Natural Phenolic Acid, Product of the Honey Bee, for the Control of Oxidative Stress, Peritoneal Angiogenesis, and Tumor Growth in Mice.

Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer, and the interplay between TAM and tumor cells represents a promising target of future therapeutic approaches. We investigated the effect of gallic acid (GA) and caffeic acid (CA) as strong antioxidant and anti-inflammatory agents on tumor growth, angiogenesis, macrophage polarization, and oxidative stress on the angiogenic model caused by the intraperitoneal (ip) inoculation of Ehrlich ascites tumor (EAT) cells (2.5 × 106) in Swiss albino mouse. Treatment with GA or CA at a dose of 40 mg/kg and 80 mg/kg ip was started in exponential tumor growth phase on days 5, 7, 9, and 11. On day 13, the ascites volume and the total number and differential count of the cells present in the peritoneal cavity, the functional activity of macrophages, and the antioxidant and anti-angiogenic parameters were determined. The results show that phenolic acids inhibit the processes of angiogenesis and tumor growth, leading to the increased survival of EAT-bearing mice, through the protection of the tumoricidal efficacy of M1 macrophages and inhibition of proangiogenic factors, particularly VEGF, metalloproteinases -2 and -9, and cyclooxygenase-2 activity.

Angio-Suppressive Effect of Partially Purified Lectin-like Protein from Musa acuminata pseudostem by Inhibition of VEGF-Mediated Neovascularization and Induces Apoptosis Both In Vitro and In Vivo.

Lifestyle and nutritional changes have contributed much to the somatic genetic changes which have concurrently led to an increase cancer in humans. Hence the plant-based and nutritional involvements block oncogenic transformation are in good demand. We evaluate Phloem exudates of the dietary plant, Musa acuminate pseudostem, the initial domesticated plant species with the effective lectin activity for its functional role against the tumor development and its mechanism of action. Our experimental data exhibit that Musa acuminata Lectin Protein (MALP) shows a promising cytotoxic effect against the various human cancer cell lines. Supporting this, we evaluate the in vivo anti-tumor and anti-angiogenic activity of MALP in Ehrlich Ascites Carcinoma mice model (EAC). MALP treatment resulted in tumor growth inhibition and increased the lifespan of the EAC-bearing mice without showing any side effects on normal mice, as revealed by histological parameters. Further, a significant decrease in the ascites vascular endothelial growth factor (VEGF) secretion and microvessel density supports the anti-angiogenic property of the MALP. Apoptosis-inducing activity of MALP was revealed by DNA fragmentation assay, Caspase-3 inhibitor assay and cellular morphology were studied by fluorescence staining methods. Our study delivers the real evidence that MALP with a promising an anticancer potential expressively degenerates the tumor development by affecting angiogenesis and apoptosis.

Salvianolic Acid B Slows the Progression of Breast Cancer Cell Growth via Enhancement of Apoptosis and Reduction of Oxidative Stress, Inflammation, and Angiogenesis.

Breast cancer is the current leading cause of cancer death in females worldwide. Although current chemotherapeutic drugs effectively reduce the progression of breast cancer, most of these drugs have many unwanted side effects. Salvianolic acid B (Sal-B) is a bioactive compound isolated from the root of Danshen Radix with potent antioxidant and anti-inflammatory properties. Since free radicals play a key role in the initiation and progression of tumor cells growth and enhance their metastatic potential, the current study was designed to investigate the antitumor activity of Sal-B and compare it with the antitumor activity of the traditional anticancer drug, cisplatin. In vitro, Sal-B decreased the human breast cancer adenocarcinoma (MCF-7) cells proliferation in a concentration and time dependent manner. In vivo and similar to cisplatin treatment, Sal-B significantly reduced tumor volume and increased the median survival when compared to tumor positive control mice group injected with Ehrlich solid carcinoma cell line (ESC). Sal-B decreased plasma level of malondialdehyde as a marker of oxidative stress and increased plasma level of reduced glutathione (GSH) as a marker of antioxidant defense when compared to control ESC injected mice. Either Sal-B or cisplatin treatment decreased tumor tissue levels of tumor necrosis factor (TNF-α), matrix metalloproteinase-8 (MMP-8), and Cyclin D1 in ESC treated mice. Contrary to cisplatin treatment, Sal-B did not decrease tumor tissue Ki-67 protein in ESC injected mice. Immunohistochemical analysis revealed that Sal-B or cisplatin treatment increased the expression of the apoptotic markers caspase-3 and P53. Although Sal-B or cisplatin significantly reduced the expression of the angiogenic factor vascular endothelial growth factor (VEGF) in ESC injected mice, only Sal-B reduced expression level of COX-2 in ESC injected mice. Our data suggest that Sal-B exhibits antitumor features against breast cancer cells possibly via enhancing apoptosis and reducing oxidative stress, inflammation, and angiogenesis.

