Thesis (Master Diploma (Medical Technology) -- Cape Technikon, Cape Town, 1992 / The steady state in a tumour rapidly changes with its growth and the subsequent deteriorating blood and nutrient supply. This adaptation in the steady state of the tumour is shown in the increased lactate dehydrogenase and acid phosphatase activity in the tumour during it's growth. These alterations in the tumour metabolism places an increased burden on the body to supply nutrient and to discard the waste products of the tumour. This is demonstrated at the macroscopic level by the decreasing body weight and food intake when the tumour burden increases, and also at the metabolic levels by the responses of certain glycolytic and Cori cycle enzymes. Furthermore three distinct stages were observed in the Corl cycle response to the influence of the tumour namely, a silent or preclinical stage, a hypermetabolic stage and a hypometabolic stage. Although the decreasing body weight cannot be directly linked to the process of gluconeogenesis, the onset of anorexia appeared to coincide with the end of the hypermetabolic stage and the beginning of the hypometabolic stage in gluconeogenesis. This clearly shows that the body's steady state is adversely affected by the presence of the tumour and that the conditions at the metabolic level seem to cause the anorexia. Furthermore, it is well known that the success of cancer therapies depends entirely on the effectiveness o{the modality to kill the tumour cell and on the ability . of the host to absorb the damage caused by the modality without being destroyed in the process itself. The second part of this study demonstrates the radioprotective effects of ATP at all levels. It is clear from this work that ATP had a bigger influence in protecting the normal tissue than it had on the tumour tissue. This was demonstrated by the response of acid phosphatase (AP) and glucose-6-phosphate dehydrogenase (G-6-PDH) in the tumour and testis. Furthermore, it would seem that ATP has a multifactorial interaction with the cell, two possible mechanisms of protection are indicated by these results. The fIrst of these interactions is through the receptors of the cell to stimulate enhanced glycolysis, for higher energy production and thus repair. The second possibility is the interaction of ATP with the receptor of the cell to inhibit the production of free radicals and thus damage, as demonstrated by the response of G-6-PDH and AP.

Thesis (BTech (Biomedical Technology))--Cape Technikon, 1992. / The steady state in a tumour rapidly changes with its growth and the subsequent deteriorating blood and nutrient supply. This adaptation in the steady state of the tumour is shown in the increased lactate dehydrogenase and acid phosphatase activity in the tumour during it's growth. These alterations in the tumour metabolism places an increased burden on the body to supply nutrient and to discard the waste products of the tumour. This is demonstrated at the macroscopic level by the decreasing body weight and food intake when the tumour burden increases, and also at the metabolic levels by the responses of certain glycolytic and Cori cycle enzymes. Furthermore three distinct stages were observed in the Cori cycle response to the influence of the tumour namely, a silent or preclinical stage, a hypermetabolic stage and a hypo metabolic stage. Although the decreasing body weight cannot be directly linked to the process of gluconeogenesis, the onset of anorexia appeared to coincide with the end of the hypermetabolic stage and the beginning of the hypometabolic stage in gluconeogenesis. This clearly shows that the body's steady state is adversely affected by the presence of the tumour and that the conditions at the metabolic level seem to cause the anorexia. Furthermore, it is well known that the success of cancer therapies depends entirely on the effectiveness ofthe modality to kill the tumour cell and on the ability' of the host to absorb the damage caused by the modality without being destroyed in the process itself. The second part of this study demonstrates the radioprotective effects of ATP at all levels. It is clear from this work that ATP had a bigger influence in protecting the normal tissue than it had on the tumour tissue. This was demonstrated by the response of acid phosphatase (AP) and glucose-6-phosphate dehydrogenase (G-6-PDH) in the tumour and testis. Furthermore, it would seem that ATP has a multifactorial interaction with the cell, two possible mechanisms of protection are indicated by these results. The first of these interactions is through the receptors of the cell to stimulate enhanced glycolysis, for higher energy production and thus repair. The second possibility is the interaction of ATP with the receptor of the cell to inhibit the production of free radicals and thus damage, as demonstrated by the response of G-6-PDH and AP.

