pretreatment of the cells with BW431/26-AP prior to etoposide-P exposure resulted in a dramatic increase in cytotoxicity (IC50 70 microM). The pharmacokinetics and tumour-localizing properties of BW431/27 and the AP conjugate were assessed in nude mice bearing SW1398 tumours. BW431/26 showed excellent tumour localization (10% of the injected dose/g tissue retained from 8 h to 120 h), whereas the AP conjugate showed a reduced tumour uptake (3%-0.3% of the injected dose/g tissue at 8-120 h), a faster clearance from the circulation and a high liver uptake. Radiolabelled AP showed a similar pharmacokinetic profile to the AP conjugate. Gel filtration analysis of blood, liver, and tumour samples indicated good stability of the conjugate.
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PMID:Analysis of a conjugate between anti-carcinoembryonic antigen monoclonal antibody and alkaline phosphatase for specific activation of the prodrug etoposide phosphate. 154 Sep 81

Careful patient selection for hepatic resection of colorectal cancer metastases is essential to improve current poor results. Carcinoembryonic antigen level and number of metastases were significant preoperative prognostic indicators of 5-year disease-free survival in patients selected clinically for hepatic surgery. Surgical margin, weight of hepatic tissue resected, carcinoembryonic antigen level, and flow cytometry were significant postoperative prognostic indicators. Patients with a carcinoembryonic antigen level less than 200 ng/mL, 1-cm surgical margins, and less than 1,000 g of liver tissue removed had a greater than 50% estimated 5-year disease-free survival rate. If the metastases were diploid on flow cytometry, an additional survival advantage may have been gained. Inadequate surgical margins led to high rates of liver-only recurrence. Nonhepatic recurrence was unrelated to surgical margins. Intraoperative liver examination by ultrasound during primary colon cancer resection and adjuvant chemotherapy may offer earlier selection of biologically appropriate patients and improved outcome; both recommendations require clinical trials.
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PMID:Technical and biological factors in disease-free survival after hepatic resection for colorectal cancer metastases. 157 26

We measured alpha(1----3)-L-fucosyltransferase (alpha 13FT) activity in human plasma samples obtained from a group of 111 patients with malignant diseases, 86 patients with benign diseases, and 58 healthy controls using a newly developed assay method (Clin. Chem., 37: 2081-2086, 1991). The cutoff value was arbitrarily set at 73 units/ml (mean +/- 3SD of results for healthy controls). Forty-one of the 111 (36.9) plasma samples from patients with cancer showed high enzyme activity, and twelve of the 86 (13.6%) samples from patients with benign diseases were above the cutoff value. The levels of alpha 13FT were considerably high in samples obtained from the patients with esophagus, lung, liver and pancreatic and biliary cancer, and corresponding positive rates were 66.7, 64.7, 62.5 and 62.5%, respectively. The elevation of the enzyme activity was found in many samples from advanced cancer, whereas samples from patients with gastric and colon cancer in the clinical stage I showed high positive rates. No correlation was observed between the level of alpha 13FT and tumor--associated antigens such as carcinoembryonic antigen, CA19-9, and sialyl Tn (STN). These results suggest that alpha 13FT activity measured by the present assay method could have a potentiality for a new type of tumor marker.
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PMID:[Clinical significance of alpha(1----3)-L-fucosyltransferase activities in sera from patients with malignant diseases with a special reference to a potential tumor marker]. 158 Jun 44

Tumor targeting by monoclonal antibodies (MAbs) can be enhanced by (a) increasing the percentage of injected dose taken up by the tumor and/or (b) increasing the tumor:nontumor ratios. Several groups have demonstrated that one can increase tumor to nontumor ratios by the use of antibody fragments or the administration of second antibodies. Several other modalities are also possible: (a) the use of recombinant interferons to up-regulate the expression of specific tumor associated antigens such as carcinoembryonic antigen or TAG-72 on the surface of carcinoma cells and thus increase MAb tumor binding has proved successful in both in vitro and in vivo studies; (b) the intracavitary administration of MAbs. Recent studies have demonstrated that when radiolabeled B72.3 is administered i.p. to patients with carcinoma of the peritoneal cavity, it localizes tumor masses with greater efficiency than does concurrent i.v. administered antibody. Studies involving the comparative pharmacology of intracavitary administration of radiolabeled MAb in patients and several animal models will be discussed; (c) it has been reported that prior exposure of hepatoma to external beam radiation will increase radiolabeled MAb tumor targeting. We and others have not been able to duplicate this phenomenon with a human colon cancer xenograft model and radiolabeled MAbs to two different colon carcinoma associated antigens. The possible reasons for these differences will be discussed; (d) the cloning and expression of recombinant MAbs with human constant regions and subsequent size modification constructs will also undoubtedly alter the pharmacology of MAb tumor binding in both diagnostic and therapeutic applications.
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PMID:Innovations that influence the pharmacology of monoclonal antibody guided tumor targeting. 168 34