Thymus in experimental carcinogenesis of the prostate gland.

We studied structural changes in the prostate gland, thymus, and lymph nodes in CBA mice after transplantation of Ehrlich ascites tumor cells into the prostate gland. On experimental day 5, the number of blood and lymph vessels decreased in the gland; the percentage of connective tissue elements and glandular tissue and the number of immunoblasts in the thymus increased. On day 18, the number of blood vessels in the tumor decreased; the width of the cortex and glandular tissue increased in the thymus, while the number of immunoblasts was reduced. On day 28, tumor infiltration and increased number of lymphatic vessels in its stroma were observed; parenchyma was reduced, and the area of the connective tissue increased in the thymus. These structural changes indicated the development of accidental involution of the thymus during carcinogenesis of the prostate.

Bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex a new apoptotic agent through Flk-1 down regulation, caspase-3 activation and oligonucleosomes DNA fragmentation.

New bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex was synthesized and characterized. In vivo anti-angiogenic activities of bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex against Ehrlich ascites carcinoma (EAC) cells are described. The newly synthesized complex resulted in inhibition of proliferation of EAC cells and ascites formation. The anti-tumor effect was found to be through anti-angiogenic activity as evident by the reduction of microvessel density in EAC solid tumors. The anti-angiogenic effect is mediated through down-regulation of VEGF receptor type-2 (Flk-1). The complex was also found to significantly increase the level of caspase-3 in laboratory animals compared to the acridine ligand and to the control group. This was also consistent with the DNA fragmentation detected by capillary electrophoresis that proved the apoptotic effect of the new complex. Our complex exhibited anti-angiogenic and apoptotic activity in vivo, a thing that makes it a potential effective chemotherapeutic agent. The interaction of calf thymus DNA (ct-DNA) with bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex has been investigated using fluorescence technique. A competitive experiment of the europium(III)-acridine complex with ethidium bromide (EB) to bind DNA revealed that interaction between the europium(III)-acridine and DNA was via intercalation. The interaction of the synthesized complex with tyrosine kinases was also studied using molecular docking simulation to further substantiate its mode of action.

Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy.

BACKGROUND: Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma. METHODS: Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry. RESULTS: Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown in vitro. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R. CONCLUSIONS: We suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.

cis-[RuCl(BzCN)(bipy)(dppe)]PF6 induces anti-angiogenesis and apoptosis by a mechanism of caspase-dependent involving DNA damage, PARP activation, and Tp53 induction in Ehrlich tumor cells.

