Biomedical subjects

Efthimios Sivridis

Publications and source records attributed to Efthimios Sivridis.

At least 37 records · Page 2Linked to original sources

PubMed2005

Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer.

Lactate dehydrogenase 5 (LDH5) is one of the five LDH isoenzymes and, apparently, the most important for promoting anaerobic glycolysis. LDH5 is transcriptionally regulated by the hypoxia inducible factors (HIF) 1alpha and 2alpha. In this study, the possible aggressive advantages that colorectal tumours may gain from a high LDH5 content was investigated. To this end, 75 colorectal adenocarcinomas were studied immunohistochemically for the expression of LDH5, and the results were related to tumor differentiation, lymph node and distant metastases, the expression of HIF1alpha and HIF2alpha, vascular density (VD) and vascular endothelial growth factor (VEGF). A high LDH5 content was noted in 51 of 75 (68%) colorectal adenocarcinomas. The reactivity was nuclear and/or cytoplasmic. Nuclear LDH5 reactivity was correlated with lymph node involvement and distant metastases. There was a direct association between LDH5 up-regulation and HIF1alpha and HIF2alpha accumulation. HIF1alpha was linked with VEGF, VD and also with extramural invasion, nodal and distant metastases. It is concluded that a high LDH5 content in tumor cells is directly related to an up-regulated HIF pathway and is linked with an aggressive phenotype in colorectal adenocarcinomas.

Adenocarcinoma↗

PubMed2005

The HIF-2alpha/VEGF pathway activation in cutaneous capillary haemangiomas.

AIM: To investigate the pathogenesis of capillary haemangiomas, a common form of vascular malformation. METHODS: Twenty-five cutaneous capillary haemangiomas, excised from patients under 14 years of age, were studied immunohistochemically for endothelial cells, the angiogenic factors thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF), the proliferation index Ki-67, and the hypoxia inducible factors-1alpha (HIF-1alpha) and -2alpha (HIF-2alpha). RESULTS: Endothelial-lined channels reacted strongly with CD31 in all cases, clearly definining capillary spaces. Between 5 and 20% of the endothelial cells were Ki-67 positive, indicating an intense proliferative activity; more importantly, they consistently expressed VEGF and HIF-2alpha, and in many cases TP, but failed to react with HIF-1alpha. CONCLUSION: It is suggested that the activation of the HIF-2alpha pathway and the consequent overexpression of VEGF by the endothelial cells are involved in the pathogenesis of cutaneous capillary haemangiomas.

Adolescent↗

PubMed2005

Hypofractionated accelerated radiotherapy with cytoprotection combined with trastuzumab, liposomal doxorubicine, and docetaxel in c-erbB-2-positive breast cancer.

OBJECTIVES: Trastuzumab, an antic-erbB-2 monoclonal antibody, has become a standard component of chemotherapy for c-erbB-2-positive advanced breast carcinoma. Despite the experimental evidence of its radiosensitizing properties, trastuzumab has never been used in combination with radiotherapy for the treatment of patients with locally advanced disease. PATIENTS AND METHODS: Twenty-two patients with c-erbB-2-positive locally advanced chemoresistant (7 patients) or with high-risk breast cancer (15 patients) were recruited in a treatment protocol combining hypofractionated/accelerated radiotherapy (hypoARC) supported with high-dose amifostine (1000 mg subcutaneous), concurrently with trastuzumab (4 mg/kg every 2 weeks). Thirteen of these patients (including all 7 inoperable cases) received concurrently chemotherapy with liposomal doxorubicin and docetaxel (25 mg/m2 and 40 mg/m2 every 2 weeks, respectively). RESULTS: Administration of trastuzumab together with highly accelerated amifostine-supported radiotherapy was feasible without an increase in early and late radiation toxicity. This was obtained despite the concurrent administration of aggressive chemotherapy. Complete responses were noted in 5 of 7 patients with locally, often far advanced, chemoresistant disease. None of the complete responders or the 15 high-risk breast cancer patients relapsed within the 3- to 26-month follow-up period. CONCLUSION: Inclusion of trastuzumab in the radiochemotherapy protocols for breast cancer does not increase radiation or systemic toxicity. The concurrent administration of aggressive radiotherapy with docetaxel and liposomal doxorubicin is feasible when supported with amifostine. The value of such regimens in the treatment of locally advanced or high risk c-erbB-2 positive breast cancer patients deserves further evaluation.

