Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We are interested in the interaction of pulsed high energy shock waves (PHEUS) on soft tissues treated in situ to evaluate its potential for therapeutic use. The experimental apparatus built by us was adapted from a lithotripter designed for clinical use. For the present studies we used the R3327-AT1 Dunning prostate tumor growing s.c. in the thigh of Copenhagen rats. The treatments consisted of four groups of eight animals each who received 500 or 2000 pulses at 1 or 5 Hz. Sham-treated tumor bearing animals served as controls (n = 11). During each PHEUS treatment, petechial bleeding of the skin at the point of entry and exit of sound appeared. Sonication at a repetition rate of five Hz seemed to induce more macroscopic damage in terms of hematomas and skin effects. The cytotoxic effects of PHEUS to tumor tissue were sufficient to induce a significant delay (p less than 0.05) in tumor growth but no clear-cut dose relationship was established. Histological studies revealed widespread early rupture of the fine vasculature with extravasation of erythrocytes. By 72 hr., in PHEUS treated tumors, a large necrosis was seen within the central zone which was never observed in sham-treated tumors. Our results clearly indicate that PHEUS has a cytotoxic potential. The observation of a rapid onset of hemostasis, stark hemorrhage and necrosis in the treatment field would suggest that vascular damage is an important contributing factor.
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PMID:Treatment of the Dunning prostate rat tumor R3327-AT1 with pulsed high energy ultrasound shock waves (PHEUS): growth delay and histomorphologic changes. 189 42

Almost 200 patients have been treated for head and neck tumors at two different dose levels. Based on the clinically observed probabilities for tumor control and fatal normal tissue complications at the two dose levels, the dose giving maximum uncomplicated control has retrospectively been calculated and compared with the clinical data. A Poisson statistical model for control and complications has been used including a correlation parameter, delta, to describe the fraction of patients where control and complications are statistically independent. The clinically observed probability of uncomplicated tumor control, P+, is consistent with only a small fraction of the patients treated being statistically independent (delta = 0.2 or 20%). Customarily, 100% of the patients are assumed to be statistically independent with regard to tumor control and normal tissue complications. More precisely, the clinical data are consistent, with almost 20% of the patients being significantly more sensitive to radiation since they gain local tumor control but simultaneously suffer fatal complications. An even larger fraction of the patients (almost 30%) seemed to be more resistant to radiation, showing neither serious treatment complications nor control of the local tumor growth. It is suggested that if these patient groups could be identified by a predictive assay for the radiation sensitivity of their normal tissues and preferably also for their tumors, the uncomplicated tumor control could be increased by about 20%. This figure is based on the actuarial survival of the patients and has been corrected for the inevitable uncertainty in dose delivery. It is also pointed out that about 20% of the patients can never be saved by a predictive assay because of the considerable statistical variance associated with the Poisson process and the eradication of the last clonogenic tumor cell. Finally, note that the possible existence of radiation sensitive and resistant patient groups is consistent with known genetic deficiencies such as ataxia telangiectasia for the sensitive patients and the existence of repair efficient head and neck tumors that are unusually efficient in repairing double strand breaks. If such sensitive and resistant patient groups do exist, it should be sufficient to perform a predictive assay on normal tissues alone avoiding the often impossible task of sampling the most radiation resistant tumor cell line.
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PMID:Optimization of uncomplicated control for head and neck tumors. 221 Dec 46