Antimetastatic activities, low toxicity to normal cells and high selectivity for tumor cells make of the ruthenium complexes promising candidates in the search for develop new chemotherapeutic agents for the treatment of cancer. This study aimed to determine the cytotoxic, genotoxic and to elucidate the signaling pathway involved in the death cell process induced by cis-[RuCl(BzCN)(bipy)(dppb)]PF6(1) and cis-[RuCl(BzCN)(bipy)(dppe)]PF6(2) in Ehrlich ascites carcinoma (EAC) in vitro. Moreover, we report for the first time the anti-angiogenic potential on chick embryo chorioallantoic membrane (CAM) model. Peripheral blood mononuclear cells (PBMC) were isolated from healthy controls with an age range of 20-30 years and used to calculate the selectivity index (SI). The complex 2 (IC50 = 8.5 ± 0.4/SI = 6.3) showed high cytotoxic and selectivity index against EAC cells than complex 1 (IC50 = 14.9 ± 0.2/SI = 0.2) using the MTT assay. Complex 2 induced DNA damage on Ehrlich tumor cells at concentrations and time periods evalueted. In consequence, it was observed an increase of Tp53 gene expression, G0/G1-arrest cells, and increased levels of cleaved PARP protein. Beside that, the treatment of EAC with complex 2 led to an increase in Annexin V-positive cells and apoptosis induction by Caspase-7. Additionally, the complex 2 inhibited the angiogenesis caused by Ehrlich tumor cells in CAM model. This complex is active and selective for Ehrlich tumor cells, inducing DNA damage, cell cycle arrest and cell death by caspase-dependent apoptosis involving PARP activation (PARP1), and Tp53 induction.

Angiogenic and proliferative effects of the cytokine VEGF in Ehrlich ascites tumor cells is inhibited by Glycyrrhiza glabra.

Blood vessel plays a crucial role in solid tumor development. It has been suggested that blocking of angiogenesis and the action of the cytokine VEGF could be possible in cancer therapy. In a screen for naturally occurring angiogenic inhibitors, we have identified an extract from the roots of Glycyrrhiza glabra, which has potent antiangiogenic and antitumor activity. The aqueous extract inhibits the in vivo and in vitro proliferation of Ehrlich ascites tumor cells. The angioinhibitory activity of G. glabra was confirmed by its inhibition of angiogenesis in in vivo assays, peritoneal and chorioallantoic membrane assay. Reduction in the levels of the cytokine VEGF and microvessel density count in the peritoneum of mice treated with G. glabra indicated that the plant extract decreased VEGF production and the cytokine induced neovascularization. Our results suggest that the extract from the roots of G. glabra may be a potential supplemental source for cancer therapy.

Vascular endothelial growth factor immunoneutralization in combination with cisplatin reduces EAC tumor growth.

In the present study, we evaluated the effects of a neutralizing anti-Vascular Endothelial Growth Factor (VEGF) polyclonal antibody on murine EAC tumor growth both in vitro and in vivo. Furthermore, we investigated if in the presence of effective VEGF blockade, a conventional chemotherapeutic drug Cisplatin could be effective, and if so would there be an additive effect of the combination regimen. An in vitro cell proliferation assay using MTT kit showed that VEGF antibody alone inhibited proliferation of EAC cells significantly in all the three time intervals (p<0.05). But cisplatin treatment in combination with VEGF antibody resulted in highly significant inhibition (p<0.001) of cell proliferation. Apoptosis assay by FACS analysis showed that VEGF antibody-cisplatin combination treatment induced apoptosis in cultured EAC cells. Intraperitoneal administration of VEGF antibody (100 mug/dose) and cisplatin (0.5 mg/kg/dose) combination was observed to be more effective in reducing tumor burden and increasing life span when compared to VEGF antibody or cisplatin treatment alone in EAC solid tumor bearing mice. In EAC ascites tumor model, all the three types of treatment inhibited tumor burden and increased life span, but the inhibition was less compared to EAC solid tumor bearing mice. VEGF antibody singly and in combination with cisplatin reduced neoangiogenesis and vascular hyperpermeability. However, it is clear from the results that the combination treatment had no additive effect in reducing vascular hyperpermeability. Serum VEGF was not reduced significantly after treatment in EAC ascites tumor bearing mice, whereas in EAC solid tumor bearing mice it was reduced significantly after treatment. The results clearly show that though alone cisplatin showed antitumor efficacy but it had no significant inhibitory effect on neoangiogenesis and vascular hyperpermeability. Thus the present study suggests that anti-VEGF agent can be combined with traditional treatment modalities to ensure more effectiveness.

Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid.

