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Biomedical subjects

A B Alexandroff

Publications and source records attributed to A B Alexandroff.

At least 19 recordsLinked to original sources
PubMed2003

Woody hands.

Explore the source record for details and available documents.

Cystadenocarcinoma, Papillary↗
PubMed2000

Role for CD40-CD40 ligand interactions in the immune response to solid tumours.

CD40-mediated interactions play an important role in the response to infections, transplantation, and cancer by affecting the development, activation, proliferation and differentiation of a variety of immune cells. In the current study we examined the role of CD40-mediated interactions in immune responses to bladder, pancreatic and breast carcinomas as well as melanoma cell lines using soluble human CD40L (rhCD40L) or anti-CD40 mAb in vitro. CD40 expression was readily detected in a large proportion of the cell lines and was augmented but not induced de novo by treatment with IFNgamma. Treatment of CD40-positive cell lines with rhCD40L or anti-CD40mAb enhanced cell surface expression of ICAM-1 and FAS and stimulated the production of IL-6, IL-8, GROalpha, GM-CSF and TNFalpha but not IL-4, IL-10, TGFbeta, MCP-1, RANTES, MIP-1beta, or IP-10. In addition, incubation of CD40+ tumour cell lines with immobilised rhCD40L or anti-CD40 mAb in vitro resulted in significant inhibition of proliferation and a corresponding decrease in viability. This CD40-mediated inhibition of cell growth was due, at least in part, to alterations in cell cycle and the induction of apoptosis. Transfection of CD40-negative tumour cell lines with the cDNA for CD40 conferred responsiveness to rhCD40L and anti-CD40 antibody. Finally, the presence of CD40 on the surface of carcinoma lines was found to be an important factor in the generation of tumour-specific T cell responses.

3T3 Cells↗
PubMed2000

Mechanisms of action of intravesical bacille Calmette-Guérin: local immune mechanisms.

The local immune response to mycobacteria is complex, but mycobacterial antigen presentation by phagocytes to T helper cells is the pivotal interaction. Bacille Calmette-Guérin (BCG) vaccination is associated with the development of antituberculosis immunity but not necessarily with antitumor immunity. Animal studies have shown that an intact host immune system is required for the antitumor activity of BCG. Immunosuppressed and, particularly, T cell-depleted individuals fail to respond to BCG immunotherapy. Clinical and laboratory evidence suggest that the antitumor activity is concentrated at the site of BCG administration, which reinforces the view that local immune mechanisms are responsible for this phenomenon.

Administration, Intravesical↗
PubMed1998

Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer.

The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College (London, UK) on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion in immunosurveillance and tumour dissemination. In addition, recent achievements in the areas of chemokines, cytotoxic T-lymphocyte (CTL) and natural killer (NK) cells, co-stimulation, gene and adoptive immunotherapy were also addressed. The purpose of this report is to outline current trends in tumour immunology.

Animals↗
PubMed1998

Prognosis of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer by immunological urinary measurements: statistically weighted syndrome analysis.

PURPOSE: The goal of this research was to discover new biological indicators in urine which could be used for short-term prognosis of local Bacillus Calmette-Guerin (BCG) therapy outcome in patients with superficial bladder cancer. PATIENTS AND METHODS: We measured and statistically evaluated soluble immunological molecules in urine from bladder cancer patients (n = 34) receiving BCG intravesically. Urine was collected following each of 6 weekly treatments, processed and assayed. The data base included measurements of interleukin-1 (IL-2, IL-4, IL-6, IL-10, IL-12, soluble intercellular adhesion molecule-1 (sICAM-1), tumour necrosis factor-alpha (TNF alpha), soluble CD14 (sCD14), interferon-gamma (IFN gamma), GM-CSF, volume of urine and its pH. The clinical response was evaluated by urine histology and random quadrant biopsy 3 months after the start of therapy. Patients were divided into 2 groups, with good and poor therapeutic effect. The initial complete response rate was 62% (21/34). The data base was analyzed using traditional multivariate statistical methods and a pattern recognition method which deals with combinatorial-statistical analysis (statistically weighted syndromes (SWS) method) of the gradated features. The SWS method is capable of identifying robust patterns in small "fuzzy" sets with high dimensional objects and some missing values. RESULTS: Only one parameter gave significant differences at p < 0.05, GM-CSF at instillation 6. Repeated measurement analysis of variance, backward stepwise multiple logistic regression and linear discriminant analysis failed to show any significance. However, significant differences in the structure of correlation between features in the groups with and without therapeutic effect were observed and four highly informative variables (the masses of sICAM-1, TNF alpha, sCD14 and pH) relating to 5th-6th installations were selected by SWS. These features provided accurate individual prediction of therapeutic outcome for all our patients. Cross-validation analysis and computer simulation showed the statistically significant stability of the prediction. CONCLUSION: We have selected a set of urinary variables that could be considered as a perspective combination of indicators (syndromes) of outcome of pre-operation BCG therapy of patients with superficial bladder cancer. A larger patient database will provide testing and evaluation of the biological and clinical significance of selected features. The computational syndrome-disease approach should be applicable for the solution of decision-making problems for management of cancer.

Adjuvants, Immunologic↗
PubMed1997

Soluble urinary CD14 after intravesical bacille Calmette-Guérin immunotherapy for carcinoma in situ.