Adult↗

PubMed2005

Giant multilocular epidermoid cyst on the left buttock.

BACKGROUND: Epidermoid cysts are the most common cysts of the skin. They are generally small and slow-growing and rarely reach more than 5 cm in diameter. OBJECTIVE: We present a patient with a giant multilocular epidermoid cyst. METHODS: A 75-year-old man presented with a giant, soft, painless, tumorlike mass on the left buttock that had gradually enlarged over a 12-year period. Excision of the mass from the surrounding tissue was extremely easy because of a well-defined capsule. RESULTS: The 28 x 14 x 12 cm mass was totally excised. A histopathologic examination revealed that it was an epidermoid cyst. CONCLUSION: This rare case of giant epidermoid cyst was treated successfully by local excision followed by primary closure. Dissection of the mass from the surrounding tissue was extremely easy because of a well-defined capsule.

Aged↗

PubMed2005

Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma.

Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate to acetyl-coenzyme A, which enters into the Krebs cycle, providing adenosine triphosphate (ATP) to the cell. PDH activity is under the control of pyruvate dehydrogenase kinases (PDKs). Under hypoxic conditions, conversion of pyruvate to lactate occurs, a reaction catalyzed by lactate dehydrogenase 5 (LDH5). In cancer cells, however pyruvate is transformed to lactate occurs, regardless of the presence of oxygen (aerobic glycolysis/Warburg effect). Although, hypoxic intratumoral conditions account for HIF1alpha stabilization and induction of anaerobic metabolism, recent data suggest that high pyruvate concentrations also result in HIF1alpha stabilization independently of hypoxia. In the present immunohistochemical study, we provide evidence that the PDH/PDK pathway is repressed in 73% of non small cell lung carcinomas, which may be a key reason for HIF1alpha stabilization and "aerobic glycolysis." However, about half of PDH-HIF pathway, and patients harboring these tumors have an excellent postoperative outcome. A small subgroup of clinically aggressive tumors maintains a coherent PDH and HIF/LDH5 expression. In contrast to cancer cells, fibroblasts in the tumor supporting stroma exhibit an intense PDH but reduced PDK1 expression favoring maximum PDH activity. This means that stroma may use lactic acid produced by tumor cells, preventing the creation of an intolerable intratumoral acidic environment at the same time.

Autopsy↗

PubMed2005

Thymidine phosphorylase expression in patients with chronic viral hepatitis.

BACKGROUND: The role of thymidine phosphorylase (TP), an angiogenic factor, in chronic viral hepatitis is unclear. In the present study we investigated TP expression in chronic viral hepatitis due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. METHODOLOGY: Fifty-eight patients suffering from chronic viral hepatitis and 13 cirrhotic patients due to either HBV or HCV were studied. TP expression was investigated using a standard immunohistochemical technique and the specific antibody P-GF.44C. RESULTS: The pattern of TP staining was predominantly nuclear, or mixed nuclear/cytoplasmic, but no significant difference in such expression was noted between chronic hepatitis B and C: nuclear immunostaining, t=0.0616, p=0.9511; cytoplasmic immunostaining, t=0.5188, p=0.6060. There was, however, a marked difference in TP expression between patients with chronic hepatitis B/C and cirrhosis. Notably, this finding applied to both nuclear (p=0.00754, p=0.0143, respectively) and cytoplasmic (p=0.000091, p=0.000031, respectively) expression. CONCLUSION: These observations indicate that TP expression, although linked to liver cirrhosis, may not be virus-related.

Adult↗

PubMed2004

Comparison of angiogenic activities after urethral reconstruction using free grafts in rabbits.