Macrophage polarization is a process when macrophage expresses different functional programs in response to microenvironmental signals and two extreme forms exist; M1 and M2 macrophages. M1 macrophages are highly microbicidal and anticancer with enhanced ability to kill and phagocytose pathogens, upregulate pro-inflammatory cytokines and reactive molecular species, and present antigens; M2 macrophages and the related tumour associated macrophages (TAMs) regulate tissue remodelling and promote tissue repair and angiogenesis and can amplification of metabolic pathways that can suppress adaptive immune responses. It is demonstrated that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAMs differentiation and tumorigenesis in mouse models of cancer. In order to study how caffeic acid (CA), a natural antioxidant, affects macrophage function, polarization, angiogenesis and tumour growth we injected mice with Ehrlich ascites tumour (EAT) cells and treated them for 10 days with CA in a dose of 40 and/or 80 mg kg(-1.) Macrophage polarization was further characterized by quantifying secreted pro- and anti-inflammatory cytokines, nitric oxide and arginase 1 activity. CA may increase the cytotoxic actions of M1 macrophages and inhibit tumour growth; inhibitory activity on TAMs may be mediated through its antioxidative activity. Taken together, we conclude that the antitumour activity of CA was the result of the synergistic activities of different mechanisms by which CA acts on proliferation, angiogenesis, immunomodulation and survival. The continuous administration of CA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by antioxidants can be a potentially effective method for cancer treatment.

Effect of glutamine analogue-acivicin on tumor induced angiogenesis in Ehrlich ascites carcinoma.

The inhibition of tumor growth and tumor induced angiogenesis by the glutamine antimetabolite acivicin was evaluated in 6-7 weeks old male Swiss albino mice bearing Ehrlich ascites carcinoma (EAC) transplanted by intraperitoneal (ip) injections of EAC cells. Treatment involving ip injections with two different doses of acivicin (0.05 and 0.41microg/g body weight/day) in saline revealed decrease in tumor volumes and reduced number of blood vessels on peritoneal wall after 10 and 15 days of treatment when compared to control (i.e. injected with saline only). Vascular hyperpermeability was found to be lesser in the treated groups of mice than the control as indicated by the FITC- D and colloidal carbon assay. Serum VEGF level was found to decrease in the drug treated groups both after 10 and 15 days of treatment. The results thus suggest that acivicin may suppress tumoral angiogenesis through regulation of VEGF level.

Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich's Ascites Tumor in Mice.

BACKGROUND: Dietary energy restriction (DER) has been well established as a potent anticancer strategy. Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake. Glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has recently been shown to possess potential as an energy restriction mimetic agent (ERMA). In the present study we evaluated the effect of dietary 2-DG administration on a mouse tumor model, with a focus on several potential mechanisms that may account for the inhibition of tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: Swiss albino strain 'A' mice were administered with 0.2% and 0.4% w/v 2-DG in drinking water for 3 months prior to tumor implantation (Ehrlich's ascites carcinoma; EAC) and continued till the termination of the study with no adverse effects on general physiology and animal growth. Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival. We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice. Also, reduced levels of certain key players of metabolic pathways such as phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and hypoxia inducible factor-1 alpha (HIF-1α) were also noted in tumors of 2-DG fed mice. Further, decrease in CD4+/CD8+ ratio and T-regulatory cells observed in 2-DG fed mice suggested enhanced antitumor immunity and T cell effector function. CONCLUSION/SIGNIFICANCE: These results strongly suggest that dietary 2-DG administration in mice, at doses easily achievable in humans, suitably modulates several pleotrophic factors mimicking DER and inhibits tumorigenesis, emphasizing the use of ERMAs as a promising cancer preventive strategy.

Diltiazem enhances tumor blood flow: MRI study in a murine tumor.