OBJECTIVE: To characterize the production of the monocyte activation marker, soluble CD14 (sCD14), after bacille Calmette-Guérin (BCG) immunotherapy for superficial bladder cancer. PATIENTS AND METHODS: Nineteen patients with carcinoma in situ were treated with a standard regimen of intravesical BCG. Urine samples were collected after each instillation and analysed; the levels of soluble CD14 were determined by an enzyme-linked immunosorbent assay, the molecular weight confirmed by Western blotting and the possible cell source investigated using immunohistochemistry. RESULTS: The mean levels of sCD14 were higher in patients with persistent carcinoma (designated as failures) than in those who had successful complete responses (responders) to BCG immunotherapy. The differences were statistically significant, with P = 0.034 at instillation 4 and P = 0.027 at instillation 5 for the total mass of sCD14, and P = 0.049 at instillation 4 for the concentration of sCD14. The predominant type of sCD14 in urine was the 48 kDa form, although in most patients there was a minor band of reactivity at 54 kDa. A panel of human bladder cancer cell lines did not react with the anti-CD14 monoclonal antibodies 3C10, 5C5 and BA8, and the antibodies also failed to react with malignant epithelial cells in frozen sections of untreated bladder tumour. Furthermore, sCD14 was not secreted by cultured bladder tumour cells. The source of urinary sCD14 is likely to be the resident and infiltrating macrophages in the bladder wall. Freshly isolated peripheral blood monocytes secreted sCD14 in response to BCG in a manner analogous to stimulation with bacterial lipopolysaccharide. CONCLUSION: A soluble form of CD14 is secreted into the urine of patients who receive intravesical BCG. The measurement of soluble urinary CD14 could be of prognostic significance for the response to immunotherapy.

BCG Vaccine↗
PubMed1995

Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines.

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.

BCG Vaccine↗
PubMed1995

Interleukin-6 production by bladder tumors is upregulated by BCG immunotherapy.

PURPOSE: To determine whether BCG therapy could upregulate interleukin-6 (IL-6) production in human transitional cell carcinomas (TCC). MATERIALS AND METHODS: Immunohistochemistry of tumor biopsies and urinary cytospins and ELISA studies of urine from bladder cancer patients and TCC cell-line supernatants, before and after exposure to BCG, were performed. RESULTS: Constitutive staining for IL-6 was found in the majority of bladder tumors. Interleukin-6 was detected in the urine of all 13 patients with carcinoma in situ and increased 5-fold during BCG therapy. Levels were variable but were greater in nonresponders (p < 0.01). During therapy both detached bladder urothelial cells and polymorphonuclear leukocytes stained for IL-6. Production of IL-6 increased in only 3 cell lines after exposure to BCG, but all 7 cell lines showed increases after exposure to interferon-gamma (p = 0.015). Grade 3 cell lines showed much greater upregulation than grade 1 and 2 cell lines. CONCLUSIONS: The increase in IL-6 during BCG therapy may be caused by urothelial cells as well as leukocytes. The higher levels seen in nonresponders may be due to either higher grade or persisting tumor.

BCG Vaccine↗
PubMed1995

Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guérin (BCG) immunotherapy.

Intravesical immunotherapy for carcinoma in situ of the bladder is arguably the most effective form of tumour immunotherapy described to date. Following repeated instillations of BCG organisms into the bladder, large quantities of cytokines are detected in patients' urine. This study concerns the production of IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and soluble ICAM-1 (sICAM-1) throughout the six weekly instillations which comprise a therapeutic course. Sequential instillations of BCG induced secretion of IL-1 beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and sICAM-1 into urine. The responses were heterogeneous between patients and cytokines, but some general trends were evident. Although cytokine levels were initially low, their concentration increased with repeated instillation of BCG. Certain cytokines (e.g. IL-6, IL-8 and IL-10) could be detected after the first instillation, whilst others (e.g. IL-2 and IFN-gamma) were not detected until after the third or fourth instillation. Interestingly, IL-4 was not detected, perhaps suggesting a differential effect on Th2-like responses. Some patients produced particularly elevated or non-detectable levels of cytokines, and a positive correlation was found between the production of various cytokines. The production of a particular cytokine did not correspond with lack of production of another species. Whether monitoring the production of cytokines following therapy may be of prognostic value will be determined in a larger series of patients. However, as these potent immunomodulators are thought to be important for the 75% complete clinical response observed with BCG therapy, there remains the possibility that detection of the products of an activated immune system may correlate with eventual clinical outcome. This study is a necessary forerunner to full prognostic evaluation of such immunological data.

BCG Vaccine↗
PubMed1994

Autocrine regulation of ICAM-1 expression on bladder cancer cell lines: evidence for the role of IL-1 alpha.

We have studied the autocrine regulation of essential expression of the intercellular adhesion molecule-1 (ICAM-1) on 8 transitional cell carcinoma (TCC) cell lines (histopathological grades 1-3). The constitutive expression of ICAM-1 was regulated by soluble factors in an autocrine fashion. These factors were produced by all cell lines, with the exception of the MGH-U1 cell line. The effects observed could be largely attributed to IL-1 alpha. However, the residual ICAM-1 inducing activity (up to 30% of ICAM-1 induction) could not be associated with any known ICAM-1 inducers (IFN gamma, TNF alpha, TNF beta, IL-1 alpha, IL-1 beta, IL-4, retinoic acid, LPS). In contrast to recombinant derived cytokines, the IL-1 alpha present in tissue culture supernatant was only able to induce ICAM-1 on high-grade tumours and not low-grade cells. This discriminative effect is similar to that noted following in vitro culture of tumour cells with bacillus Calmette-Guerin organisms. Whether the production of soluble factors (e.g., IL-1 alpha) by TCC cell lines plays an essential autocrine role for bladder tumours and/or affects the interaction with cells of the immune system needs to be investigated further.

Antigens, CD↗