Cell kinetics were measured in vivo in four experimental rat prostatic adenocarcinomas grown in normal or castrated rats. The aim was to investigate the effect of castration on growth rate and cell kinetics in hormone sensitive and hormone insensitive prostatic carcinomas. We used two anaplastic, hormone insensitive, fast growing tumors (Dunning R-3327-AT1 H and E), as well as two well differentiated, hormone sensitive, slow growing tumors (R-3327-H and R-3327-PAP). DNA ploidy, S-phase transit time (Ts), the labeling index (LI) and potential doubling time (Tpot) was determined by dual parameter flow cytometry, after in-vivo labeling, using bromodeoxyuridine (BUdR) and the tumor doubling time (DT) was determined from growth curves. After castration DT in the hormone sensitive H-subline changed from 21.7 days to 82.0 days, and in the PAP-subline from 22.2 days to 33.2 days. No significant changes in Tpot were observed. In the anaplastic tumors no differences in neither DT nor Tpot were seen. The cell loss factor (CLF) was relatively low in the two anaplastic tumors (0.55-0.59) compared to the well differentiated tumors. The CLF was unaffected by castration in the poorly differentiated tumors, whereas it increased significantly (from 0.75 to 0.92, P = 0.005) after castration in the H-tumor, and showed a non-significant increase in the PAP-tumor. This implies that the decrease in tumor growth in the hormone sensitive tumors is due to an increase in cell death, not a decrease in cell proliferation. These data indicate that CLF is the dominating factor in the reduced growth following androgen ablation in an androgen sensitive tumor. This study suggests that Tpot might be an additional predictor of a tumors proliferating rate and it may provide important information of the human prostatic cancer.
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PMID:The effect of castration on tumor growth rate and cell kinetics in hormone sensitive and hormone insensitive rat prostatic adenocarcinomas. 857 60

Breast-carcinoma development presumably results from multiple mutational events in tumor-associated genes. Certain results indicate that some tumor-suppressor genes may combine their pathogenetic potential to synergistically promote tumor growth. In an effort to identify such mechanisms in breast tumors, a series of 77 (group I) paired blood tumor samples from patients with sporadic mammary carcinomas was analyzed for loss of heterozygosity with 15 polymorphic markers on the chromosomal arms 7q, 11q, 13q, 16q, 17p and 17q. A significant association was observed for the combination of allelic losses on chromosomes 11q and 16q. In order to confirm these findings, we studied a second independent series of 189 breast-tumor patients (group 2) with comparable histopathological tumor stages. Group 2 was examined for the same genetic alterations using the identical set of polymorphic markers. The data from this group confirmed the detected association of loss of heterozygosity on chromosomes 11q and 16q and indicate the cooperation of putative tumor-suppressor genes on the chromosomal arms 11q and 16q in a sub-set of breast carcinomas. The regions involved harbor the candidate genes ATM (mutated in ataxiatelangiectasia) on chromosome 11q23 and UVO (uvomorulin, cadherin E) and BBCI (breast basic conserved I) on chromosome 16q22-q24.
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PMID:Association of allelic losses on human chromosomal arms 11Q and 16Q in sporadic breast cancer. 879 73

Both p53 and ATM are checkpoint regulators with roles in genetic stabilization and cancer susceptibility. ATM appears to function in the same DNA damage checkpoint pathway as p53. However, ATM's role in p53-dependent apoptosis and tumor suppression in response to cell cycle dysregulation is unknown. In this study, we tested the role of murine ataxia telangiectasia protein (Atm) in a transgenic mouse brain tumor model in which p53-mediated apoptosis results in tumor suppression. These p53-mediated activities are induced by tissue-specific inactivation of pRb family proteins by a truncated simian virus 40 large T antigen in brain epithelium. We show that p53-dependent apoptosis, transactivation, and tumor suppression are unaffected by Atm deficiency, suggesting that signaling in the DNA damage pathway is distinct from that in the oncogene-induced pathway. In addition, we show that Atm deficiency has no overall effect on tumor growth and progression in this model.
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PMID:Atm is dispensable for p53 apoptosis and tumor suppression triggered by cell cycle dysfunction. 1008 76

Pulsed high-energy ultrasound shock waves (PHEUS), similar to those used for clinical lithotripsy, can deposit energy deep in tissue and thereby destroy the microvasculature of solid tumors. We investigated the potential of PHEUS, generated by an electromagnetic shockwave source (19 kV capacitor voltage, 1 Hz pulse frequency), as a local cancer-therapy modality alone and in combination with local tumor hyperthermia (43.5 +/- 0.1 degrees C, 30 min). Copenhagen rats transplanted with the anaplastic Dunning-prostate-tumor sub-line R3327-AT1 received 1000 PHEUS pulses, which delayed tumor growth by one tumor-doubling time (5 days). Histopathology revealed hemorrhage, disruption of tumor vasculature, and necrosis in the focus of the sound field. Bromodeoxyuridine (BUdR) incorporation was significantly lower in PHEUS-treated tumors than in controls. Dynamic magnetic resonance imaging (MRI) studies using gadolinium-DTPA as contrast agent showed a strong reduction of tumor perfusion after PHEUS treatment, although this effect was partly reversible within 3 days after PHEUS. While hyperthermia alone produced no significant delay in tumor growth, the combination of PHEUS and hyperthermia produced tumor-growth delay by 2 tumor-volume-doubling times. The maximum growth delay was achieved when PHEUS and hyperthermia were separated by 24 hr at the time of maximum perfusion reduction indicated by MRI. Thus, the cytotoxic effect of PHEUS was enhanced by hyperthermia in the anaplastic prostate tumor R3327-AT1 grown on Copenhagen rats in a synergistic manner, due to blood-flow reduction. In conjunction with other agents, such as hyperthermia, PHEUS might become a local cancer-therapy modality in solid tumors accessible to ultrasound.
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PMID:Synergistic interaction of ultrasonic shock waves and hyperthermia in the Dunning prostate tumor R3327-AT1. 1036 Aug 25

