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N C Armitage

Publications and source records attributed to N C Armitage.

At least 55 records · Page 3Linked to original sources
PubMed1988

Biodistribution of a monoclonal antibody-methotrexate conjugate (791T/36-MTX) in patients with colorectal cancer.

The monoclonal antibody (MAb) 791T/36 which has previously been shown to localise in colorectal cancer has been conjugated to methotrexate (MTX) for potential use as a chemotherapeutic agent in malignant disease. To examine its biodistribution and tumour localisation, 16 patients with primary colorectal cancer were injected intravenously with 131I-labelled 791T/36-MTX conjugate and imaged using a gamma camera after 48-72 hr. Serial blood samples were taken to determine the levels of circulating conjugate and samples of tumour and normal colon were assayed for uptake of radioactivity. Whole body biodistribution, visualised by gamma scintigraphy, and blood clearance of both the antibody and drug moieties of 791T/36-MTX were similar to that previously found with unconjugated antibody. Assays of tissue radioactivity showed positive tumour uptake of drug-antibody conjugate (T:NT greater than 1.9:1) in 13/15 primary tumour specimens (median T:NT = 2.9:1). These studies indicate that 791T/36-MTX conjugates may have potential in the treatment of metastatic colorectal carcinoma.

Aged↗
PubMed1987

Influence of non-steroidal anti-inflammatory drugs on the outcome of faecal occult blood tests in screening for colorectal cancer.

Non-steroidal anti-inflammatory drugs have been accused of causing false positive results in faecal occult blood tests for colorectal cancer. A study was therefore performed in 10,931 people undergoing faecal occult blood screening tests to assess the effect of these drugs on the predictive value of a positive test result. Those with a positive result were interviewed and a full drug history was taken before they underwent a full colorectal examination. Of the 455 people with a positive result, 50 were taking non-steroidal anti-inflammatory drugs: 10 (20%) had colonic neoplasia. Of the 405 who were not taking non-steroidal anti-inflammatory drugs, 129 (32%) had colonic neoplasia. These detection rates were not significantly different, and the predictive value of a positive result for an adenoma larger than 1 cm was 14% in the group not taking anti-inflammatory drugs and 26% in the group taking them (not significant). These results suggest that a finding of occult faecal blood cannot be attributed to upper gastrointestinal tract bleeding caused by non-steroidal anti-inflammatory drugs and should be followed by a thorough colorectal examination.

Aged↗
PubMed1987

Quantitation of MHC antigen expression on colorectal tumours and its association with tumour progression.

A flow cytometric technique has been established for accurately quantitating the cell surface density of MHC antigens and the percentage of cells expressing MHC antigens in 38 colorectal tumours. Thirty-four percent of tumours were partially or completely negative for HLA-ABC antigen expression. Although the quantity of HLA-ABC antigens varied widely, there was no correlation between the density of HLA-ABC antigens, or the percentage of cells expressing these antigens and clinicopathological stage. Fifty percent of the colorectal tumours expressed HLA-DR with varying antigen densities. All of the poorly differentiated tumours expressed HLA-DR but there was no correlation between expression of HLA-DR and clinicopathological stage. The aneuploid tumours expressed more HLA-ABC and HLA-DR antigens on a higher percentage of cells than the diploid tumours. Abnormal expression of the tumour associated antigens CEA, Y haptenic blood group and 791T p72 also correlated with expression of HLA-ABC and HLA-DR antigens on colorectal tumours. The majority of early derived in vitro dividing cells failed to express both HLA-ABC and HLA-DR antigens although they expressed high levels of tumour associated antigens. If there is a correlation between in vitro and in vivo growth perhaps tumours are maintained and seeded by MHC antigen negative cells.

Antigens, Neoplasm↗
PubMed1987

Sensitivity of newly established colorectal cell lines to cytotoxic drugs and monoclonal antibody drug conjugates.

