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)

We have synthesized 90Y-labeled immunotoxin (IT) containing ricin A chain and C110 anti-carcinoembryonic antigen monoclonal antibody (MAb) to produce a therapeutic immunoconjugate for human colon cancer. The C110 IT was labeled with 90Y via a benzylisothiocyanate derivative of diethylenetriaminepentaacetic acid. The efficiency of 90Y labeling was consistently 90 to 98%, with a specific activity of about 1 microCi/microgram. In in vitro stability studies, more than 80% of 90Y remained bound to the C110 IT for up to 5 days after incubation. The percentage of binding of 90Y-labeled C110 IT to carcinoembryonic antigen-coated microbeads was 86%, indicating good retention of the initial immunoreactivity of the C110 MAb. In in vitro protein synthesis inhibition assays, 90Y-labeled C110 IT was approximately 3.7-fold more toxic to the LS174T human colon carcinoma cell line than unmodified C110 IT and 1380-fold more toxic than 90Y-labeled C110 MAb. Biodistribution studies of 90Y-labeled C110 IT in LS174T tumor-bearing mice showed that, at 24 h following i.p. injection, high accumulation of radioactivity was seen in the i.p. tumor and liver and, thereafter, high accumulation in these tissues remained almost unchanged until up to 168 h, with percentage of injected dose/g ranging from 15 to 18% in the tumor and 10 to 15% in the liver. The radioactivity in the spleen and bone gradually increased with time and reached their highest levels (approximately 8% of injected dose/g) at 168 h. Estimation of absorbed radiation doses to the tissues showed that i.p. tumor would have received an approximately 1.5 to 7 times higher radiation dose than normal organs. In in vivo therapeutic trials, 90Y-labeled C110 IT provided survival prolongation of LS174T tumor-bearing mice superior to that with either unmodified C110 IT or 90Y-labeled C110 MAb (4 less than 0.01; Mann-Whitney U test). These results indicate that 90Y-labeled C110 anti-carcinoembryonic antigen IT may be a potent therapeutic immunoconjugate for human colon cancer and that it may have direct relevance for i.p. treatment of peritoneal carcinomatosis from colon cancers.
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PMID:Preclinical assessments of 90Y-labeled C110 anti-carcinoembryonic antigen immunotoxin: a therapeutic immunoconjugate for human colon cancer. 198 87

Ten previously untreated patients with gastric cancer were treated with etoposide, 120 mg/m2 intravenously (i.v.) on days 4, 5, and 6, Adriamycin, 20 mg/m2 i.v. on days 1 and 7, and cisplatin, 40 mg/m2 i.v. on days 2 and 8 (EAP). Etoposide, 240 mg/m2 on days 4, 5, and 6, was administered orally instead of intravenously in alternating cycles, and pharmacokinetic studies were performed in those who had previously undergone gastrectomy or who had tumor infiltrating the stomach to determine oral bioavailability. Nine patients had advanced measurable gastric cancer, and one patient had an elevated carcinoembryonic antigen after surgery for synchronous gastric and colon cancer. The median age was 54 years (range 38-69), and the median Eastern Cooperative Oncology Group (ECOG) performance status was 2 (range 0-3). Nine of 10 patients had poorly differentiated adenocarcinoma. Twenty-four cycles were administered to 10 patients, and hematologic data were available for 23 courses. ECOG grade 4 neutropenia and thrombocytopenia developed in 19 (83%) and 8 (53%) courses, respectively. Thirteen courses (54%) were complicated by fever requiring parenteral antibiotics. Two patients (20%) died due to neutropenic sepsis. The profound myelotoxicity observed in our study prompted us to terminate the investigation prior to completing accrual. The oral bioavailability of etoposide was 21% and 36% in the two patients who had had prior gastrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phase II trial of etoposide, doxorubicin (Adriamycin), and cisplatin (EAP regimen) in advanced gastric cancer. 222 Jun 57

