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Biomedical subjects

M Distefano

Publications and source records attributed to M Distefano.

At least 37 records · Page 2Linked to original sources
PubMed1998

Antitumor activity of paclitaxel (taxol) analogues on MDR-positive human cancer cells.

A series of newly developed paclitaxel analogues have been tested for their growth inhibitory activity on two human breast cancer cell lines, one of which expresses the MDR (multidrug resistance) phenotype. Paclitaxel (taxol) was used as a reference compound. Three new classes of taxanes were analyzed: the cephalomannine compounds, the pyrazoline derivatives and the seco-derivatives. Our results demonstrated an increased antiproliferative activity of pyrazoline derivatives on drug-resistant cancer cells with respect to paclitaxel. These compounds were able to block MDR-bearing MCF-7 ADRr cells in the G2/M phase of cell cycle and, consequently, induce programmed cell death. In keeping with the antiproliferative effects, cells treated with paclitaxel derivatives showed a more pronounced cell cycle arrest than the parent compound paclitaxel. Also, apoptotic cell death, calculated as a percent of DNA fragmentation, occurred to a greater extent in cells exposed to pyrazoline derivatives. The development of new paclitaxel analogues with greater antitumour activity on MDR-positive cells may be useful in selecting new taxanes effective on resistant tumors.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Anti-proliferative activity of a new class of taxanes (14beta-hydroxy-10-deacetylbaccatin III derivatives) on multidrug-resistance-positive human cancer cells.

Paclitaxel, docetaxel and a series of new analogs synthesized from 14beta-hydroxy-10-deacetylbaccatin III (14-OH-DAB), a natural diterpene closely related to the core synthon of the 2 above prototypes, were tested in vitro for their growth-inhibitory activity on different human cancer cell lines, including some expressing the classic multidrug-resistant (MDR) phenotype (MCF-7 ADRr and CEM VBLr). The 14-OH-DAB derivatives showed enhanced anti-proliferative activity as compared to the parent compounds on the MDR-positive cancer cell lines. Particularly, IDN 5109 showed a 25- to 30-fold higher activity than paclitaxel. The fold change in activity between paclitaxel and analogs (IC50 paclitaxel/IC50 analogs) on the MDR-positive cell lines was calculated and a significant correlation observed. As far as the MDR-negative MDA-MB 231 cells are concerned, docetaxel and IDN 5109 exhibited a more potent activity than paclitaxel. On the basis of the data obtained on cell growth inhibition, we selected the most active compounds to study their effect on the cell cycle. Cell cycle analysis showed that all of the compounds tested were able to induce cell cycle block at G2/M in a concentration-dependent manner. The amount of cell block, measured as a G1/G2 ratio, was correlated significantly (p < 0.001) with apoptosis, as evaluated in the sub-G1 region (% of DNA fragmentation), thereby suggesting that the G2/M-blocked cells underwent apoptosis. To confirm the occurrence of apoptosis in this system, DNA gel agarose electrophoresis was performed and showed the typical ladder pattern.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis.

The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) content was determined by a radioligand receptor assay in 140 primary laryngeal squamous cell carcinomas (median value of 8.4 fmol mg-1 protein, range 0-169.9 fmol mg-1 protein). Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels are directly associated with the risk of death (chi 2 = 14.56, P-value = 0.0001) and relapse (chi 2 = 7.77, P-value = 0.0053). A significant relationship between EGFR status and survival was observed at the different arbitrary cut-off values chosen (8, 16 and 20 fmol mg-1 protein). The cut-off value of 20 fmol mg-1 protein was the best prognostic discriminator. In fact, the 5 year survival was 81% for patients with EGFR- tumours compared with 25% for patients with EGFR+ tumours (P < 0.0001). The 5 year relapse-free survival was 77% for patients with EGFR- tumours compared with 24% for patients with EGFR+ tumours (P < 0.010). When clinicopathological parameters and EGFR status were examined in the multivariate analysis, T classification and EGFR status retained an independent prognostic value. In this study we demonstrated that high EGFR levels single out patients with poor prognosis in laryngeal cancer.