Surgical specimens from 2 patients with chronic ulcerative colitis accompanied with colon cancer were evaluated by immunoperoxidative staining using monoclonal antibodies A7 (against human colon cancer), S202 (against human gastric cancer), and anti-carcinoembryonic antigen (CEA). The three monoclonal antibodies were reactive with cancerous tissue, anti-CEA antibody and monoclonal antibody S202 reacted with dysplasia tissues, whereas monoclonal antibody A7 did not. Using high-iron diamine technique for mucosubstances (sialomucin and sulfomucin), cancer and dysplasia showed no secretory elements. Surrounding mucosa showed both sialomucin and sulfomucin secretion.
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PMID:[Two cases of ulcerative colitis with colon cancer: immunoperoxidase staining using monoclonal antibodies against gastrointestinal tumor and mucin staining]. 169 18

The authors investigated by immunohistochemical study the drainage of three tumor-associated antigens in unaffected regional lymph nodes of colon cancer patients. The study was conducted using monoclonal antibodies (MoAb) directed against different epitopes of the tumor-associated glycoprotein, TAG-72 (CC-49, CC-83, B72.3), of the carcinoembryonic antigen (CEA) (COL-4, COL-12), and of the colon-associated antigen, CAA (anti-CAA). The authors detected immunohistochemical reactions of MoAb CC-49 and anti-CAA with antigen-presenting cells (APC), such as peritumoral and sinus macrophages and lymphatic endothelial cells and with specific areas of germinal centers in lymph nodes draining 11 of 24 colorectal carcinomas studied. The corresponding primary tumors expressed the TAG-72 and CAA antigens. No immunostaining was detectable in lymph nodes using the anti-CEA MoAb, even when the primary tumors strongly expressed the specific epitopes. In germinal centers of regional lymph nodes, the immunostaining was often distributed at the periphery with a characteristic crescentic or circular pattern, which strongly suggested the exposure of the specific epitopes defined by MoAb CC-49 and anti-CAA on follicular dendritic cells. This would indicate that these epitopes are selectively recognized and presented to germinal center B-cells. This phenomenon may have clinical and diagnostic implications.
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PMID:Immunohistochemical evidence of immune responses to tumor-associated antigens in lymph nodes of colon carcinoma patients. 170 62

To determine the etiology of the increased incidence of postoperative deep venous thrombosis (DVT) in patients with carcinoma of the colon, serum levels of protein C were measured preoperatively in 65 patients with colorectal adenocarcinoma. Noninvasive lower-extremity Doppler studies were performed on all patients prior to discharge to assess patency of the deep veins. Six patients (9%) were found to have DVT. The protein C level was considered elevated if it was greater than 125% of control values and reduced if less than 75% of control values. The development of DVT was found to be independent of the serum carcinoembryonic antigen, albumin, total protein, hemoglobin, hematocrit, platelet count, prothrombin time, partial thromboplastin time, and the patient's age and percentage of ideal body weight. There was an inverse relationship between the protein C level (p less than 0.001), Dukes stage of the tumor (p less than 0.001), and the development of DVT. Linear regression analysis revealed that only the tumor stage and the protein C level could be used to predict the development of DVT. The data show that for these patients with colorectal malignancy, the development of DVT may be related to decreased levels of protein C.
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PMID:Protein C activity, stage of disease, and vascular thrombosis in colon carcinoma. 173 77

The relationship between cellular differentiation and carcinoembryonic antigen (CEA) production by human colorectal tumor cells and their ability to form hepatic metastases was studied. Eight human colon cancer cell lines were injected into athymic mice using different routes of administration to characterize their metastatic potential. The four poorly differentiated, non or low CEA producing cell lines were poorly metastatic to the liver after intrasplenic injection. After intraperitoneal implantation the same cell lines were highly tumorigenic, and subsequently metastatic to the liver. In contrast, the four moderate to well-differentiated cell lines that produced moderate to high levels of CEA were highly metastatic to the liver following intrasplenic injection. After intraperitoneal implantation they were less tumorigenic, and metastatic to the liver. We conclude that in this system poorly differentiated non or low CEA producing colorectal cell lines have a lower metastatic capacity compared to the well-differentiated high CEA producing colorectal cell lines. These data correlate directly with the pattern of metastatic spread and clinical course observed in patients with these tumors, suggesting that degree of differentiation and level of CEA production may play a role in development of site-specific metastases.
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PMID:Metastatic potential of human colon cancer cell lines: relationship to cellular differentiation and carcinoembryonic antigen production. 173 44

