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The present study explores the potential of the anti-neoplastic action of aspirin in a transplantable murine tumour model of a spontaneously originated T-cell lymphoma designated as Dalton's lymphoma. The antitumour action of aspirin administered to tumour-bearing mice through oral and/or intraperitoneal (intratumoral) routes was measured via estimation of survival of tumour-bearing mice, tumour cell viability, tumour progression and changes in the tumour microenvironment. Intratumour administration of aspirin examined to assess its therapeutic potential resulted in retardation of tumour progression in tumour-bearing mice. Oral administration of aspirin to mice as a prophylactic measure prior to tumour transplantation further primed the anti-neoplastic action of aspirin administered at the tumour site. The anti-neoplastic action of aspirin was associated with a decline in tumour cell survival, augmented induction of apoptosis and nuclear shrinkage. Tumour cells of aspirin-treated mice were found arrested in G0/G1 phase of the cell cycle and showed nuclear localization of cyclin B1. Intratumoral administration of aspirin was accompanied by alterations in the biophysical, biochemical and immunological composition of the tumour microenvironment with respect to pH, level of dissolved O2, glucose, lactate, nitric oxide, IFNγ (interferon γ ), IL-4 (interleukin-4), IL-6 and IL-10, whereas the TGF-γ (tumour growth factor-γ) level was unaltered. Tumour cells obtained from aspirin-treated tumourbearing mice demonstrated an altered expression of pH regulators monocarboxylate transporter-1 and V-ATPase along with alteration in the level of cell survival regulatory molecules such as survivin, vascular endothelial growth factor, heat-shock protein 70, glucose transporter-1, SOCS-5 (suppressor of cytokine signalling-5), HIF-1α (hypoxiainducible factor-1α) and PUMA (p53 up-regulated modulator of apoptosis). The study demonstrates a possible indirect involvement of the tumour microenvironment in addition to a direct but limited anti-neoplastic action of aspirin in the retardation of tumour growth [ABSTRACT FROM AUTHOR]

Abstract: Proton pump inhibitors (PPI) are being considered for antineoplastic therapeutic regimens due to their ability to reverse H+ homeostasis in tumor microenvironment and induce tumor cell death. In order to explore additional mechanism(s) underlying antitumor action of PPI, the present investigation was undertaken to investigate the effect of a PPI pantoprazole (PPZ) on the activation of tumor-associated macrophages (TAM) to tumoricidal state in a murine model of a transplantable T cell lymphoma of spontaneous origin growing in ascitic form. In vivo administration of PPZ to tumor-bearing mice resulted in an enhanced TAM recruitment in tumor microenvironment with M1 macrophage phenotype and augmented activation of TAM to tumoricidal state along with expression of tumor cytotoxic molecules. The study also demonstrates that TAM activating action of PPZ is of indirect nature mediated via its antitumor activity, reversal of tumor-induced immunosuppression and a consequent shift of cytokine balance in the tumor microenvironment favoring polarization of macrophages to M1 type. The study further shows that adoptive transfer of TAM harvested from PPZ-administered tumor-bearing hosts causes an efficient retardation of tumor growth. Possible mechanisms and significance of these observations with respect to the designing of antitumor therapy using PPI are discussed. [ABSTRACT FROM AUTHOR]

In the present study using a transplantable murine T cell lymphoma designated as Dalton’s lymphoma, we investigated the role of oxygen, glucose and other environmental factors in evolution of altered survival responses in tumor cells during the late tumor-bearing stages. Tumor progression was observed to be associated with an improvement in the survival ability of tumor cells. Moreover, tumor serum and ascitic fluid obtained from the late tumor bearing stage was found to augment tumor cell survival in vitro, indicating that these humoral components of tumor bearing host contain factors capable of modulating tumor survival. Progressive tumor growth was also shown to be associated with depletion in glucose and oxygen content in the fluids of tumor microenvironment along with a concomitant augmentation in the production of lactate and lactate dehydrogenase. Moreover, tumor cells expressed higher amount of mRNA for inducible nitric oxide synthase, Hypoxia inducible factor-1 and 2 and Hsp70 and VEGF proteins during the late tumor bearing stages. Splenic macrophages and non-adherent splenic lymphocytes from tumor-bearing mice showed an increased production of IL-6, TGF-β, IFN-γ, IL-2R and VEGF during the late tumor-bearing stage, which could be implicated in the differential regulation of tumor growth in a tumor stage dependent manner. In conclusion, the observations of the present study suggest that factors contained in altered tumor microenvironment may act in concert to cause behavioral alterations in tumor cells, with respect to survival, during the course of the progression of a nonsolid T cell lymphoma. [ABSTRACT FROM AUTHOR]