Carcinoma, Squamous Cell↗
PubMed1995

Significance of cathepsin-D expression in uterine tumours.

Cathepsin-D (Cath-D) expression was evaluated by an immunoradiometric assay in 67 primary endometrial carcinomas and 70 cervical cancers. In the endometrial tumours, an inverse correlation was observed between Cath-D levels and stage (P = 0.027) and myometrial invasion (P = 0.046). A significant correlation between Cath-D levels and hormone receptor status was demonstrated (P < 0.05). In cervical cancer, no differences in the distribution of Cath-D levels according to clinicopathological parameters and hormone receptors were observed. However, patients not responding to neoadjuvant chemotherapy had significantly lower Cath-D values than those showing complete or partial response (P = 0.011). As far as prognostic significance is concerned, it appears that Cath-D expression might have a different role in the two uterine neoplasias. While our preliminary data in endometrial cancer suggest that high Cath-D levels may be a favourable prognostic indicator, cervical cancer patients with Cath-D+ tumours had a shorter disease-free survival than those with Cath-D- tumors (P = 0.017).

Adult↗
PubMed1995

Epidermal growth factor, oestrogen and progesterone receptor expression in primary ovarian cancer: correlation with clinical outcome and response to chemotherapy.

The expression of epidermal growth factor receptor (EGFR), oestrogen receptor (ER) and progesterone receptor (PR) was assayed by a radioreceptor method in 117 primary ovarian cancers. EGFR was not significantly related to any of the clinicopathological parameters examined. In patients with stage II-IV disease who underwent second-look surgery after primary chemotherapy, a significant correlation between high EGFR levels and poor response to chemotherapy was demonstrated (P = 0.031). Moreover, post-operative residual tumour showed an independent role in predicting chemotherapy response (P = 0.0007) and EGFR status showed a borderline significance (P = 0.052) in the multivariate analysis. No correlation between steroid hormone receptors and clinicopathological parameters was observed. Whereas a significant relationship was shown between EGFR positivity and a shorter overall survival (OS) (P = 0.0022) and progression-free survival (PFS) (P = 0.0033), patient survival was not related to steroid hormone receptor status. Among the parameters tested only stage, ascites and EGFR status retained an independent prognostic value in the multivariate analysis.

Adult↗
PubMed1995

Childhood IQ measurements in infants with transient congenital hypothyroidism.

OBJECTIVE: In view of the fact that, during the first period of life, thyroid hormones are critical for brain development, we investigated whether even transient congenital hypothyroidism could affect the long-term intellectual development of affected infants. DESIGN: A case-control study of intellectual development, auxometric parameters and thyroid function performed in late infancy in children with documented transient congenital hypothyroidism or hyperthyrotrophinaemia at birth. PATIENTS: Nine children born in an endemic goitre area who had short-term transient congenital hypothyroidism or hyperthyrotrophinaemia after birth (TCH) were studied and compared to nine matched children born in the same area at the same time but having normal thyroid function at birth (N). MEASUREMENTS: Global, verbal and performance IQs were evaluated on the Wechsler scale. Height, bone age, total and free thyroid hormones, thyroid volume, thyroglobulin, basal and TRH stimulated TSH were also measured. RESULTS: Height and bone age were similar in the two groups. Thyroid function tests were also similar in the two groups except for basal and TRH stimulated serum TSH and serum Tg which were higher in the TCH than in the control group. Global, verbal and performance IQs were systematically lower in the TCH than in the N group. (78.3 +/- 11.1 vs 90.9 +/- 14.2, P < 0.05; 84.4 +/- 15.4 vs 96.2 +/- 14.8, P NS; 75.0 +/- 8.5 vs 89.2 +/- 12.5, P < 0.01 respectively). CONCLUSION: Infants born and living in an academic goitre area, who had biochemical signs of thyroid hypo-function at birth, had a lower intelligence quotient at the age of 7-8 years than matched controls living in the same environmental conditions but with normal thyroid function at birth. The present findings strongly suggest that abnormalities in thyroid function at birth, even when transient, can adversely affect long-term intellectual development.