In this study, a site-specific glycyl-tyrosyl-(N-epsilon-diethylenetriaminepentaacetic acid)-lysine (GYK-DTPA) immunoconjugate of the anti-carcinoembryonic antigen monoclonal antibody C46 (C46-GYK-DTPA) was characterized by immunohistological and immunofluorescence methods for reactivity with normal and neoplastic human tissues. In addition, pharmacokinetic studies assessed the ability of C46-GYK-DTPA labeled with 111In to localize to and image human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar patterns of reactivity with normal human tissues. C46 did not bind to the surface of normal human granulocytes, which indicates lack of reactivity with normal cross-reacting antigen. C46-GYK-DTPA reacted with 100% of the colon, breast and renal carcinomas examined and with two of three lung carcinomas, but did not react with any sarcomas, melanomas or lymphomas examined. Intravenously administered C46-GYK-DTPA-111In rapidly localized to and imaged LS174T human colon adenocarcinoma xenografts in nude mice, reaching maximal levels of about 25% of injected dose/g tumor within 1 day. No unusual localization to any non-tumor tissue or organ was seen; the level of radioactivity in the normal tissues and organs was at or below that in the blood. The accessible binding sites in 1 g tumors appeared to be saturated at an antibody dose between 100 micrograms and 1000 micrograms/mouse. Further, in a direct in vivo comparison, the site-specific conjugate C46-GYK-DTPA had more favorable pharmacokinetics and better tumor localization than a randomly derivatized C46 immunoconjugate (C46-DTPA). These findings suggest that the site-specific immunoconjugate C46-GYK-DTPA may be useful in the diagnosis and therapy of colon cancer and other adenocarcinomas expressing carcinoembryonic antigen.
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PMID:Carbohydrate-derivatized immunoconjugate of the anti-(carcinoembryonic antigen) monoclonal antibody C46: immunohistological reactivity and pharmacokinetic comparison with a randomly derivatized C46 immunoconjugate. 226 96

The early detection and management of recurrence following curative resection for colorectal carcinoma can prolong survival. However, at the present time there is no consensus on the appropriate follow-up protocol for such patients. This investigation was undertaken to determine which tests and procedures are most useful in detecting recurrence and the frequency with which they should be employed. Another purpose of this study was to identify those patients at high risk for recurrence. Sixty-five patients who underwent curative resection of adenocarcinoma of the colon and rectum were followed for at least two years or until recurrence. Thirty were classified as Duke's A carcinoma of the colon, 18 were Duke's B, and 17 were Duke's C. Mean follow-up was 44.9 months. The follow-up regimen consisted of clinical exam, liver function tests, carcinoembryonic antigen (CEA) level, and chest x-ray every three months for the first two years postoperatively and every six months thereafter, and colonoscopy or barium enema and proctoscopy every six months for the first two years postoperatively and every year thereafter. Seventeen patients (26%) had a recurrence; 24% per cent of these developed within one year, 65 per cent developed within two years, 82 per cent developed within three years, and 94 per cent developed within four years of resection. Recurrence was detected by CEA in eight patients, chest x-ray in five, endoscopy in three, and laparotomy for small-bowel obstruction in one patient.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postoperative surveillance of patients with carcinoma of the colon and rectum. 229 7

The purpose of this study was to examine the mechanism of specific antibody pretreatment for reduction of liver uptake of 111In-labeled monoclonal antibody (MAB). Previous work with an anti-carcinoembryonic antigen (CEA) MAB (T84.66) and LS174T human colon cancer xenografts in nude mice has shown that giving a high dose (0.2 mg) of unlabeled T84.66 in conjunction with the same MAB (T84.66) labeled with 111In (Indacea) significantly lowered the liver uptake of 111In. High performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were used to assess the radiolabeled components in serum and liver at different times following administration of Indacea in normal and tumor bearing mice. In serum the 111In remained associated with the IgG in both tumor bearing and non-tumor bearing mice. Liver uptake of 111In in mice without tumor was low (8-12% injected dose/g) and both IgG and a low molecular weight metabolite were found in the liver homogenates. Liver uptake in tumor bearing mice increased dramatically (15-40% injected dose/g) with size of tumor and in addition to the IgG and low molecular weight components, a high molecular weight compound was identified. Administration of CEA: Indacea complexes to non-tumor bearing mice produced the same high pressure liquid chromatography and gel patterns as those seen in mice with large (greater than 1 g) tumors. Liver homogenates from tumor bearing mice given specific antibody pretreatment showed the same patterns seen with non-tumor bearing mice (no high molecular weight peak). In conclusion, CEA:Indacea complexes are formed in tumor bearing mice and rapidly cleared by the liver. Specific antibody pretreatment results in the production of unlabeled CEA:MAB complexes causing a reduction in the formation of CEA:Indacea complexes and a lower liver uptake of 111In.
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PMID:Mechanism of decreasing liver uptake of 111In-labeled anti-carcinoembryonic antigen monoclonal antibody by specific antibody pretreatment in tumor bearing mice. 229 32

Methods of single-tracer whole-body autoradiography (WBAR) have been developed in our laboratory which allow imaging and measurement of the zonal distribution of radioiodinated antibodies and their fragments within GW-39 colon carcinoma xenografts varying in size from large, cystic masses with necrotic cores to micrometastases. The whole-animal distribution of 90Y-labeled anti-carcinoembryonic antigen monoclonal antibody NP-2 was evaluated by WBAR in nude mice bearing s.c. implants of GW-39 colon cancer and revealed antitumor uptake specifically as well as significant accumulation of 90Y in the bones. Dual-tracer qualitative WBAR methods have also been applied in order to examine the biodistribution of labeled immunoglobulins in the GW-39 animal tumor model as a function of the underlying rapid cell proliferation index ([3H]-thymidine assay) in the same tumor. In addition, extension of the WBAR method was made to permit imaging of the biodistribution of 10B compounds in mice bearing Harding-Passey melanoma implants by using a track-etch procedure to produce alpha-particle WBAR. Further applications of single and multiple radionuclide WBAR are offered and discussed as an effective means of assessing the degree of penetration of immunoglobulins in tumors in which vascular patterns, local glucose metabolism, protein synthesis, and rapid cell proliferation indices may be characterized.
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PMID:Use of whole-body autoradiography in cancer targeting with radiolabeled antibodies. 229 39

The carcinoembryonic antigen (CEA) test was studied in 54 patients with advanced stages of colon cancer which was treated with high doses of folinic acid + fluorouracil. The CEA test correlates evaluated included: prognostic value, performance status, metastatic pattern, histologic grading, predictive value for response to chemotherapy, and value differences in cases with partial response to therapy. CEA levels less than 5 ng/ml corresponded to a greater survival time than did levels greater than 5 ng/ml. A correlation of CEA with performance status and with metastatic pattern was demonstrated. A progressive increase in average CEA values corresponded to increases in neoplastic mass. Although CEA levels were not found to be an index for predicting the response to chemotherapy, there was a significant different between pre- and posttreatment levels for partial response. The results suggest that CEA offers an additional criterion for evaluating the response of colon cancer to chemotherapy and it also has a role in the staging of advanced disease.
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PMID:Advanced colon cancer: staging and prognosis by CEA test. 231 25