A major problem in the chemotherapy of colorectal cancers is their resistance to most cytotoxic drugs which may be due to insufficient cellular transport. Drugs conjugated to monoclonal antibodies recognising tumour antigens may overcome these difficulties by providing access of active agents to the tumour cells. The anti-tumour monoclonal antibody shown to localise in patients with colorectal cancer, 791T/36, has been investigated as a potential targeting antibody. Eight cell lines were established from surgically resected material and were shown to bind 791T/36 antibody. They were screened for their sensitivity to methotrexate, 5-fluorouracil and daunomycin. Although 5-fluorouracil is the drug of choice for chemotherapy of colorectal cancer it was the most cytotoxic drug in only 2 of the 8 cell lines. Only the 4 cell lines which were resistant to methotrexate showed less cytotoxicity with methotrexate than 5-fluorouracil. The cell lines which were resistant to methotrexate were more sensitive to 791T/36-methotrexate conjugates. Daunomycin was the most cytotoxic drug in 4 of the 8 cell lines. However, a similar cytotoxicity was observed for free drug and 791T/36 daunomycin in the two lines tested. Selective monoclonal antibody drug conjugates may offer a solution to treatment of tumours which are resistant to classical chemotherapeutic agents. This is the first report to show that newly established cell lines that are resistant to classical chemotherapeutic agents are rendered sensitive when the drug enters the cell as a drug monoclonal antibody carrier.

Antibodies, Monoclonal↗
PubMed1987

Screening for colorectal cancer--the Nottingham experience.

The advanced stage of most colorectal cancers at the time of presentation is largely responsible for the poor prognosis of the majority of patients with this tumour. Symptoms attributable to colorectal cancer are nonspecific and there is often considerable delay between their onset and diagnosis. By offering faecal occult blood (FOB) tests to patients presenting to their family doctors with abdominal symptoms the delay in diagnosis was significantly reduced but the pathological stage of the cancers was similar to that of a control group managed by their family doctors in their standard manner. In order to detect cancers at an earlier, asymptomatic stage a randomised control trial of FOB testing was instituted. A total of 26,975 individuals from the general population between the ages of 45 and 75 years were randomised to receive FOB tests or to be controls. 4,917 (36%) completed the tests and a total of 18 cancers were detected of which 13 (72%) were confined to the bowel wall. At rescreen a further six cancers (3 stage A) were detected by FOB tests. In the control group 20 cancers were diagnosed at two years of which only one (5%) was stage A. Asymptomatic screening showed a significant increase in the proportion of early stage tumours but the effect on mortality will await long term follow up.

Aged↗
PubMed1987

Imaging of primary and metastatic colorectal carcinoma with monoclonal antibody 791T/36 and the therapeutic potential of antibody-drug conjugates.

Monoclonal antibody 791T/36, prepared against a tumour-associated 72,000 dalton glycoprotein, reacted with cells from primary and metastatic colorectal carcinomas. I-131 or In-111-labelled antibody localized in xenografts of colorectal carcinomas established from in vitro clonogenic populations. Clinically, with I-131-labelled antibody, 8/11 colonic tumours imaged positively. Imaging was negative in four patients with benign colon disease. 5/11 rectal tumours were positively imaged, but excreted I-131 in the bladder obscured tumours in several studies. In-111-labelled antibody gave superior images and positively imaged primary and metastatic sites in 13/14 patients. Prospectively in the detection of recurrent disease, I-131 or In-111-antibody detected 29/33 separate sites in 24 patients. Seven negative patients remain disease free. There were 3 false positives; overall sensitivity was 88%, with 70% specificity. Specific localization of radiolabel was confirmed immunochemically and by counting radioactivity in resected specimens. Antibody conjugates with methotrexate, vindesine and daunomycin retained drug activity and antibody function, including xenograft localization and conjugates were therapeutically effective against xenografts. 791T/36 antibody has potential for immunodetection of primary and recurrent colorectal carcinoma and for targeting of therapeutic agents.

Animals↗
PubMed1986

Fecal occult blood screening for colorectal cancer in the general population. Results of a controlled trial.

A total of 26,975 asymptomatic individuals were identified from family doctors' age/sex registers and randomly allocated to test or control group. The first test group (10,253) were offered 3-day fecal occult blood (FOB) testing; 3,613 (37%) completed the tests and 77 (2.1%) were found to be positive. In this group, 13 cancers were detected (3.5/1000 persons screened), of which 9 (70%) were Stage A. Of these subjects, 3349 have been rescreened at 2 years; 2799 (85%) completed the tests and 80 (2.8%) were found to be positive. Four cancers have been detected (three Stage A). In the whole test group followed for 2 years (10,462), 34 cancers have presented (17 screening detected, 3 interval cases in test responders, 14 symptomatic cancers in nonresponders), of which 14 (43%) were Stage A. In the control group (10,272 individuals), 17 patients have presented with symptomatic colorectal cancer during the 2-year follow-up, with rates of 0.9/1000 and 0.8/1000 persons/year in the first and second years of follow-up, respectively. No Stage A tumors were present. In the second test group (3,225) offered both guaiac (Hemoccult; Smith Kline Diagnostics) and immunologic (Feca EIA; Nordic) FOB tests, 1304 (44%) completed the tests, of which 126 (9.7%) were positive. Five cancers were detected (four Stage A), of which only three were positive by Hemoccult testing. In this group of test responders, one cancer has presented symptomatically at 1 year follow-up. Thus, at 2-year follow-up of the responding individuals of both cohorts of the initial screen of the test group, 5 of 21 cancers (24%) were negative by Hemoccult testing. Fecal occult blood testing has doubled the detection of colorectal cancer in the test group compared with the number presenting with symptoms in 2 years in the control group, and increased the proportion of early stage cancers (chi 2 = 8.0, P = less than 0.001).

Aged↗
PubMed1986

Imaging of bone tumors using a monoclonal antibody raised against human osteosarcoma.

The radiolabeled monoclonal antibody 791T/36 raised against a human osteosarcoma was injected into 20 patients with known or suspected bone tumors. Gamma camera images were acquired at 48 or 72 hours after injection, and assessed for antibody localization. Positive images were obtained in all five osteosarcomas and four other primary malignant sarcomas. Two of the four other primary bone tumors gave positive images. Three patients with trauma had negative images as did one patient with Paget's disease. Two patients with suppurative disease gave positive images. The antibody localized in the majority of malignant sarcomas tested. In one tumor where tissue was available, a tumor:non-tumor ratio of 2.8:1 was measured. Repeat imaging was performed in five patients. Immunoscintigraphy using the monoclonal antibody 791T/36 has shown tumor localization in patients with bone and soft tissue sarcomas.

Adolescent↗
PubMed1986

In vitro binding and in vivo localization in colorectal cancer of a high affinity monoclonal antibody to carcinoembryonic antigen.

A monoclonal antibody to carcinoembryonic antigen (CEA) (C46) was tested for its binding properties to colorectal cancer cells in vitro and for its localization in patients with primary colorectal cancer. Strong binding was found to disaggregated primary colorectal cancer cells, with a median of 66 per cent of the cells in the tumour gate binding the antibody. There was a median binding ratio of 8.6:1 compared with normal immunoglobulin. The pattern of immunohistological staining was typical of that for an antibody to CEA. All seven patients with primary colorectal cancer imaged pre-operatively using 111In-labelled C46 gave positive images. The median tumour:non-tumour antibody uptake ratio from resected specimens (n = 8) was 5.8:1. (1.7-7.6:1). Eight of 11 sites of secondary colorectal cancer gave positive images. The high affinity and good tumour localization of C46 have improved clinical imaging and increase the possibilities for targetting of antitumour agents.

Aged↗
PubMed1986

Faecal occult blood screening of first degree relatives of patients with colorectal cancer.

A full first-degree family history was taken from 161 patients with colorectal cancer (Group 1) and from a group of 203 subjects previously investigated and found to have no colorectal neoplasia (Group 2). Twenty-six (16%) of patients in Group 1 compared with 23 (11%) in Group 2 had at least 1 first-degree relative with colorectal cancer (p = 0.23). Contact of first-degree relatives was possible in 123 patients in Group 1. Of these, 4 were members of 'cancer families' with 26 available first-degree relatives. The remaining 119 patients had 341 contactable first-degree relatives. They were approached by post and offered faecal occult blood (FOB) screening. One hundred and sixty-two (47%) completed FOB tests of which 12 (8%) were positive. Investigation of these individuals detected 4 adenomas. In the subgroup of 20 patients with 1 or 2 first-degree relatives with colorectal cancer, there were 78 potential relatives of whom 71 were contacted. Thirty-two (45%) FOB tests yielded 1 positive found to have an adenoma. A control group of 332 individuals was selected randomly from general practitioners' lists and offered FOB testing. One hundred and fifty-five (47%) complied of whom 7 (4.5%) were positive. Investigation yielded 1 adenoma. Thirteen of the 26 relatives of the 4 'cancer family' patients were investigated by endoscopy and 2 (15%) had large polyps detected. Although there may be an increased risk of colorectal neoplasia in first-degree relatives of patients with sporadic colorectal cancer, this risk is not sufficiently high to justify separate screening.

Adult↗
PubMed1986

Antigenicity of newly established colorectal carcinoma cell lines.

Cells from two adenocarcinomas, an adenoma and a metastatic node were isolated in soft agar. Expression of antigens, CEA, Y haptenic blood group and 791T-p72, defined by a range of candidate antibodies for tumour targeting was assessed. All of the cells expressed low levels of CEA but high levels of the Y haptenic blood group antigen although there was enormous inter and intraclonal variation. Of particular interest was the membrane expression of 791T-p72 antigen on all of the dividing tumour cells as previous studies had shown that 791T/36 antibody reacted with tumour stromal elements rather than malignant cell surfaces. The DNA content was abnormal in all of the cells whether they were derived from diploid or aneuploid primary tumours. They all grew readily in athymic mice and at least one monoclonal antibody, 791T/36, localised efficiently within these xenografts. Clonogenic cells therefore expressed the three tumour-associated antigens, several at higher levels than observed in the primary tumour. Monoclonal antibody 'cocktails' should therefore allow antibody mediated drug cytotoxicity to be effective at eradicating rapidly dividing tumour cells.

Adenocarcinoma↗
PubMed1986

The localization of anti-tumour monoclonal antibodies in colorectal cancer.

The localization of antitumour monoclonal antibodies was studied in patients with colorectal cancer after intravenous injection. The monoclonal antibody 791T/36 was shown to localise in primary and secondary disease with a preferential uptake of 2.5:1 compared with normal colon. Improved imaging properties were achieved by changing the radiolabel from 131I to 111In and by emission tomography. Using an anti-CEA antibody, C46, a preferential rate of uptake of 5.8:1 was achieved giving superior images and enhancing the prospects of effective targeting of antitumour agents.

Antibodies, Monoclonal↗
PubMed1986

Association of antigen expression and DNA ploidy in human colorectal tumors.

Fifty colorectal tumors were screened by indirect immunofluorescence and flow cytometry for antigen expression using a panel of monoclonal antibodies that recognize determinants preferentially expressed on tumor cells (carcinoembryonic antigen, Y haptenic blood group, 791T/36 defined antigen 791T-P72). Fifty % of the tumors expressed all three antigens, 41%, two, and 9%, one. Over a third reacted strongly with at least one monoclonal antibody, although the majority of tumors stained with a moderate intensity. Extranuclear membranes from tumors showed similar antigen expression to disaggregated tumor cells and were particularly useful for providing the relative tumor:normal tissue binding ratios. The carcinoembryonic antigen specific monoclonal antibody showed the strongest tumor selectivity with a tumor:normal tissue ratio of 24 +/- 7:1. Lack of correlation between expression of the three antigens suggested that the monoclonal antibodies recognizing them may have potential as a "cocktail." One-third of the tumors contained cells with an aneuploid DNA content and expressed elevated levels of carcinoembryonic antigen and Y haptenic blood group antigen when compared to tumors with diploid DNA content. Aneuploid cells within a tumor were also preferentially stained with all of the monoclonal antibodies.

Adenocarcinoma↗
PubMed1985

The influence of tumour cell DNA abnormalities on survival in colorectal cancer.

The cellular DNA content was measured from paraffin-embedded material in 134 colorectal cancers from patients in whom the outcome was known. Seventy-two (55 per cent) were found to contain cells with abnormal DNA (DNA aneuploid). The presence of such a population of cells was not related to pathological stage or histological grade. However, only 14 (19 per cent) patients with DNA aneuploid tumours survived 5 years compared with 27 (43 per cent) of patients with diploid tumours (chi 2 = 8.0, P = 0.005). Stepwise logistic analysis showed cellular DNA content to be an important prognostic factor in colorectal cancer, independent of pathological stage and histological grade.

Aneuploidy↗
PubMed1985

Localization of an anti-CEA monoclonal antibody in colo-rectal carcinoma xenografts.

A mouse monoclonal anti-CEA antibody (11.285.14) has been examined for tumour localization potential by assessing its distribution in immunodeprived mice with xenografts of human colon carcinoma cell lines HCT-8, HRT-18, HT-29, and LS174T and a xenograft (HRVB) established from a primary rectal carcinoma. With four carcinomas (HCT-8, HT-29, LS174T, and HRVB) preferential tumour localization of 125I anti-CEA was seen. Compared with 131I normal IgG1 localization indices of up to 4.4:1 were achieved. Up to 10% of the injected dose of 125I anti-CEA was present/g of tumour tissue and with the largest xenografts examined (3-4 g) up to 40% of the total body reactivity was localized in tumour tissue. The tumour localization of 131I labelled antibody was visualized by external gamma camera imaging. Overall antibody localization correlated with the CEA content of the xenografts and the fourth colon carcinoma xenograft (HRT-18) and an osteogenic sarcoma xenograft (791T), both with very low CEA levels, showed no localization of the monoclonal antibody.

Animals↗