Local tumor therapy using focused ultrasonic waves may become an important treatment option. This technique exploits the ability of mechanical waves to induce thermal and nonthermal effects noninvasively. The cytotoxicity to cultured cells and biological tissues in vivo that results from exposure to ultrasonic shock waves is considered to be a nonthermal effect that is partly a consequence of ultrasound-induced cavitation. Cavitation is defined as the formation of bubbles during the negative wave cycle; their subsequent oscillation and/or violent implosion can affect surrounding structures. To investigate cavitational effects in cells and tissues, defined cavitation doses must be applied while ideally holding all other potential ultrasound parameters constant. The application of independent cavitation doses has been difficult and has yielded little knowledge about quantitative cavitation-tissue interactions. By using a special shock-wave pulse regimen and laser optical calibration in this study, we were able to control the cavitation dose independently of other physical parameters such as the pressure amplitudes, and averaged acoustic intensity. We treated Dunning prostate tumors (subline R3327-AT1) transplanted into Copenhagen rats with shock waves at three cavitation dose levels and then determined the tumor growth delay and the histopathological changes. All of the treated animals exhibited a significant tumor growth delay compared to the controls. Higher cavitation doses were associated with a greater delay in the growth of the tumor and more severe effects on tumor histopathology, such as hemorrhaging, tissue disruption, and necrosis. In vitro, the cavitation dose level correlated with the amount of radical formation. We concluded that the process of acoustic cavitation was responsible; higher cavitation doses caused greater effects in tumors both in vivo and in vitro. These findings may prove important in local tumor therapy and other applications of ultrasound such as ultrasound-mediated drug delivery.
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PMID:Tumor cytotoxicity in vivo and radical formation in vitro depend on the shock wave-induced cavitation dose. 1150 Jan 39

It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention.
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PMID:Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. 1205 31

Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor-deficient (AT1a-/-) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a-/- mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the beta-galactosidase gene was inserted into the AT1a gene locus in AT1a-/- mice, the site of beta-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a-/- mice, the major site of the beta-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a-/- mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo.
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PMID:Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. 1284 60

Tumor oxygenation has long been recognized as a significant factor influencing cancer therapy. We recently established a novel magnetic resonance in vivo approach to measuring regional tumor oxygen tension, FREDOM (Fluorocarbon Relaxometry Using Echo Planar Imaging for Dynamic Oxygen Mapping), using hexafluorobenzene (HFB) as the reporter molecule. We have now investigated oxygen dynamics in the two Dunning prostate R3327 rat tumor sublines, AT1 and H. FREDOM revealed considerable intratumoral heterogeneity in the distribution of pO(2) values in both sublines. The anaplastic faster-growing AT1 tumors were more hypoxic compared with the size-matched, well-differentiated, and slower-growing H tumors. Respiratory challenge with oxygen produced significant increases in mean and median pO(2) in all the H tumors (P<.001), but no response in half of the larger AT1 tumors (>3 cm(3)). Immunohistochemical studies using the hypoxia marker, pimonidazole, and the vascular endothelial cell marker, CD31, confirmed that the H tumors had more extensive vasculature and less hypoxia than the AT1 tumors. These results further validate the utilization of FREDOM to monitor tumor oxygenation and concur with the hypothesis that the level of hypoxia is related to tumor growth rate and poor vascularity.
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PMID:Tumor oxygen dynamics: correlation of in vivo MRI with histological findings. 1451 2


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