OBJECTIVE: To determine the most suitable type of graft-free penile skin grafts or mucosal grafts from bladder or buccal regions - for urethral reconstruction in an animal model, as evaluated on the basis of angiogenic activity. METHODS: Twenty-two male White New Zealand rabbits were randomly divided into four groups. In the control group (group O, n=4) a simple urethrotomy and closure was performed, whereas a ventral urethral defect was created in groups A, B, and C and then bridged using the following onlay patches: free penile skin (group A, n=6), buccal mucosal graft (group B, n=6), and bladder mucosal graft (group C, n=6). On the 21st postoperative day, the animals were sacrificed and the retrieved implants were subjected to macroscopic and microscopic analysis. The angiogenic activity was assessed with immunohistochemistry, using the anti-CD31 MoAb and the phosphatase antialkaline phosphatase procedure. The native vascularity of penile skin as well as buccal and bladder mucosa was assessed in rabbits from group O (n=3). Statistical analysis was performed using the one-way ANOVA. RESULTS: The angiogenesis in a magnification of x200 in groups O, A, B, and C was 34.1+/-4.1 (mean+/-SD), 61.7+/-6.4, 94.3+/-6.4, and 91.5+/-7.2 vessels per optical field, respectively. There were, statistically significant differences (p<0.001) between groups A and B and between groups A and C, but not (p>0.05) between groups B and C. The native vascularity of penile skin, buccal mucosa and bladder mucosa was 23.3+/-3.0, 24.6+/-3.7 and 17.0+/-2.6 vessels per optical field, respectively. CONCLUSION: The viability of mucosal grafts from bladder or buccal regions is better than that of a free penile graft because of higher angiogenic activity. Although the mucosal grafts showed the same angiogenic activity, the buccal mucosa graft is preferable because of its easier harvesting.

Animals↗

PubMed2004

c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent.

c-erbB-2-positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1alpha (HIF1alpha) production (Laughner et al., Mol Cell Biol 2001;21:3995-4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1alpha expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2-positive and 90 c-erbB-2-negative carcinomas) were stained immunohistochemically for HIF1alpha and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1alpha protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1alpha expression. If activation of c-erbB-2 in humans results in overexpression of HIF1alpha independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2-positive breast tumors.

Biomarkers, Tumor↗

PubMed2004

BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer.

BNIP3 is a proapoptotic protein regulated by hypoxia-inducible factor 1. We analyzed BNIP3 expression in 105 tumor samples from early operable, non-small lung cancer and the relationship of expression to hypoxia-inducible factor 1alpha, other hypoxia-regulated pathways, and prognosis. There was strong cytoplasmic expression in >10% of cells in 40 of 105 cases. BNIP3 expression was associated significantly with high hypoxia-inducible factor 1alpha (P = 0.003), carbonic anhydrase 9 (P = 0.04), and was inversely associated with bcl-2 expression (P = 0.009). High BNIP3 expression was a major independent factor for overall survival. Thus, high expression of a hypoxia regulated proapoptotic pathway was associated with a selection of an aggressive phenotype in vivo.

Adenocarcinoma↗

PubMed2004

Interferon regulatory factor-1 (IRF-1) suppression and derepression during endometrial tumorigenesis and cancer progression.

Interferon regulatory factor-1 (IRF-1) is a tumor suppressor gene presumed to be involved in the control of cellular proliferation and transformation. Given that the IRF-1 is consistently expressed in the normally cycling endometrium, the question was raised of the possible role of IRF-1 in the genesis of endometrial adenocarcinoma. A series of 25 normal and 86 malignant endometria was investigated using immunohistochemical techniques and the anti-IRF-1 polyclonal antibody c-20. Normal endometrial glands were, indeed, consistently reactive with IRF-1. Excluding the invading tumor front, malignant endometria were deprived of IRF-1 reactivity, as 81 of the 86 cases (94.2%) were negative for this antigen. At the invading tumor front, however, IRF-1 was derepressed in tumor cells in 35% of the cases. This phenomenon was independent of the extent of lymphocytic response, but it was associated with thymidine phosphorylase (TP) expression. Furthermore, TP up-regulation and host's lymphocytic response in the area were directly associated. IRF-1 derepression by invading tumor cells was associated with poor prognosis, independently of FIGO stage. It is concluded that down-regulation of IRF-1 is a constant finding in endometrial tumorigenesis. However, derepression of IRF-1 may occur in a subset of tumors, and this event is associated with TP up-regulation and aggressive tumor behavior.

Adenocarcinoma↗

PubMed2004

Hypoxia-activated tumor pathways of angiogenesis and pH regulation independent of anemia in head-and-neck cancer.