The present study was conducted to investigate the effect of prolactin (PRL) on the progressive growth of a T cell lymphoma. Using a murine model of a transplantable T cell lymphoma, designated as the Dalton's lymphoma (DL) it is shown that in vivo administration of PRL to tumor bearing mice reduces the survival duration of tumor-bearing host due to an augmentation of tumor growth. In vitro studies demonstrated that PRL directly stimulates the proliferation of DL cells in a dose and time dependent manner. PRL-treated DL cells showed an increase in cell size along with a decrease in cells with apoptotic morphology. Evidence also is presented to show the involvement of tumor and macrophage-derived cytokines: IL-1, IL-2, TGF-β, and M-CSF in PRL-dependent augmentation of tumor growth. Moreover, PRL treatment was found to inhibit Caspase-activated DNase (CAD) expression in DL cells indicating that PRL acts through modulation of caspase dependent pathway of apoptosis. The study is of novel significance as it demonstrates for the first time that PRL can promote growth of a T cell lymphoma involving host and tumor-derived tumor growth promoting cytokines. [ABSTRACT FROM AUTHOR]

Abstract: The present study investigates the effect of in vivo administration of alcoholic extract of Tinospora cordifolia whole plant (ALTC) on the proliferation and myeloid differentiation of bone marrow hematopoietic precursor cells in mice bearing a transplantable T cell lymphoma of spontaneous origin designated as Dalton''s lymphoma (DL). BMC obtained from ALTC administered DL-bearing mice showed an enhanced BMC proliferation and colony forming ability in vitro in response to L929 conditioned medium as a source of colony stimulating factor (CSF). The number of granulocyte–macrophages colony (CFU-GM) was predominantly higher in the cultures of BMC obtained from ALTC administered mice as compared to mice injected with PBS alone. An increase in the count of bone marrow derived macrophages (BMDM) from ALTC administered mice was also observed along with an increase in the count of tumor associated macrophages. The BMDM obtained from ALTC administered mice showed an enhanced response to signal of LPS for activation to produce IL-1 and TNF. This study indicates that the T. cordifolia can influence the myeloid differentiation of bone marrow progenitor cells and the recruitment of macrophages in response to tumor growth in situ. [Copyright &y& Elsevier]

We and others previously have reported that extract prepared from medicinal plant Tinospora cordifolia shows a wide spectrum of immunoaugmentary effects. Tinospora cordifolia was shown to upregulate antitumor activity of tumor-associated macrophages (TAM). In this article we present evidence to show that an alcoholic extract of Tinospora cordifolia (ALTC) enhances the differentiation of TAM to dendritic cells (DC) in response to granulocyte/macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor. DC differentiated in vitro from TAM that were harvested from tumor-bearing mice after i.p. administration of ALTC (200 mg/kg body weight) 2 days posttumor transplantation shows an enhanced tumor cytotoxicity and production of tumoricidal soluble molecules like TNF, IL-1, and NO. Adoptive transfer of these TAMderived DC to Dalton's lymphoma-bearing mice resulted in prolongation of survival of tumor-bearing mice. This is the first report regarding the differentiation and antitumor functions of TAM-derived DC obtained from tumor-bearing host administered with ALTC. The possible mechanisms involved also are discussed. [ABSTRACT FROM AUTHOR]

We have previously suggested that thymosin α1 (thyα1), an immunomodulating thymic hormone, can activate tumor-associated macrophages to a tumoricidal state in a murine model bearing a transplantable T-cell lymphoma of spontaneous origin designated as Dalton’s lymphoma (DL). Since tumor-infiltrating dendritic cells (DC) also play an important role in the host’s antitumor response and are as such in an immunocompromised state in a tumor-bearing host, in the present investigation we studied if thyα1 is able to influence the differentiation of tumor-associated macrophages (TAM) into DC with granulocyte macrophage colony stimulating factor (GM-CSF), interleukin (IL)-4 and tumor necrosis factor (TNF) and whether these TAM-derived DC show enhanced antitumor activity. It was observed that DC generated from thyα1-administered tumor-bearing mice showed augmented antitumor activity in vitro. Adoptive immunotherapy using TAM-derived DC showed a significant delay in the tumor growth and a prolongation of the survival time in tumor-bearing mice. DC obtained from TAM of thyα1-administered mice also produced an enhanced amount of cytokines like IL-1 and TNF-α. This is the first study of its kind regarding the effect of thyα1 on the differentiation of DC from TAM and the role of TAM-derived DC in tumor progression. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The present investigations were under taken to study whether the tumor-associated macrophages (TAM) of Dalton's lymphoma (DL), a spontaneous transplantable T cell lymphoma, can be activated by the alcoholic extract of medicinal plant Tinospora cordifolia (ALTC). Intraperitoneal administration of ALTC in DL-bearing mice not only augments the basic function of macrophages such as Phagocytosis as well as their antigen presenting ability and secretion of IL-1, TNF and RNI. The results of the present investigation also indicate that the intraperitoneal administration of ALTC slow down the tumor growth and increases the life span of tumor bearing host, thus showing its anti tumor effect through destabilizing the membrane integrity of DL cells directly or indirectly. This is the first study of it's kind regarding the effect of alcoholic extract of Tinospora cordifolia on the activation of tumor associated macrophages and showing the antitumor effect on the spontaneous T-cell lymphoma (DL), thus may have clinical implications. [ABSTRACT FROM AUTHOR]

