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  • 1
    Electronic Resource
    Electronic Resource
    Targeting gene expression to hypoxic tumor cells (1997)
    [s.l.] : Nature Publishing Group
    Nature medicine 3 (1997), S. 515-520 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Solid tumors with areas of low oxygen tension (hypoxia) have a poor prognosis, as celts in this environment often survive radiation and chemotherapy. In this report we describe how this hypoxic environment can be used to activate heterologous gene expression driven by a hypoxia-responsive element ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm0597-515
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  • 2
    Electronic Resource
    Electronic Resource
    An open study to assess the safety, tolerance and pharmacokinetics of an intravenous infusion of granisetron given at 3 mg over 30 s in patients receiving chemotherapy for malignant disease (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 134-138 
    Details
    ISSN: 1432-0843
    Keywords: Key words Granisetron ; Tolerance ; Rapid infusion ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Granisetron is a highly potent and selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist indicated for the prevention of cytotoxic-induced nausea and vomiting. Clinical trials have demonstrated granisetron to be effective and well tolerated at a standard dose of 40 μg/kg or 3 mg given i.v. as a 5-min infusion. In this study, the efficacy and safety of granisetron given as a 30-s infusion was assessed. A total of 21 patients, scheduled to undergo chemotherapy, received a single 3-mg i.v. dose of granisetron over 30 s, completed at 1 h before chemotherapy administration. Patients were allowed two further i.v. doses of granisetron at 3 mg within the 24-h assessment period. Changes from baseline values in vital signs were analysed prior to granisetron administration and at 30 s as well as 1, 10, 15, 30 and 60 min after granisetron administration. Holter ECG recordings were taken for 6 h prior to and 1 h after administration. No significant change was found in vital signs at 30 s or 1 min after granisetron infusion. There was a small but statistically significant fall in diastolic blood pressure as compared with baseline and a non-significant trend in favour of a reduction in heart rate at 10 and 15 min. No ECG abnormality was recorded post-infusion that had not been present pre-infusion. None of these changes was considered to be clinically relevant. The treatment was well tolerated. The most frequently reported adverse events were constipation (n=6) and headache (n=5). Maximal plasma levels of granisetron were within the range of 44.57–410 ng/ml except in one patient. The median values recorded for peak concentration (Cmax) and area under the curve (AUC) were 195 ng/ml and 71.2 ng h ml-1, respectively. In conclusion, granisetron at 3 mg was shown to be safe and well tolerated when given as a 30-s i.v. infusion to patients receiving chemotherapy for malignant disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050378
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  • 3
    Electronic Resource
    Electronic Resource
    An open study to assess the safety, tolerance and pharmacokinetics of an intravenous infusion of granisetron given at 3 mg over 30 s in patients receiving chemotherapy for malignant disease (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 134-138 
    Details
    ISSN: 1432-0843
    Keywords: Granisetron ; Tolerance ; Rapid infusion ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Granisetron is a highly potent and selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist indicated for the prevention of cytotoxic-induced nausea and vomiting. Clinical trials have demonstrated granisetron to be effective and well tolerated at a standard dose of 40 μg/kg or 3 mg given i.v. as a 5-min infusion. In this study, the efficacy and safety of granisetron given as a 30-s infusion was assessed. A total of 21 patients, scheduled to undergo chemotherapy, received a single 3-mg i.v. dose of granisetron over 30 s, completed at 1 h before chemotherapy administration. Patients were allowed two further i.v. doses of granisetron at 3 mg within the 24-h assessment period. Changes from baseline values in vital signs were analysed prior to granisetron administration and at 30 s as well as 1, 10, 15, 30 and 60 min after granisetron administration. Holter ECG recordings were taken for 6 h prior to and 1 h after administration. No significant change was found in vital signs at 30 s or 1 min after granisetron infusion. There was a small but statistically significant fall in diastolic blood pressure as compared with baseline and a non-significant trend in favour of a reduction in heart rate at 10 and 15 min. No ECG abnormality was recorded post-infusion that had not been present pre-infusion. None of these changes was considered to be clinically relevant. The treatment was well tolerated. The most frequenctly reported adverse events were constipation (n=6) and headache (n=5). Maximal plasma levels of granisetron were within the range of 44.57–410 ng/ml except in one patient. The median values recorded for peak concentration (Cmax) and area under the curve (AUC) were 195 ng/ml and 71.2 ng h ml−1, respectively. In conclusion, granisetron at 3 mg was shown to be safe and well tolerated when given as a 30-s i.v. infusion to patients receiving chemotherapy for malignant disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685640
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  • 4