PURPOSE: Anemia is considered a major factor that counteracts the efficacy of radiotherapy, presumably because of reduced oxygen availability that leads to tumor hypoxia. Nevertheless, anemia is not the only factor defining oxygen availability, because a poor and/or immature vascular network may prevent blood flow and tumor oxygenation. Furthermore, the ability of tumors to upregulate hypoxia-regulated molecular pathways may affect radiosensitivity by mechanisms independent of the traditional concept of "oxygen effect." METHODS AND MATERIALS: In this study, we investigated whether the preoperative blood hemoglobin levels affect the activation status of hypoxia/angiogenic pathways (hypoxia inducible factors [HIF1 alpha and HIF2 alpha], carbonic anhydrase 9, differentiated embryo-chondrocyte protein, vascular endothelial growth factor, and microvessel density), in squamous cell head-and-neck cancer. RESULTS: Hypoxia/angiogenesis pathways were equally activated in tumors, independent of the patient's hemoglobin levels. The expression of HIF alphas was associated with microvessel density (p = 0.01). CONCLUSION: In the present study, we failed to show that a patient's anemia is a main contributor to the activation of hypoxia-regulated molecular pathways in squamous cell head-and-neck cancer. Impaired intratumoral blood flow or tumor-related gene/protein pathologic features may account for this finding. Targeting the hypoxia-regulated molecular cascade emerged as a complementary radiosensitization strategy for a large group of patients with hypoxic tumors, who are unlikely to benefit from conventional approaches aiming to improve intratumoral oxygen delivery through anemia correction.

Anemia↗

PubMed2004

Impact of Helicobacter pylori infection on histological changes in non-erosive reflux disease.

AIM: The evidence for an association between Helicobacter pylori (H pylori) and gastroesophageal reflux disease, either in non- erosive (NERD) or erosive esophagitis (ERD) remains uncertain. The available data on the histological changes in NERD and the effect on H pylori infection on them are elusive. The aim of this study therefore was to prospectively evaluate the histological findings and the impact of H pylori infection on a group of symptomatic patients with NERD. METHODS: Fifty consecutive patients were prospectively evaluated for symptoms compatible with GORD. In all cases, routine endoscopy and lugol directed biopsies were performed and assessed histologically in a blinded manner. RESULTS: The overall prevalence of H pylori infection was 70%. Twenty-nine patients out of 50 (58%) were NERD patients. No statistical significance was observed between the H pylori status and NERD. The remaining 21 (42%) were diagnosed as follows: 13 (26%), 6 (12%), 2(4%) with esophagitis grade A, B and C respectively. A statistically significant correlation was observed between the H pylori+ and esophagitis grade A, as well as between H pylori- and grade B. Biopsies from 2 patients were not included because of insufficient materials. Histologically, a basal zone hyperplasia was found in 47 (97.91%) patients, alterations of glycogen content in 47 (97.91%), papillae elongation in 33 (68.75%), blood vessels dilatation in 35(72.91%), chronic inflammation in 21 (43.75%), infiltration with eosinophils, neutophils and T-lymphocytes in 4 (8.33%), 6 (12.5%) and 39 (81.25%) respectively. No correlation was observed between the H pylori status and the histological parameters studied either in NERD or GERD. CONCLUSION: Histological assessment can not differentiate symptomatic patients with erosive versus non-erosive reflux disease. Moreover, H pylori infection may not act as an important factor in patients with NERD.

Biopsy↗

PubMed2004

Assessment of highly angiogenic and disseminated in the peripheral blood disease in breast cancer patients predicts for resistance to adjuvant chemotherapy and early relapse.

The assessment of tumor molecular features in combination with the detection of occult malignant cells may provide important clinical information, beyond the standard staging of breast cancer. Using a nested RT-PCR technique, we assessed prospectively the presence of cytokeratin-19 (CK19) mRNA positive cells in the blood of 100 operated patients with breast cancer before the initiation of adjuvant chemotherapy and local radiotherapy. Tissue samples were prospectively collected and analyzed for estrogen (ER) and progesterone (PgR) receptor, c-erbB-2 overexpression, mutant-p53 and bcl-2 protein accumulation, proliferation index and microvessel density (MVD). CK-19 mRNA-positive cells were detected in the peripheral blood of 33% of patients. Simultaneous display of high intratumoral MVD and of CK-19 mRNA-positive cells, which characterized highly angiogenic and disseminated in the peripheral blood (HAD) disease was noted in 25% of patients. Detection of CK-19 positive cells was significantly associated with increased MVD (p = 0.002). In univariate analysis (median follow-up 30 months) CK19 mRNA detection and MVD were the most significant factors related to a short relapse-free survival (RFS), (p < 0.0001). In multivariate analysis, CK19 positivity, high MVD and c-erbB-2 overexpression were the only significant and independent variables associated with relapse (p = 0.0005, 0.03 and 0.04, respectively). Patients with HAD had an expected relapse rate close to 70% vs. <5% in the remaining patients irrespectively of the used chemotherapy regimen. The simultaneous presence of high MVD and CK19-positive cells in the blood of patients with early breast is linked with poor prognosis, which cannot be improved with standard chemotherapy regimens.