Gangliosides (DLG) derived from a spontaneous T cell lymphoma (Dalton’s lymphoma) have been shown to impair the ability of lipopolysaccharide-activated macrophages to produce nitric oxide (NO). However, the mechanism and nature of this effect is not known. In this investigation, we sought to (1) determine whether the inhibitory action of DLG on macrophages is through the modulation of inducible nitric oxide synthase (iNOS) expression and (2) identify the possible mechanisms and signal transduction events underlying the inhibitory action of DLG. Immunoblot analysis of DLG-treated macrophages showed a decrease in iNOS expression. DLG also inhibited the production of monokines interleukin-1 and tumor necrosis factor by macrophages. However, the DLG-induced inhibition was reversible in nature. Studies showed that DLG-induced inhibition of macrophage activation could be blocked by sodium orthovanadate, indicating a role of phosphatase activity in ganglioside-induced inhibition. [Copyright &y& Elsevier]

Abstract: Background: Orlistat, a fatty acid synthase (FASN) inhibitor, has been demonstrated to inhibit tumor cell survival. However, the mechanism(s) of its tumor growth retarding action against malignancies of hematological origin remains unclear. It is also not understood if the antitumor action of orlistat implicates modulated susceptibility of tumor cell to anticancer drugs. Therefore, the present investigation focuses to study the antitumor and chemosensitizing action of orlistat in a murine host bearing a progressively growing T cell lymphoma. Methods: Tumor-bearing mice were administered with vehicle alone or containing orlistat followed by administration of PBS with or without cisplatin. Tumor progression and survival of tumor-bearing host were monitored along with analysis of tumor cell survival and apoptosis. Tumor ascitic fluid was examined for pH, NO and cytokines. Expression of genes and proteins was investigated by RT-PCR and western blot respectively. ROS was analyzed by DCFDA staining and FASN activity by spectrophotometry. Results: Orlistat administration to tumor-bearing mice resulted in tumor growth retardation, prolonged life span, declined tumor cell survival and chemosensitization to cisplatin. It was accompanied by increased osmotic fragility, modulated acidosis, expression of ROS, NO, cytokines, MCT-1 and VH+ ATPase, Bcl2, Caspase-3, P53, inhibited FASN activity and declined expression of MDR and MRP-1 proteins. Conclusion: Orlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype. General significance: These observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin. [Copyright &y& Elsevier]

Abstract: Background: De novo fatty acid synthesis catalyzed by fatty acid synthase (FASN) is crucial for tumor cell survival. Thus therapeutic targeting of FASN is considered as a novel antineoplastic strategy. However, little is understood in this respect regarding malignancies of hematological origin. The present investigation was therefore, undertaken to study the molecular mechanisms of the antitumor action of FASN inhibitor orlistat (tetrahydrolipstatin) using a murine model of a T cell lymphoma. Methods: The antitumor efficacy of orlistat was investigated in vitro by estimating cell survival by MTT assay and apoptosis by Wright Giemsa, TUNEL, Annexin-V/PI staining and % DNA fragmentation. Generation of reactive oxygen species (ROS) in tumor cells was studied using fluorescence microscopy. Expression of genes and proteins was carried out by RT-PCR and western blot analyses respectively. FASN and CPT-1 activity was estimated by spectrophotometer. Cytokines expression was analyzed by ELISA. Results: We report that inhibition of FASN with its specific inhibitor orlistat manifests tumor-specific inhibition of cell survival, accompanied by induction of apoptosis. Orlistat-treated tumor cells showed an altered ROS generation, shift in cytokine balance and modulated expression of cell survival regulatory molecules like HSP70, Bcl2, p53, PUMA, Caspase-3 and CAD. It was observed that IFN-γ mediates orlistat-dependent modulation of FASN expression. Conclusion and general significance: In this study, we report some of the so far unexplored novel aspects underlying the molecular mechanisms associated with orlistat-dependent modulation of tumor cell survival. These observations will help in designing antineoplastic therapeutic protocols using orlistat against malignancies of hematological origin. [Copyright &y& Elsevier]

Abstract: We have reported that the ascitic growth of a transplantable T cell lymphoma of spontaneous origin, designated as Dalton''s lymphoma (DL), is associated with a concomitant immunosuppression. We have also reported that progressive in vivo growth of DL resulted in an inhibition of macrophage functions. In present investigation we report that physical exercise by DL-bearing mice, on a treadmill on a daily basis for various time durations for 10 days, increased the life span along with an inhibition of tumor growth. A significant decrease in the volume of ascitic fluid and number of cells in the tumor was obtained in mice, which underwent exercise. DL cells obtained from exercised groups showed a decreased proliferation in vitro. An augmentation in the percent of cells showing apoptotic morphology and percent specific DNA fragmentation was observed, suggesting that physical exercise increased the incidence of apoptosis in tumor cells. Moreover, macrophages obtained from tumor-bearing mice, which underwent exercise training, showed an augmented tumoricidal activity and production of tumoricidal molecules like interleukin-1 (IL-1), tumor necrosis factor (TNF) and nitric oxide (NO). On the basis of this study it is suggested that the regression of tumor growth consequent to physical exercise training of tumor bearing host, may be due to an exercise-dependent augmentation of macrophage tumoricidal functions. [Copyright &y& Elsevier]