Case-Control Studies↗
PubMed1995

Influence of glucose load on cardiovascular and humoral responses to a cold pressure test.

To investigate the relationship between insulin and reactivity to the cold pressure test four groups of mildly obese patients (12 per group: normotensive, essential hypertensive, normotensive (N-NIDD) and hypertensive non-insulin-dependent diabetics (H-NIDD)) underwent a standardised oral glucose tolerance test. During the test, BP and heart rate were monitored and venous blood samples were obtained at 0, 60 and 120 minutes to determine serum levels of glucose, insulin (microU/ml), sodium, potassium (mEq/I), renin activity (ng/ml/hour), aldosterone, noradrenaline and adrenaline. The cold pressure tests were performed before glucose ingestion (I-CPT) and again at 60 minute after ingestion (II-CPT). As expected, glucose ingestion caused a significant increase in glycaemia and serum insulin; the latter rose significantly more at 60 minutes in normotensives (85 +/- 6) and essential hypertensives (83 +/- 5) than in N-NIDD (30 +/- 4) and H-NIDD (29 +/- 3). Plasma K significantly decreased in normotensives (4.4 +/- 0.1 vs. 3.6 +/- 0.1, P < 0.05) and essential hypertensives (4.3 +/- 0.1 vs. 3.5 +/- 0.1, P < 0.05) but did not change in either N-NIDD or H-NIDD. PRA significantly increased in normotensives (0.6 +/- 0.1 vs. 1.2 +/- 0.1, P < 0.01) and essential hypertensives (0.8 +/- 0.1 vs. 1.5 +/- 0.2, P < 0.05) but did not change in N-NIDD or H-NIDD. Plasma sodium and catecholamines did not change in any group. I-CPT induced similar reactivity in all the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Significance of epidermal growth factor receptor expression in primary human endometrial cancer.

Radioreceptorial assessment of EGFR expression was prospectively performed on 60 primary human endometrial tumors. Of these, 26 were EGFR-positive while 13 expressed high EGFR levels. High EGFR levels correlated well with poor histopathological grading. No correlation with histopathological type, stage, myometrial invasion, lymph-node involvement or steroid hormone receptor status was observed. Disease-free survival rate was significantly shorter in the cases with high than in the cases with low EGFR levels. These results suggest a potential role of EGFR expression assessment in prognostic characterization of endometrial cancer patients.

Adult↗
PubMed1994

Clinical significance of cathepsin D in primary ovarian cancer.

Cathepsin D (Cath D) levels were assayed in a prospective series of 72 patients with primary ovarian carcinoma, by using an immunoradiometric assay. Cath D levels ranged from 2.00 to 45.60 pmol/mg protein with a median value of 15.80 pmol/mg protein. Cath D levels were higher in metastatic deposits than in primary tumors (median 24.12, range 9.33-98.33 pmol/mg protein versus median 12.76, range 2.00-45.20 pmol/mg protein; P = 0.04). The cut-off levels of the lower, median and upper quartiles of the distribution of Cath D were identified to distinguish patients with low, intermediate, and high Cath D content. Cases with low Cath D content showed a lower percentage of complete response to chemotherapy than cases with intermediate and high Cath D content (22% versus 65% and 47%, respectively) (P = 0.003). Moreover cases with high Cath D content showed a worse prognosis with respect to patients with intermediate Cath D levels (P = 0.09). Interestingly, cases with low Cath D content had a shorter progression-free survival with respect to cases with intermediate Cath D content (P = 0.04). Cath D status retained an independent prognostic value when assessed in the multivariate analysis.

Adult↗
PubMed1994

Expression of ras oncogene p21 protein in normal and neoplastic laryngeal tissues: correlation with histopathological features and epidermal growth factor receptors.