Thesis (MTech (Medical Technology))--Cape Technikon, 1992. / The steady state in a tumour rapidly changes with its growth and the subsequent deteriorating blood and nutrient supply. This adaptation in the steady state of the tumour is shown in the increased lactate dehydrogenase and acid phosphatase activity in the tumour during it's growth. These alterations in the tumour metabolism places an increased burden on the body to supply nutrient and to discard the waste products of the tumour. This is demonstrated at the macroscopic level by the decreasing body weight and food intake when the tumour burden increases, and also at the metabolic levels by the responses of certain glycolytic and Cori cycle enzymes. Furthermore three distinct stages were observed in the Cori cycle response to the influence of the tumour namely, a silent or preclinical stage, a hypermetabolic stage and a hypometabolic stage. Although the decreasing body weight cannot be directly linked to the process of gluconeogenesis, the onset of anorexia appeared to coincide with the end of the hypermetabolic stage and the beginning of the hypometabolic stage in gluconeogenesis. This clearly shows that the body's steady state is adversely affected by the presence of the tumour and that the conditions at the metabolic level seem to cause the anorexia. Furthermore, it is well known that the success of cancer therapies depends entirely on the effectiveness of the modality to kill the tumour cell and on the ability' of the host to absorb the damage caused by the modality without being destroyed in the process itself. The second part of this study demonstrates the radioprotective effects of ATP at all levels. It is clear from this work that ATP had a bigger influence in protecting the normal tissue than it had on the tumour tissue. This was demonstrated by the response of acid phosphatase (AP) and glucose-ó-phosphate dehydrogenase (G-6-PDH) in the tumour and testis. Furthermore, it would seem that ATP has a multifactorial interaction with the cell, two possible mechanisms of protection are indicated by these results. The first of these interactions is through the receptors of the cell to stimulate enhanced glycolysis, for higher energy production and thus repair. The second possibility is the interaction of ATP with the receptor of the cell to inhibit the production of free radicals and thus damage, as demonstrated by the response of G-6-PDH and AP.

Functions and phenotypes change in macrophages (Mφ) during tumor growth. Although analyzing functional and phenotypic changes are important in understanding the mechanism of tumor-induced immunosuppression, it is necessary to look beneath the surface and expose the mechanisms behind these changes. Flow cytometrically isolated Mac-1⁺, -2⁺, or -3⁺ Mφ showed that although both normal host and tumor-bearing host (TBH) Mac-2⁺ Mφ were the primary source of prostaglandin E2, no specific TBH suppressor Mφ could be identified. To determine if normal host and TBH Mφ respond to in vitro activating agents differently, normal host and TBH Mø, were treated with lipopolysaccharide. Functional, phenotypic, and molecular changes were observed in the lipopolysaccharide-treated M4J. Three- and 24-h lipopolysaccharide treatment reduced TBH Mφ-mediated suppression, while only 24-h lipopolysaccharide treatment reduced it in normal host Mφ. Prolonged adherence, which induces Mφ differentiation, increases the number of Mac-2⁺ TBH Mφ. Tumor growth causes an increase of Mφ in the S and G₂/M phases of the cell cycle. Lipopolysaccharide and adherence increase the number of normal host Mφ in Sand G₂/M; however, these same treatments reduce the number of TBH Mφ in these same phases. Earlier work showed an increase in the number of TBH Mφ that did not express class II major histocompatibility complex molecules and that there was an increase in the suppression mediated by these Mφ. TBH Mφ have a decreased response to interferon-γ-induced class II mRNA expression and a decrease in its mRNA stability. TBH Mφ have an increase in lipopolysaccharide- and prostaglandin E₂-mediated suppression of class II mRNA. Tumor necrosis factor-α can induce class II mRNA expression in TBH Mφ, but suppresses it in normal host Mφ. The effects of tumor necrosis factor-α on class II mRNA is due, in part, to the maturation stage of the Md. To examine further mechanisms that regulate Mφ maturation, intracellular Mac-2 expression was examined. The expression of nuclear Mac-2 increases during tumor growth and after 24-h adherence. This increase in Mac-2 protein parallels the increase in Mac-2 mRNA expression. Because there is a change in TBH Mφ cell-cycle kinetics and maturation, proto-oncogene expression was examined in normal host and TBH Mφ. The proto-oncogenes c-myb, c-myc, c-fos, and c-fms are constitutively expressed in TBH Mφ, while normal host M@ express c-fos and c-fms but at lower levels. Adherence suppresses the expression of the proto-oncogenes c-myb, c-myc, and c-fms in TBH Mφ, while inducing c-fos and c-fms in the normal host. Lipopolysaccharide induces c-myc, c-fos and c-fms in both normal and TBH Mφ, but suppresses c-myb expression in TBH Mφ. The results suggest that tumor growth causes a shift in Mφ maturity, and that this shift is responsible for alterations in Mφ function and phenotype. It is possible, however, to activate Mφ by lipopolysaccharide in the absence of triggering differentiation, and to trigger differentiation by adhesion without activating Mφ. TBH Mφ are more suppressive than normal host Mφ, but TBH Mφ can respond to activating signals. / Ph. D.