Adult↗

PubMed2004

Non linear analysis of magnetoencephalographic signals as a tool for assessing malignant lesions of the brain: first results.

BACKGROUND AND PURPOSE: Non linear signal analysis is a powerful technique that reveals qualitative and quantitative differentiations between different dynamical systems (biological or otherwise). Presented here are the first results of a work in progress to investigate the Magnetoencephalograms (MEG) from patients with malignant CNS lesions and from healthy volunteers. METHODS: We present MEG recordings of 10 patients diagnosed with malignant CNS lesions and the corresponding ones from 10 healthy volunteers. A 122-channel SQUID biomagnetometer in an electromagnetically shielded room was used to record the MEG signals and the Grassberger-Procaccia method for the estimation of the correlation dimension was applied on the phase space reconstruction of the recorded signal from each patient. RESULTS: Evidence linking MEG signal characteristics (existence of low dimensionality chaotic dynamics) with the existence of the tumour was found from this analysis. CONCLUSION: The obtained results substantiate our hypothesis of a relation between tumours of the brain and the mathematically chaotic nature of the neural dynamics derived from their MEG recordings.

Aged↗

PubMed2004

VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer.

Different vascular endothelial growth factor (VEGF) gene polymorphisms have been shown to result in different VEGF gene responsiveness to various stimuli and different capacity for VEGF protein production. In the present study, we examined four VEGF gene polymorphisms in thirty-six individuals with non-small cell lung cancer (NSCLC). Gene polymorphisms were correlated with the VEGF protein expression in cancer cells and the tumor angiogenic activity. The -2578C/C, -634G/G and -1154A/A and G/A alleles in the VEGF gene were linked with low VEGF expression, while the -2578C/A, the -634 G/C and the -1154G/G alleles were linked with high VEGF expression. Tumors with -2578C/C had a significantly lower vascular density (VD) compared to the -2578C C/A. Similarly, cases with the -634G/G VEGF polymorphism had a singinificanltly lower vascular density compared to the combined C/C and G/C groups. In addition, the -1154A/A polymorphism seemed to relate with poor vaccularization but the difference did not reach significance. It is concluded that inherited VEGF sequence variations, which characterize the tumor genome itself, are strong determinants of the molecular VEGF and VEGF-downstream phenotype of NSCLC. The large variation in angiogenicity between tumors of similar histologic morphology emerges as a consequence of the 'parental' VEGF gene ability to produce VEGF.

Carcinoma, Non-Small-Cell Lung↗

PubMed2004

"Stromatogenesis" and tumor progression.

"Stromatogenesis" is the formation of new stroma occurring, in parallel with the neoplastic process, at sites of active tumor invasion, i.e., at the free surface of a developing exophytic tumor, at the invading tumor front of an advancing endophytic tumor, and at sites of tumor metastasis, wherein the newly formed stroma disrupts the continuity of normal structures, cleaving paths for the invading tumor cells. Stroma is also present at the heart of the tumor, but only as a secondary event following tumor advancement and subsequent incorporation of its periphery into inner tumor areas. The new stroma, composed of stromal cells and extracellular matrix (ECM), is loose and edematous at the expanding tumor fronts, and rather dense in central tumor areas and sites of tumor metastasis. The stromal cells facing tumor invasion are intensely proliferating (high MIB-1 index) spindle-shaped cells, alpha-smooth muscle actin positive, and loaded with thymidine phosphorylase (TP) and SPARC (secreted protein acidic and rich in cysteine). The associated ECM is rich in collagen III, SPARC, and new blood vessels (CD31) but is depleted of collagen I and fibronectin. These constitutional changes render stromatogenesis amenable to tumor cell invasion and are, in cases of incipient neoplasia, a prospective criterion of early stromal invasion. Other stromal cell or ECM constituents, such as the lactate dehydrogenase-5 (LDH-5), the acidic fibroblast growth factor (aFGF), the basic FGF (bFGF), and the collagens II and IV, remain unchanged, and others are negative: myosin, desmin, S-100 protein and epidermal growth factor receptor (EGFR). The mechanism of stromatogenesis is obscure but is probably stimulated by specific stromatogenic growth factors, released by neoplastic and inflammatory cells. It appears that the process is neither neoplastic nor reactive, but rather is a, hereto unexplained, phenomenon of host's complicity in tumor progression.