Of 124 patients who underwent endoscopic polypectomy, 70 were colonoscopically reevaluated during a mean period of 10 years. On the basis of the clinical outcome, the patients were divided into three groups: group 1, 31 patients who had a colon still with no adenomas or cancer; group 2, 35 patients in whom one or more metachronous adenomatous polyps developed; and group 3, 4 patients in whom a carcinoma of the colon subsequently developed. In addition to the clinical and pathological features, the pattern of the immunohistologic staining for carcinoembryonic antigen and secretory component was studied. Moreover, the mucin histochemical staining intensity of neutral mucins, sulfomucins, and sialomucins was evaluated. The features of the 40 index adenomas obtained from patients in group 1 were compared with the features of the 51 index adenomas from patients in group 2. Furthermore, these characteristics of the index adenomas were compared with those in the 69 metachronous adenomas of the group 2 patients. It was found that male sex (P less than 0.005) and a history of colorectal neoplasia (P less than 0.02) are main factors for the development of new adenomas. The neutral mucins were less abundant in the group 2 index adenomas (r = -0.21; P less than 0.05). The expression of the other evaluated markers was not significantly different between both groups, although the group 2 index adenomas were significantly smaller (r = -0.22; P less than 0.05) and showed a trend toward a more pronounced cytoplasmic expression of carcinoembryonic antigen than the index adenomas from group 1 (22% vs. 12.5%). Moreover, it was found that in comparison with the index adenomas, metachronous adenomas were significantly smaller (r = -0.24; P less than 0.01) and more sessile (r = 0.20; P less than 0.002). Significant negative correlations, i.e., decrease, were also found in the expression of carcinoembryonic antigen (surface P less than 0.001; cytoplasmic P less than 0.05) and neutral mucins (P less than 0.005) between the index adenomas and the metachronous adenomas, whereas positive correlations were found for secretory component (P = 0.0001) and sulfomucins (P less than 0.05). These findings suggest that a limited production of neutral mucins in the goblet cells of a small index adenoma from a male patient with a history of colorectal neoplasia is indicative of an increased risk for the development of new colorectal adenomas. Furthermore, the clinical, mucin histochemical, and immunohistochemical findings of the metachronous adenomas show less malignancy-associated features than those of the index adenomas.
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PMID:Comparative evaluation of carcinoembryonic antigen, secretory component, and mucins in index and metachronous adenomas of the colorectum. 188 15

Recombinant human gamma-interferon (IFN-gamma) has recently been shown to enhance localization of radiolabeled monoclonal antibodies (MAb) to human colon carcinoma xenografts in athymic mice. The present study investigates the ability of gamma-interferon to enhance radioimmunotherapy of a low carcinoembryonic antigen-expressing human colon cancer (WiDr) in athymic mice. Growth curve analysis, antibody localization, and dose estimation studies were performed. A significant tumor growth delay, measured as the time to reach 1.0 g, was noted for animals receiving specific anti-carcinoembryonic antigen 90Y-MAb (ZCE025, 120 microCi) plus IFN-gamma (61.8 days) as compared to animals that received specific 90Y-MAb with phosphate-buffered saline (34.9 days; P less than 0.005). IFN-gamma (100,000 units) was given i.p. every 8 h for 2 days before and 4 days after 90Y-MAb therapy. The time required to reach 1.0 g for animals treated with nonspecific 90Y-MAb (ZME018) was significantly less either with (38.3 days) or without (34.4 days) IFN-gamma. The difference was more apparent when compared to animals receiving IFN-gamma alone (30.0 days) or phosphate-buffered saline alone (28.9 days; P less than 0.001). Increased antibody localization in the tumors of animals treated with IFN-gamma plus specific 90Y-MAb (43.2% injected dose/g) was seen in comparison to animals treated with specific 90Y-MAb without IFN-gamma (18.2% injected dose/g). The estimate of radiation dose delivered to the tumors, based on biodistribution data over time, revealed significantly higher levels in animals treated with specific 90Y-MAb with IFN-gamma (2477 cGy) compared to animals treated without IFN-gamma (1217 cGy). These results provide support for the use of gamma-interferon as an immunomodulating agent prior to radioimmunotherapy.
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PMID:Interferon enhancement of radioimmunotherapy for colon carcinoma. 190 60


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