PURPOSE: Diltiazem, a calcium-channel blocker, is known to differentially influence the radiation responses of normal and murine tumor tissues. To elucidate the underlying mechanisms, the effects of diltiazem on the radiation response of Ehrlich ascites tumor (EAT) in mice have been investigated, and the hemodynamic changes induced by diltiazem in tumor and normal muscle have been studied using magnetic resonance imaging (MRI) techniques. METHODS AND MATERIALS: Ehrlich ascites tumors were grown subcutaneously in Swiss albino strain A mice. Dynamic gadodiamide and blood oxygen level dependent (BOLD) contrast enhanced 1H MR imaging studies of EAT and normal muscle were performed after administration of diltiazem in mice using a 4.7 Tesla MR scanner. Tumor radiotherapy experiments (total dose = 10 Gy, 0.4-0.5 Gy/min, single fraction) were carried out with 30 min preadministration of diltiazem (27.5 or 55 mg/kg i.p.) to EAT-bearing mice using a teletherapy machine. RESULTS: The diltiazem+ radiation treated group showed significant tumor regression (in approximately/= 65% of the animals) and enhanced animal survival. MR-gadodiamide contrast kinetics revealed a higher magnitude of signal enhancement in diltiazem treated groups as compared to the controls. The observed changes in the magnitude of kinetic parameters were the same for both tumor and normal muscle. BOLD-MR images at 30 min after diltiazem administration showed a 25% and 8% (average) intensity enhancement from their basal values in tumor and normal muscle regions, respectively. The control group showed no significant changes. CONCLUSION: The present studies demonstrate the radiosensitization potential of diltiazem in the mice EAT model. The enhanced radiation response observed with diltiazem correlates with the diltiazem-induced increase in tumor blood flow (TBF) and tumor oxygenation. The present results also demonstrate the applications of BOLD-MR measurements in investigating the alterations in tumor oxygenation status.

Tumor angiogenesis: evidence of new blood channels from plasma infiltrations.

Stroma formation in Ehrlich carcinoma, studied with histochemical and TEM techniques, is similar to wound healing. In this tumour mast cells, macrophages, adipocytes, platelets and fibrin seem to co-operate locally with malignant cells in regulating stroma formation. The gaps opened in the tumor parenchyma by plasma outpouring from local blood vessels seem to offer easy routes for endothelial cell migration towards ill-nourished areas, and may explain the irregular aspect of tumor microvascularity.

Thermoradiotherapy with hydralazine: the effect of preirradiation of the tumor bed on blood flow and growth delay of Ehrlich carcinoma.

Ehrlich carcinoma transplanted into preirradiated calf muscle of mice was used as a model for tumor recurrence after unsuccessful radiotherapy. Due to the tumor bed effect (TBE), these grafts grew more slowly than control tumors implanted in the unirradiated tissue. When these tumors achieved the same volume (0.3-0.4 cm3), in 10-11 days for tumors implanted in irradiated tissue and 7-8 days for control tumors, they were treated with radiation, the tumor blood flow inhibitor hydralazine, and hyperthermia, alone or in different combinations. In the case of the trimodality treatment, single irradiation of tumors at a dose of 12.5 Gy was followed 2.5-3 h later by administration of hydralazine (2.5 mg/kg) and local hyperthermia (water bath, 43 degrees C for 30 min). The growth delay induced in the different tumor types by irradiation, hydralazine and hyperthermia, alone or in different combinations, was related to the blood flow measured in the tumors by the 133Xe clearance technique 24-48 h after treatment. It was shown that the reduction of blood flow after treatment with hyperthermia or hydralazine was approximately equal in both types of tumors. However, the combined inhibiting effect of these agents differed in the tumors: It was synergistic in control tumors and close to additive in tumors implanted in irradiated tissue. In terms of the specific tumor growth delay, the latter tumors were slightly more sensitive to hyperthermia, but were more resistant to radiation and thermoradiotherapy compared to control tumors. Hydralazine potentiated the tumoricidal effects of heat alone and heat combined with radiation. The enhancement was more substantial in control tumors compared to tumors implanted in irradiated tissue. A general correlation between the hydralazine-induced enhancement of the effects of heat on tumor blood flow and growth delay was observed. In tumors implanted in irradiated tissue, the inhibition of perfusion after treatment with hydralazine plus hyperthermia was smaller, and presumably a less marked treatment response to these agents (with or without radiation) was therefore achieved as a result in these tumors compared to the control tumors.

Angiogenesis a putative new approach in glutamine related therapy.