Biomarkers, Tumor↗

PubMed2004

Endometrial adenocarcinoma: beliefs and scepticism.

The incidence of endometrial adenocarcinoma is high in North America and northern Europe, and low in Asia and Africa. This variance in frequency rates occurred in the late 1970s and its real cause has remained in question since. There is a widespread belief that endometrial adenocarcinomas associated with endometrial hyperplasia have a much better prognosis than those related to endometrial atrophy. This view is, in general terms, true but only because a high proportion of tumors arising from an atrophic endometrium are of serous/papillary, clear cell, or Grade 2-3 endometrioid carcinomas, in contrast to those developing from a hyperplastic endometrium, which are nearly all G1 endometrioid adenocarcinomas. These adenocarcinomas have, however, an excellent prognosis, no matter whether they are related to hyperplasia or atrophy, and taxonomically they form a single tumor group. In this regard, it is most reasonable to separate endometrial carcinomas into low- and high-grade tumors. The first are formed solely of G1 or "authentic" endometrioid adenocarcinomas, i.e., endometrioid neoplasms composed in their entirety of glandular elements without having traces of nonsquamous solid components. The high-grade tumors are formed of both endometrioid Grade 2-3 adenocarcinomas and nonendometrioid carcinomas-all of particularly aggressive behavior. The question of grading endometrioid adenocarcinomas in a precise and reproducible way becomes obvious. It is also believed that endometrial adenocarcinomas associated with endometrial hyperplasia are estrogen-primed, while those related to endometrial atrophy are deprived of hormonal stimulation. However, as we have shown in this laboratory recently, estrogen stimulation may be very common in endometrial neoplasms developing in an atrophic endometrium. For indeed most, if not all, postmenopausal atrophic endometria harboring adenocarcinomas contain actively proliferating glands, with high Ki-67 proliferation index, high epidermal growth factor receptor (EGFR) activity, high microvessel density (MVD), and rich in estrogen and progesterone receptors (ER and PR), indicative of a continuous low-level estrogenic stimulation. That there is a number of endometrial carcinomas that tend to develop in a milieu of antiestrogenic domination, following treatment for breast carcinoma, this may well represent a form of breast-endometrial hereditary disease and, certainly, merits further investigation.

Adenocarcinoma↗

PubMed2003

Amifostine induces anaerobic metabolism and hypoxia-inducible factor 1 alpha.

PURPOSE: The cytoprotective mechanism of amifostine (WR-2721) implies free radical scavenging and DNA repair activities. We investigated additional cytoprotective pathways involving intracellular hypoxia and the activation of the hypoxia-inducible factor (HIF) pathway, a key transcription factor regulating glycolysis, angiogenesis and apoptosis, which is also linked with radioresistance. MATERIALS AND METHODS: The glucose and oxygen levels in the peripheral blood of patients receiving 1000 mg amifostine were determined at various time-points in order to investigate the metabolic changes induced by amifostine. MDA468 breast tumor cell lines were incubated with a high amifostine concentration (10 m M) to overcome the natural resistance of cancer cells to influx of the non-hydrolyzed WR-2721, and the HIF1 alpha protein levels were determined by Western blot analysis. In vivo experiments with Wistar rats were performed in order to assess immunohistochemically changes in the intracellular accumulation of HIF1 alpha induced by amifostine (200 mg/kg). RESULTS: By 30 min following amifostine administration, the hemoglobin oxygen saturation and pO(2) levels had increased in the peripheral blood while glucose levels had reduced, providing evidence that normal tissue metabolism switches to glycolytic pathways. Incubation of cell lines with amifostine resulted in HIF1 alpha induction. In Wistar rats administration of amifostine resulted in increased HIF1 alpha accumulation in normal tissues. CONCLUSIONS: Since it is doubtful whether dephosphorylation of amifostine to the active metabolite WR-1065 occurs within tumoral tissues (an acidic environment that lacks vascular alkaline phosphatase activity), intracellular hypoxia and upregulation of HIF1 alpha represents an additional, normal tissue-specific, amifostine cytoprotective pathway.

Amifostine↗