by Leung Wing Chung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 67-68). / Abstract also in Chinese. / Chapter 1 --- Background and Modelling --- p.5 / Chapter 1.1 --- Treatment of Cancer --- p.5 / Chapter 1.2 --- Tumour Growth Model ´ؤ Gompertz Model --- p.5 / Chapter 1.3 --- Drug Concentration and Drug Effects --- p.7 / Chapter 1.3.1 --- Drug Effects on Tumour Cells --- p.9 / Chapter 1.3.2 --- "Drug Effects with Different Values of λG,k, vth" --- p.9 / Chapter 1.4 --- Constraints on the Gompertz Model --- p.11 / Chapter 2 --- Minimization on the Gompertz Model --- p.12 / Chapter 2.1 --- Mathematical Modelling on the Gompertz Model --- p.12 / Chapter 2.1.1 --- Constraints Transformation --- p.13 / Chapter 2.2 --- Simplified Minimization Problem --- p.15 / Chapter 2.2.1 --- Avoiding Non-Minimal Stationary Points --- p.16 / Chapter 2.2.2 --- The Final Minimization Problem --- p.23 / Chapter 2.2.3 --- Existence of Optimal Solutions --- p.24 / Chapter 2.3 --- Gradients of the Objective Function and the Constraints --- p.25 / Chapter 2.3.1 --- First Derivatives --- p.25 / Chapter 2.3.2 --- Second Derivatives --- p.29 / Chapter 3 --- Numerical Methods for Minimization Problems --- p.31 / Chapter 3.1 --- Lagrangian Multiplier Method --- p.32 / Chapter 3.1.1 --- Kuhn-Tucker Condition --- p.33 / Chapter 3.1.2 --- Model Augmented Lagrangian Algorithm --- p.34 / Chapter 3.1.3 --- Armijo Algorithm --- p.36 / Chapter 3.1.4 --- Modified Augmented Lagrangian Algorithm --- p.40 / Chapter 3.2 --- Data on the Gompertz Model --- p.42 / Chapter 3.2.1 --- Optimality of Solutions --- p.42 / Chapter 3.3 --- Numerical Results --- p.45 / Chapter 3.4 --- Well-Conditioned Penalty Function Method for Constrained Optimization --- p.56 / Chapter 3.5 --- Discussion --- p.64 / Chapter 3.5.1 --- Model Augmented Lagrangian Algorithm and Modified Augmented Lagrangian Algorithm --- p.65 / Chapter 3.5.2 --- Modified Augmented Lagrangian Algorithm and Penalty Function Algorithm --- p.65 / Bibliography

Prostaglandin E2 (PGE2), a byproduct of arachidonic acid metabolism, has been suspected to be involved in tumor promotion. It has been suggested that diet may modulate PGE2 level in organisms thus affecting the implantation and growth of the tumor tissue. PGE2 content was investigated in mice fed ad libitum four types of fatty acid diets: saturated fatty acid diets: a stearic acid and a palmitic acid, and polyunsaturated fatty acid diets: a low fat (safflower 1%) and a high fat diet (safflower 15%). Tumor cells were implanted subcutaneously in mice and harvested when tumors reached .05- 4g. The extracted PGE2 were derivatized and quantified by High Performance Liquid Chromatography (HPLC). The results showed that there is a negative correlation between the level of PGE2 and the size of the tumors. PGE2 level declined as the tumor grew. This suggests that during the early stage of growth the tumor requires higher level of PGE2 to boost its growth. As the tumor becomes more adapted to its environment, it no longer depends on PGE2 to survive. Diet was also seen to be important in tumor suppression. Saturated fatty acid diet (SA-1) showed a suppressive effect on tumor growth. A visual comparison showed that polyunsaturated high fat diet produced more PGE2 than saturated fatty acid. This high level of PGE2 correlate with the highest tumor weights obtained in the Polyunsaturated high fat diet group. / Department of Biology