    Electronic Resource
    Electronic Resource
    Markers of tumor angiogenesis: clinical applications in prognosis and anti-angiogenic therapy (1997)
    Springer
    Investigational new drugs 15 (1997), S. 15-28 
    Details
    ISSN: 1573-0646
    Keywords: angiogenesis ; prognosis ; histology ; methods
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Numerous studies in many tumor types have demonstrated that quantitation by microvessel as a measure of angiogenesis is a powerful prognostic tool. However, the ability to exploit tumor angiogenesis as a prognostic marker is limited by the methods currently used for capillary identification and quantitation. This report critically evaluates all aspects of the techniques and their associated problems used for assessing tumor angiogenesis in tissue sections including the area of tumor assessed, the vascular parameter measured, the method of quantitation, the stratification of patients and the practical utility of computer image analysis systems. The potential of angiogenic factors assays, proteolytic enzymes, and cell adhesion molecules as surrogate endpoints for quantifying tumor angiogenesis are discussed and other methods for quantifying tumor angiogenesis are described. The potential clinical applications of these angiogenic markers in prognosis, stratification for adjuvant treatments (both cytotoxic and anti-angiogenic/vascular targeting) and other aspects of patient management is also discussed, particularly design of phase I and II trials.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005714527315
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  • 5
    Electronic Resource
    Electronic Resource
    bcl-2 and c-erbB-2 proteins are involved in the regulation of VEGF and of thymidine phosphorylase angiogenic activity in non-small-cell lung cancer (1999)
    Springer
    Clinical & experimental metastasis 17 (1999), S. 545-554 
    Details
    ISSN: 1573-7276
    Keywords: angiongenesis ; bcl-2 ; c-erB-2 ; non-small-cell lung cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tumour angiogenesis has been recently recognised as one of the most important prognostic factors in lung cancer. Although a variety of angiogenic factors have been identified, the angiogenesis process remains poorly understood. Bcl-2, c-erbB-2 and p53 are well-known oncogenes involved in non-small-cell lung cancer pathogenesis. A direct correlation of thymidine phosphorylase (TP) and of vascular endothelial growth factor (VEGF) with intratumoural angiogenesis has been reported. In the present study we investigated the possible regulatory role if bcl-2, c-erB-2 proteins in angiogenesis and in VEGF and TP expression in non-small-cell lung cancer. Two hundred sixteen specimens from T1,2-N0,1 staged patients treated with surgery alone were immunohistochemically examined. Bcl-2 and c-erbB-2 were significantly inversely related to each other (P=0.04) and both were inversely associated with microvessel density (P〈0.02). High TP and VEGF reactivity was statistically related to loss of bcl-2 expression (P〈0.01). A significant co-expression of c-erbB-2 with TP was noted (P=0.01). However, TP expression was related to high angiogenesis only in cases with absence of c-erB-2 expression (P〈0.0001). c-erbB-2 expression in poorly vascularised tumours was linked with poor outcome (P=0.03). The present study provides strong evidence that the bcl-2 gene has a suppressive function over genes involved in both angiogenesis (VEGF and TP) and cell migration (c-erbB-2) in NSCLC. TP and c-erbB-2 proteins are significantly, and often simultaneously, expressed in bcl-2 negative cases. However, expression of the c-erbB-2 abolishes the TP-related angiogenic activity. Whether this is a result of a direct activity of the c-erbB-2 protein or a consequence of a c-erbB-2-related immune response remains to be further investigated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006780710148
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  • 6
    Electronic Resource
    Electronic Resource
    Assessing the clinical impact of prognostic factors: When is "statistically significant" clinically useful? (1998)
    Springer
    Breast cancer research and treatment 52 (1998), S. 305-319 
    Details
    ISSN: 1573-7217
    Keywords: tumor markers ; prognostic factors ; predictive factors ; breast cancer ; patient management ; treatment decisions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Very few tumor markers have been recommended for routine clinical care of patients with breast cancer [1]. A framework to determine the clinical utility of tumor markers is required. In a previous publication, a "Tumor Marker Utility Grading System" (TMUGS) was proposed [2]. TMUGS included a semi-quantitative grading scale (0-3+) which can be used to assign a score to a given tumor marker for a given outcome. Only those markers that are felt to be sufficiently strong to influence a therapeutic decision that results in improved clinical outcome for the patient are recommended. The studies from which data are used to assign a TMUGS grade can be placed into one of five Levels of Evidence (LOE). An extension of TMUGS ("TMUGS-Plus") is now proposed in which the relative strength of a prognostic or predictive factor can be estimated and expressed in terms of a risk ratio (RR) for prognostic factors or benefit ratio (BR) for predictive factors. Three categories of prognostic factors and three categories of predictive factors are proposed (strong, moderate, and weak). It is recommended that only LOE type I studies (prospective, highly powered studies of the tumor marker, or meta-analysis of LOE II or III datasets), be used to estimate the RR or BR of a given factor. Finally, a matrix, based on assumptions of acceptable absolute benefits relative to risks, is proposed in which any given tumor marker can be assessed for its clinical utility. TMUGS-Plus should aid in the assessment of published data regarding clinical utility of tumor markers. Perhaps more important, clinical investigators can use TMUGS-Plus to design tumor marker studies that will fulfill criteria for clinical utility, resulting in more rapid acceptance of tumor markers for routine clinical use.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006197805041