Nude mice bearing subcutaneous human colon cancer xenografts (LS174T) were treated with 120 microCi of yttrium 90-labeled anti-carcinoembryonic antigen monoclonal antibodies (specific therapy), 120 microCi of 90Y-labeled anti-melanoma monoclonal antibodies (nonspecific therapy), or phosphate-buffered saline solution (no treatment control). Mean (+/- SD) tumor growth rates (percent increase per day) over the first 30 days of the study were as follows: 0.6% +/- 0.2% per day (specific therapy); 17.7% +/- 5.7% per day (nonspecific therapy); and 30.5% +/- 4.2% per day (control). In all three groups, tumors over 1 g had similar doubling times (5.74 +/- 0.71 d). Specific therapy caused a lag in tumor growth corresponding to a 3-logarithm cell kill. Estimated tumor dose of radiation obtained by tissue analysis was 34 and 14 Gy for specific and nonspecific therapy, respectively. In conclusion, 120 microCi of 90Y-labeled anti-carcinoembryonic antigen monoclonal antibodies was effective in suppressing growth of human colon cancer xenografts. Clinical studies with this preparation are recommended.
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PMID:Radioimmunotherapy of human colon cancer in nude mice. 233 Dec 26

The inducing effect of transforming growth factor-beta (TGF-B) on carcinoembryonic antigen (CEA) secretion and the cellular expression of CEA and CEA crossreactive glycoproteins (CEA-GLY) was examined from a panel of human colonic cell lines with different phenotypic classification. This panel included carcinomas with dissimilar differentiation characteristics and metastatic behavior, and premalignant adenomas derived from colonic polyps. A great degree of heterogeneity was observed in the endogenous levels of CEA secretion and the cellular expression of CEA and CEA-GLY species. The response profiles of the different cell lines to TGF-B treatment were also found to be heterogenous. However, TGF-B was able to induce CEA secretion and up-modulated the cellular expression of CEA and CEA-GLY from a majority of the cells tested. More importantly, TGF-B was able to exert these effects on carcinoma cells that secrete or express minimal or nondetectable amounts of these glycoproteins. These biologic modifying effects of TGF-B may have potential in augmenting the efficacy of CEA as a colon cancer marker, and in antibody-directed radioimaging and therapeutics. Further investigation in vivo in an experimental animal model system is warranted.
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PMID:Induction of carcinoembryonic antigen and its crossreactive gene products in human colonic adenomas and carcinomas by transforming growth factor-beta. 233 36

Two independent multidrug-resistant (MDR) sublines, AdR1.2 and SRA1.2, were developed from the established human colon carcinoma cell line LoVo. AdR1.2 was developed by a long-term continuous exposure of LoVo cells to Adriamycin in stepwise increments of concentration; SRA1.2 was selected/induced by pulse treatments by using a single concentration of Adriamycin. The two resistant sublines were cross-resistant and cross-sensitive to a similar spectrum of cytotoxic agents. However, AdR1.2 was most resistant to Adriamycin among the nine agents tested, and SRA1.2 was most resistant to Vinca alkaloids. Although SRA1.2 had biological characteristics similar to those of LoVo, AdR1.2 had remarkably altered biological properties, including no detectable carcinoembryonic antigen secretion, a smaller proportion of proliferating cells and a lower growth rate, lower fraction of cells in S phase, a lower colony-forming ability, and smaller colonies. In addition, the resistant phenotype of AdR1.2 was reversed when the cells were grown in a drug-free medium, whereas SRA1.2 maintained its resistance for at least 10 months under similar conditions. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the plasma membrane proteins demonstrated overproduction of an Mr 130,000 protein in both the resistant sublines. The Mr 130,000 protein was not immunoreactive with C219 monoclonal antibody against p170, but the absence of Mr 130,000 protein in an AdR1.2 revertant and the parental LoVo suggests that it is an MDR-related plasma membrane protein. The absence of a 46-kDa cytosolic protein and the presence of a Mr 150,000 plasma membrane protein were found in AdR1.2 but not in SRA1.2. This Mr 150,000 protein immunoreacted with C219. This protein was also present, although in a reduced amount, in an AdR1.2 revertant that retained three times the MDR of LoVo cells and was thus comparable to SRA1.2. The two MDR sublines thus may represent two independent subclones which may serve as two different models for the study of multidrug resistance in human colon cancer.
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PMID:Biological characterization of multidrug-resistant human colon carcinoma sublines induced/selected by two methods. 233 17


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