Angiogenesis or the generation of new blood vessels, is an important factor regarding the growth of a tumor. Hence, it becomes a necessary parameter of any kind in therapeutic studies. Glutamine is an essential nutrient of tumor tissue and glutamine related therapy involves clearance of circulatory glutamine by glutaminase. So, whether this enzyme has any effect on angiogenesis of a tumor or not becomes an obvious question. To address this question, this study has been carried out with different murine tumor models. The results indicate that purified glutaminase reduces tumor volume as well as restricts the generation of new blood vessels. Glutaminase is effective in the case of solid as well as ascites tumor models. In the case of induced cancer, the host exhibits delayed onset of neoplasia following enzyme treatment and tumor host interactions determine the intensity of the neovascularisation process. Therefore, it can be concluded that this enzyme might be an effective agent against cancer metastasis.

Differential effects of thalidomide on angiogenesis and tumor growth in mice.

Thalidomide, clinically used as an antiinflammatory and antitumoral drug, inhibited sponge-induced angiogenesis when administered systemically (100 mg/kg(-1)) in mice. However, it failed to inhibit solid Ehrlich tumor in the same mouse strain. We have used functional, biochemical and histological parameters to assess neovascularization and fibrovascular tissue infiltration of the mice sponge granuloma. The neovascularization growth as detected by development of blood flow and hemoglobin content extracted from the implants showed that thalidomide inhibited fibrovascular tissue formation by 40%. The functional and biochemical parameters correlated well with the histological study. Thalidomide had no inhibitory effect in the development of Ehrlich tumor. The detection of this selective action using the same animal strain bearing two different processes, supports the hypothesis that rather than species specificity, thalidomide is tissue specific. This approach may be used to identify the specificity of other therapeutic agents against distinct angiogenesis-dependent diseases.

Influence of methoxamine, 5-hydroxytryptamine and physically induced low pH on thermal sensitivity and thermotolerance.

The influence of pH on split-dose hyperthermic response of non-resistant and thermotolerant Ehrlich tumors was studied. Vasoactive agents, methoxamine and 5-hydroxytryptamine (5-HT) and, mechanical interruption of the tumor blood flow by wire technique were applied in combination with hyperthermia at 72-hour intervals, where an increased thermal response was observed in Ehrlich tumor. A potential influence in suppressing the induction of thermotolerance (hyperthermia at 24-hour intervals) was evident in the case of 5-HT and methoxamine. These vasoactive agents and the wire technique showed a selective effect in reducing the tumor microcirculation as well as lowering its pH. However, unlike the wire technique, the pH was rather low in the postheating period in the case of 5-HT and methoxamine. Poor tumor vascularization induced by vasoactive agents or physical means would demonstrate a poor nutritional condition with a low pH, whereby an increase in thermal response would be obvious and may be expected to have maximal influence either in the decay or in delaying the induction of thermotolerance. A low tumor pH particularly during the postheating period may have some role against the development of thermotolerance.

Neovascularisation offers a new perspective to glutamine related therapy.

Angiogenesis or the generation of new blood vessel, is an important factor in the growth of a solid tumor. Hence, it becomes a necessary parameter of any kind of therapeutic study. Glutamine is an essential nutrient of tumor tissue and glutamine related therapy involves clearance of circulatory glutamine by glutaminase. Therefore, using different murine solid tumor models, the present study was undertaken to find out whether the S-180 cell glutaminase has any effect on angiogenesis of solid tumor, or not. Result indicates that the purified S-180 cell glutaminase reduces tumor volume and restrict the generation of neo blood vessels. Therefore, it can be concluded that this enzyme may be an effective device against the cancer metastasis.

[Microroentgenography of transplantable tumors]. / Mikrorentgenografiia perevivaemykh opukholei.

Ehrlich ascites tumors were transplanted into the soft tissue of albino mouse hind leg. It was found that vascularization in tumor tissue proceeds in step with relevant morphologic alterations. The formation of three patterns of blood circulation system in tumor is completed within 7 days. Tumor transplantation is followed by pronounced vascular dystonia development and venous plethora. These changes are particularly distinct in lymph nodes in the zone adjacent to tumor.