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  • 7
    Electronic Resource
    Electronic Resource
    Neoplastic stroma and epithelium show up-regulation of platelet-derived endothelial cell growth factor/thymidine phosphorylase in colorectal carcinomas but not adenomas (1998)
    Springer
    Angiogenesis 2 (1998), S. 49-55 
    Details
    ISSN: 1573-7209
    Keywords: Adenoma ; carcinoma ; colorectal cancer ; macrophage ; thymidine phosphorylase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tumor angiogenesis, a crucial step in tumor growth and progression, is regulated by an increasing number of angiogenic factors. One of those is platelet-derived endothelial cell growth factor, recently shown to bethymidine phosphorylase (TP), which reversibly catalyzes the phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. TP overexpression in tumors has been reported, but the differential expression of this enzyme in the colorectal adenoma–carcinoma sequence has not been examined in detail. In this study we analyzed 16 hyperplastic polyps, 37 solitary tubular and tubulovillous adenomas (ranging from 1 to 7.5cm, median 3.2cm), and 47 cases of colorectal carcinomas arising on the basis of pre-existing adenomas (25 cases were Dukes' A, 10 Dukes' B and 12 Dukes' C). Non-neoplastic colonic mucosa was also examined separately from all the above carcinoma cases. All samples were stained for TP and assessed for vascularity. Normal mucosa, hyperplastic polyps, and all but three adenomas and the adenomatous parts of the invading tumors did not show any epithelial cell positivity, and only occasional macrophages and fibroblasts showed weak cytoplasmic immunoreactivity for TP. Neoplastic cells in the carcinomatous part of the tumors were positive for TP in 18 out of 47 (36%) cases. Both nuclear and cytoplasmic staining was detected but in a few cases only one of these was present. There was a highly significant difference between TP expression in neoplastic epithelial cells in adenomas compared with carcinomas (p=0.0001). The same was true when the immunoreactivity of the stromal cells was compared (p=0.0001). Areas with high angiogenesis such as those at the invading edge of the tumor showed intense epithelial, endothelial and stromal TP immunoreactivity. These results show up-regulation of a major angiogenic pathway in both the tumor epithelium and stromal cells with progression from adenoma to carcinoma, and suggest TP may be a candidate target for therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009002426554
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  • 8
    Electronic Resource
    Electronic Resource
    Expression of messenger RNA for amphiregulin, heregulin, and cripto-1, three new members of the epidermal growth factor family, in human breast carcinomas (1995)
    Springer
    Breast cancer research and treatment 35 (1995), S. 293-297 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; amphiregulin ; heregulin ; cripto-1 ; EGF receptor family
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The expression of amphiregulin (AR), heregulin (HRG), and cripto-1 (CR-1) mRNA transcripts was assessed in 60 human primary breast carcinoma. AR and HRG transcripts were expressed respectively in 58% and 25% of the carcinomas as measured by Northern blot analysis. CR-1 mRNA was found in 77% of the carcinomas using Reverse Transcriptase-PCR analysis. Coexpression of two or three of these peptides was observed in several specimens. There was no significant association between AR, HRG, and CR-1 expression and nodal status, EGF receptor, or c-erbB-2 protooncogene expression in these tumors. However, a significant association between AR expression and estrogen receptor positivity was observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00665981
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  • 9
    Electronic Resource
    Electronic Resource
    Clinical trials of anti-vascular agent group B Streptococcus toxin (CM101) (1997)
    Springer
    Angiogenesis 1 (1997), S. 36-37 
    Details
    ISSN: 1573-7209
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018353015650
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  • 10
    Electronic Resource
    Electronic Resource
    Breast cancer angiogenesis — new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting (1996)
    Springer
    Breast cancer research and treatment 38 (1996), S. 97-108 
    Details
    ISSN: 1573-7217
    Keywords: angiogenesis ; angiogenesis inhibitors ; gene therapy ; hypoxic activated pro-drugs ; prognosis ; vascular targeting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGFβ1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suraminin vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize. New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01803788
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