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Les chimiokines, petites protéines sécrétées par de nombreux types cellulaires, régulent le trafic et la fonction des populations leucocytaires en interagissant avec leurs récepteurs spécifiques, qui appartiennent à la superfamille des récepteurs à 7 domaines transmembranaires couplés aux protéines G. Dans le contexte tumoral, les chimiokines jouent des rôles ambivalents, en régulant le recrutement des leucocytes, ainsi que la croissance et l’angiogenèse des tumeurs. Aussi, les chimiokines semblent également contribuer à déterminer les sites métastatiques des tumeurs malignes.<p>Notre travail porte sur l’étude du rôle de chimiokines et récepteurs, fréquemment exprimés au sein de tumeurs, dans un modèle tumoral chez la souris, la lignée cellulaire LLC (Lewis Lung Carcinoma). Chaque gène d’intérêt (CCR3, CCR6, CCR7, CXCR4, CXCR5, CCL19, CCL20, CCL21, CXCL13) a été exprimé dans la lignée LLC, ces différentes lignées ont été greffées à des souris syngéniques, et les caractéristiques phénotypiques des tumeurs ont été analysées, notamment la croissance tumorale, la fréquence et la distribution des métastases, et l’importance des réactions immunitaires de l’hôte.<p>Nous avons montré que la croissance tumorale n’est pas affectée par l’expression des différents récepteurs étudiés, ni par celle des chimiokines CCL19 et CCL21, alors que l’expression de CXCL13 et de CCL20 par les cellules LLC réduit leur croissance in vivo. La quantification des métastases pulmonaires a montré que l’expression de CCR3, CXCR5, CCR7, CCL19 ou CCL21 par les cellules tumorales n’affecte pas significativement le potentiel métastatique des cellules LLC. Par contre, l’expression de CXCR4 entraîne une augmentation, et CCR6 une diminution, du nombre de métastases pulmonaires. La diminution du potentiel métastatique des tumeurs LLC/CCR6 implique notamment l’augmentation des propriétés d’adhésion de ces cellules. Les cellules LLC produisent naturellement de petites quantités du ligand CCL20. Nous postulons que la stimulation autocrine de CCR6 par CCL20 dans ces cellules in vivo augmente leurs propriétés d’adhésion et diminue leur potentiel métastatique. Dans le contexte de l’implication des chimiokines et récepteurs dans la détermination des sites métastatiques, nous proposons dès lors un modèle plus général :les récepteurs aux chimiokines dirigent les cellules tumorales vers les sites métastatiques où est produit le ligand correspondant ;cependant, si le ligand est produit au niveau de la tumeur, il favorise le maintien des cellules tumorales au niveau du site primaire.<p>L’effet anti-tumoral de CCL20 ne dépend apparemment pas d’un recrutement plus important de cellules dendritiques, de lymphocytes T et de cellules NK exprimant le récepteur CCR6. Nos observations suggèrent plutôt un effet de CCL20 sur l’angiogenèse tumorale. <p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished