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Biomedical subjects

D M Thomson

Publications and source records attributed to D M Thomson.

At least 55 records · Page 3Linked to original sources
PubMed1983

Oxidative metabolism, cytoskeletal system, and calcium entry of leukocytes in the phenomenon of sensitizing cancer extract-induced leukocyte adherence inhibition.

We examined some of the metabolic events that regulate sensitizing cancer extract-induced leukocyte adherence inhibition and found that human leukocytes adhere in a comparatively passive manner to glass in serum-free medium. Adherence of leukocytes to glass did not require oxidative metabolism, microtubules, microfilaments, or calcium entry, whereas leukocyte mobility excited by sensitizing cancer extract did. Calcium antagonists, lanthanum chloride, cromolyn sodium, nifedipine, trifluoperazine, and lidocaine, prevented sensitizing cancer extract-induced leukocyte mobility. Calcium agonist, ionophore A23187, excited leukocyte mobility. Ouabain, which inhibits Na+-K+-adenosine triphosphatase and may increase intracellular Ca2+ as a result, also excited leukocyte mobility. Monocytes, armed with serum from patients with early cancer and challenged with the same sensitizing tumor antigen, generated a leukotriene mediator that excited leukocyte mobility; cromolyn sodium, nifedipine, and trifluoperazine antagonized the synthesis of the mediator. The calcium antagonists inhibited the leukotriene mediator and authentic leukotrienes B4, C4, and D4 from exciting leukocyte mobility. The results showed that leukocyte mobility, excited by sensitizing cancer extract, is an active process depending upon immunologically triggered release of a leukotriené mediator from armed monocytes. Leukocyte adherence inhibition requires many of the same physiological events that chemokinesis and chemotaxis do and is thus an assay to study either immunologically released chemoattractants or chemoattractants themselves on leukocyte locomotion.

Adenosine Triphosphate↗
PubMed1982

Armed human monocytes challenged with a sensitizing cancer extract release substances pharmacologically similar to leukotrienes.

Human peripheral blood monocytes were highly enriched by adherence to plastic, armed with serum from cancer patients, and challenged separately and simultaneously with the sensitizing and unrelated cancer extracts. The response of the monocytes was to release a factor that inhibited leukocyte adherence (LAI) to glass. The macrophage-like cell line U937 released a similar factor when it was armed and challenged with the sensitizing cancer extract. The production of the factor was blocked by 10(-6) M ETYA and 10(-6) M NDGA but not by 10(-6) M indomethacin. Moreover, a competitive inhibitor of leukotriene function, 10(-6) M FPL 55712, blocked the LAI reaction mediated by the factor. Arylsulfatase destroyed its activity while depletion of the monocytes' cellular glutathione pool with CyH or Et2Mal stopped production of the mediator. Pure leukotrienes (C and D) in a dose-response fashion prevented the adherence of leukocytes to glass; the nonadherence of mononuclear cells was equal to that of polymorphonuclear cells. PGE2, if added to the leukocytes immediately before challenge with LTC or LTD, increased 1,000-fold the leukocytes' sensitivity to the leukotrienes. Paradoxically, if leukocytes were washed and exposed to PGE2 15 min after being challenged with leukotrienes, their normal glass-adherence property and the ability to respond again to LTD were restored. FPL 55712 blocked the effect of LTC and LTD from inhibiting the adherence of leukocytes to glass. The present study shows that human monocytes armed with cytophilic anti-tumor antibody, when challenged with the sensitizing cancer extract, release leukotriene(s) as shown by pharmacologic evidence, implying that monocytes may play an important inflammatory role in human cancer.

Cell Adhesion↗
PubMed1982

Modulation of antigen-induced leukocyte adherence inhibition by metabolites of arachidonic acid and intracellular nucleotides.

After binding a sensitizing tumor antigen, human leukocytes undergo a series of changes that lead to a loss of their glass-adherent properties; a phenomenon called leukocyte adherence inhibition (LAI). After surgery or when patients have a large tumor burden, their test results become negative. This study shows that in vitro incubation of the leukocytes for 5 min with PGE2 converted to positive the negative test, in an immunologically specific manner. The effect was critically dose-dependent, too little or too much did not alter the result. The same effect was achieved with PGE2, PGI2, aminophylline or other drugs that raise intracellular nucleotides, including dibutyryl cyclic AMP and dibutyryl cyclic GMP. Dibutyryl cyclic AMP stimulated a stronger response and 100 times less was needed than of dibutyryl cyclic GMP. Prostaglandins did not mediate LAI since Indomethacin failed to inhibit a positive test. Nonetheless, arachidonate metabolites were critical for the LAI phenomenon since BPB and mepacrine, inhibitors of phospholipase A2, negated the LAI response. Moreover, ETYA, phenidone and NDGA, inhibitors of the lipoxygenase metabolic pathway, all negated the positive LAI response. The positive response was especially sensitive to nullification by ETYA. Although the last-named drugs inhibit other arachidonate metabolic pathways too, conclusive evidence that the metabolites of the lipoxygenase pathway, and leukotrienes in particular, mediate the LAI response was the fact that FPL 55712, a competitive antagonist of SRS, nullified a positive response at levels as low as 10(-13) M. The results imply that prostaglandins were able to modulate the expression of LAI by affecting intracellular nucleotides, but leukotrienes, it seems, were the metabolites that mediated leukocyte nonadherence after monocytes recognized and bound tumor antigen.

Antigens, Neoplasm↗
PubMed1982

Predictive value of tube leukocyte adherence inhibition (LAI) assay for breast, colorectal, stomach and pancreatic cancer.

The tube LAI assay measures accurately antitumor immunity in patients with early cancer but fails to detect up to 75% of patients with advanced cancer due to excess circulating organ-specific neoantigen (OSN). Substances such as prostaglandin E2 (PGE2) or aminophylline, which increase intracellular nucleotides in leukocytes of patients with advanced cancer reversed this nonreactivity and greatly increased the sensitivity of the assay without any loss of specificity. Antitumor immunity can now be detected in advanced cancer, and a combination of the two assays gives prognostic potential to the assay: a positive test with PGE2 and negative test without indicates the patient has a large tumor burden. The specificity of the assay for each cancer was high and in most instances was greater than or equal to 95%. The PGE2 stimulated assay retained the high specificity. The sensitivity of the regular tube assay was often low, 33-56% because of the many advanced cancer patients tested, whereas the PGE2 stimulated assay showed almost a two-fold increase in sensitivity, 67-93%. The diagnostic value of the assay was estimated by calculating the predictive value for different prevalences of cancer. It was found that at low prevalences of cancer as found in the general population, the assay had a low diagnostic value since few patients with a positive test would have the cancer tested for. With prevalences of cancer of 5% or greater as might be found in a tertiary care clinical setting, the assay would seem to have diagnostic value since one half or more patients with a positive test would have the cancer tested for. Most false positives, but not all, are found in patients who have lesions that are often considered to increase their risk for cancer: severe dysplasia of the breast, colon adenomas, chronic atrophic gastritis and chronic pancreatitis, suggesting that the assay predicts oncogenesis.

Aminophylline↗
PubMed1982

A study of the immune response to the organ-specific neoantigen of human bladder cancer.

The antitumor immune response of monocytes armed with cytophilic antitumor antibody to an organ-specific neoantigen of human bladder cancer was measured by the tube leukocyte adherence inhibition assay. Of 29 patients with Stage A bladder cancer, 27 had positive tests, whereas of 11 patients with Stage B, C and D bladder cancer, 2 had positive tests. If the leukocytes from advanced bladder cancer patients were preincubated briefly with prostaglandin E2, the negative response was converted to positive. Of 189 patients with diseases of other organs, 2 had positive tests. Patients with acute or chronic cystitis had negative tests. The sensitivity of the assay was 88 per cent; specificity was 95 per cent. The bladder cancer extracts prepared from metastatic tissue or the tissue-cultured cell line, T24, had similar activity in the assay. Normal bladder tissue did not share the bladder cancer organ-specific neoantigen nor did cancers of other organs. Bladder epithelial cells expressed the OSN before they acquired invasive properties since patients with dysplastic bladder epithelium or in-situ cancer had positive tests. Antitumor immunity was often detectable before a recurrence became obvious by cystoscopy or cytology of urine and became undetectable quickly after removal of the bladder cancer. Of 100 patients with prior bladder cancer without evidence of exophytic tumor, 18 had positive tests; the possibility must be considered seriously that some had precancerous changes which formed no visible gross abnormalities. The results suggested that antitumor immunity to bladder cancer was a sensitive indicator of precancerous or cancerous changes existing in epithelial cells.

Antibodies, Neoplasm↗
PubMed1981

A comparison of tube leukocyte adherence inhibition assay and standard physical methods for diagnosing colorectal cancer.

In vitro antitumor immunity, measured by means of a tube leukocyte adherence inhibition (LAI) assay, was able to demonstrate early colorectal cancer in cases yet undiagnosed. Testing 106 patients attending a colonoscopy clinic, we found that nine of 15 (60%) patients with colorectal cancer were LAI-positive. The nine included: five of six with Dukes' A and B; one of two with Dukes' C; and three of seven with Dukes' D lesions. Of 58 patients without colon neoplasia, one had a positive test. By contrast, barium enema results were diagnostic for 13 of 15 (87%) cases and colonoscopy for 11 of 15 (73%). There were 32 colon polyps discovered by means of barium enema and colonoscopy. Of 13 adenomas removed, four had stimulated positive LAI responses. Of another 19 polyps not removed two incited positive LAI responses. Two patients with histories of recurrent adenomas were LAI-positive, though only one had a new polyp that could be detected by means of barium enema. For a procedure to be of diagnostic value for a given disease, sensitivity and specificity must be at least 1.0. If this sum is 2.0, the test is ideal. The sum of sensitivity and specificity for the tube LAI assay, barium enema, and colonoscopy were 1.58, 1.87, and 1.73, respectively, for colorectal cancer; 1.81, 2.0, and 2.0, respectively, for early colorectal cancer; and 1.42, 1.77, and 1.55 respectively, for advanced colorectal cancer. In this limited series of patients, the barium enema seems to be superior to the tube LAI assay for diagnosing colorectal cancer, but the difference in sensitivity and specificity is not statistically valid by the paired chi square test. The results of this study shows conclusively, that the tube LAI is of diagnostic value and suggest its use for evaluating suspected cases, especially early ones, of colorectal cancer.

Adenoma↗
PubMed1981

A coded study of antitumor immunity to human lung cancer assayed by tube leukocyte adherence inhibition.

The present study was undertaken to evaluate the specificity of antitumor immunity to human lung cancer, measured by an in vitro assay--tube leukocyte adherence inhibition (LAI). We standardized and monitored the putative tumor antigen activity of the extracts by testing leukocytes from controls and patients with lung cancer in the Montreal General Hospital. A specific antitumor response to a lung cancer antigen was detected with coded leukocytes from 56% (20 out of 36) of patients with epidermoid lung cancer. By contrast, 4% (2 out of 53) of patients with inflammatory lung disease and none of 46 other patients with cancer metastatic to the lung or with other diagnoses had an LAI-positive result. The LAI response was inversely related to the extent of cancer: 80% (8 of 10) with Stage I, 66% (2 of 3) with Stage II, 54% (6 of 11) with localized Stage III, and 33% (4 of 12) with widespread Stage III were LAI positive. Leukocytes from patients with epidermoid, adenocarcinoma, or small cell lung cancer reacted to a common tumor antigen shared by extracts of epidermoid and small cell lung cancer. This study with coded samples from a remote hospital confirms the results of other investigators that the LAI measures an antitumor immune response to human organ-specific neoantigens.

Adenocarcinoma↗
PubMed1980

Partial purification of organ-specific neoantigens from human colon and breast cancer by affinity chromatography with human tumour-specific gamma-globulin.

Organ-specific neoantigens (TA) shed from the tumours of patients with metastatic breast or colon cancer and which had filtered into the urine were partially purified by a combination of physicochemical methods and affinity chromatography. TA activity of the isolated materials was monitored by the blocking Tube LAI assay. Urinary protein was precipitated by 80% saturated ammonium sulphate. Albumin was removed by affinity chromatography with blue Sepharose CL-6B. Affinity columns of human IgG were prepared from sera of patients whose leucocytes were LAI+ to the breast- or colon-cancer extracts. The anti-breast-TA affinity column bound the TA in the urine of patients with metastatic breast cancer but not that of patients with metastatic colon cancer. The TA in urine of patients with metastatic colon cancer was bound by the anti-colon-TA affinity column. Analysis by SDS PAGE revealed that the isolates with and without TA activity were composed mostly of urinary protein which had bound nonspecifically to the human IgG affinity columns. With an affinity column of anti-NHS and Protein A, some of the contaminants were removed, to reveal SDD PAGE unique bands at about 38,000 and 12,000 mol. wt in the isolate with breast-TA activity. Rabbit antisera, raised to the material that had bound nonspecically to the anti-breast-TA affinity column, were used as an anti-nonspecific affinity column to remove the contaminants in the isolates from the affinity columns of anti-breast TA and anti-colon TA. After passage through the anti-nonspecific affinity column, the material that contained the putative breast or colon cancer TA revealed a unique band at about 38,000-40,000 mol. wt and residual fine bands at about 25,000-30,000 mol. wt. Both the control material and material with TA activity had similar bands at about 25,000 and 50,000 mol. wt. The specific activity of the putative colon or breast TAs, as measured by the blocking Tube LAI assay, was increased from about 30 to 5000-10,000 u/mg, a 125-400-fold enrichment.

Antigens, Neoplasm↗
PubMed1980

Administration of drugs during cardiopulmonary bypass. An analysis of the fate of a bolus injected through different routes using radio-active technetium.

This study was conducted to determine the efficiency of delivery of drugs injected as boluses by the common routes available during cardiopulmonary bypass. Radioactive technetium (99mTc) was injected in a 50 microCi bolus into the central venous line or into the arterial or venous lines of the oxygenator and its passage monitored downstream by suitable radiation detectors. When injected into the central venous line, delivery was unpredictable and at times 50% or more of the dose may not appear for 5 min. When injected into the venous line of the oxygenator an average 5% of the total dose had not reached the detector during first passage, and had completely cleared at 2 min. No significant difference was found between the different oxygenators and it is concluded that the venous line of the oxygenator is the most efficient site for the achievement of rapid action of drugs.

Cardiopulmonary Bypass↗
PubMed1980

A computerized tube leukocyte adherence inhibition assay to detect antitumor immunity in early human cancer: a review of two years' experience.

A 2-year experience with a computerized in vitro assay of leukocyte adherence inhibition (LAI) indicated that patients with cancer of either the colorectum, stomach, pancreas, breast, or lung expressed antitumor immunity to an organ-type specific neoantigen. About 1% of the 1,299 control subjects with benign or malignant disease had a positive LAI assay and 2.5% of patients with inflammatory disease of the colorectum, stomach, pancreas, or lung had a positive LAI assay when tested against tumor extracts of the same organ. Of the 351 patients with cancer of either the colorectum (111), stomach (40), pancreas (28), lung (57), or breast (116) who harbored a microfocus of cancer, 80% or more were LAI positive. As the stage of the cancer advanced, fewer patients were LAI positive. Nine of 45 patients (20%) with colon adenomas had a positive LAI response to colon cancer antigen and 17 of 204 patients (8%) with benign breast disease reacted to the breast cancer antigen. Our results suggested that the leukocytes of some of the LAI-positive patients with either colon adenomas or benign breast disease were responding to an organ-specific neoantigen. Whether the acquisition of a cell surface tumor antigen by the colon adenomas and the dysplastic lesions of the breast implies an irretrievable step to ultimate malignancy is unknown. Most patients exhibit a vigorous antitumor immune response when the cancer exists as a microfocus, and some even before the neoplasm has acquired the capacity to invade.

Antigens, Neoplasm↗