Western blotting analysis of the p21 ras oncoprotein was performed in seven normal laryngeal mucosa specimens and 43 primary laryngeal cancers. Varying p21 levels, expressed as optical density (OD), were found in normal mucosa (median 1.94 OD, range 0.90-2.17 OD) and in primary laryngeal tumours (median 1.74 OD, range 0.30-6.37 OD). When p21 expression in laryngeal cancer was compared with the normal counterpart, higher levels were found in neoplastic than in normal laryngeal tissue (median 2.54 OD, range 1.76-6.37 OD, vs median 1.94 OD, range 0.90-2.17 OD) (P = 0.023). Immunohistochemical analysis demonstrated that most of the tumour cells (more than 70%) were immunostained while the stromal component was unreactive. No correlation between p21 expression and tumour location, stage and histopathological grade was observed. The correlation between ras p21 protein expression and epidermal growth factor receptor (EGFR) levels was also investigated. EGFR-positive cases did not show any difference in p21 expression with respect to EGFR-negative cases (median 1.52 OD, range 0.30-6.37 OD, vs median 1.84 OD, range 0.93-3.71 OD). Our findings suggest that overexpression of p21 protein is associated with a malignant phenotype in laryngeal cancer. Further studies should be undertaken to evaluate whether the assessment of p21 protein expression may have clinical significance in laryngeal cancer.

Adult↗
PubMed1993

Molecular mechanisms of the increased glucose transport in transformed FRTL-5 rat thyroid cells.

We investigated the molecular mechanisms involved in the glucose carrier (Glut 1) regulation in FRTL-5 cells and two derived transformed clones (SRC and Ki-Mol cells). When compared to the wild-type strain, SRC and Ki-Mol cells showed an increase in both glucose consumption and uptake (about 60 fold), associated with 6-8 fold higher Glut 1 mRNA levels. Transcriptional studies revealed a 2- to 3 fold increased activation of the gene in the transformed cells, suggesting that transcription alone cannot fully account for the higher Glut 1 gene expression. Western blot studies showed an increase of the Glut 1 protein in SRC and Ki-Mol cells, associated with a different gel migration pattern and a disparate distribution rate between the plasma membrane and the microsomal fraction. These data indicate that the higher rate of glucose uptake observed in SRC and Ki-Mol cells is associated to an increase in Glut 1 gene expression, and that also changes in the subcellular distribution and probably in the structure of Glut 1 protein are present.

Animals↗
PubMed1993

Type II estrogen-binding sites in human ovarian cancer: correlation with estrogen, progesterone, and epidermal growth factor receptor.

Type II estrogen-binding sites (Type II EBS) and the recently identified bioflavonoid-like ligand methyl-p-hydroxyphenyllactate may be regarded as a growth regulatory system active on both normal and neoplastic tissues. It has been reported that, in addition to estrogen and progesterone receptors, primary ovarian cancers also express Type II estrogen binding sites. These sites are able to bind estrogenic compounds and also some naturally occurring flavonoids such as quercetin. In this study we report the presence of cytosolic Type II EBS in a series of 10 normal ovaries, 42 primary ovarian tumors, and 14 metastatic deposits. Scattered levels of Type II EBS were found in normal ovarian tissues (median, 1603 fM/mg protein, range, 271-4943). In primary ovarian tumors and in omental metastases median levels of Type II EBS were 835 fM/mg protein (range, 134-4875) and 758 fM/mg protein (range, 204-2007), respectively. Although Type II EBS tend to be higher in normal than in malignant tissues the difference was not statistically significant. No correlation was found between Type II EBS levels and the common clinicopathological characteristics of the tumors. Moreover there was no relation between Type II EBS and estrogen and epidermal growth factor receptors. A significative inverse correlation with progesterone receptor levels was observed. The presence of Type II EBS in ovarian cancer could be of clinical importance since it has been demonstrated that bioflavonoids, through the interaction with Type II EBS, may exert a growth inhibitory activity both alone or in combination with chemotherapeutic agents on ovarian cancer cell lines and primary tumors.

Aged↗
PubMed1993

Expression of ras p21 oncoprotein in normal and neoplastic human endometrium.

The ras-encoded p21 protein expression was investigated in 18 normal endometrial tissues and in 37 human primary endometrial carcinomas by Western blotting analysis. Scattered p21 levels were found in normal specimens (mean = 1.29 OD; median = 1.10 OD; range = 0.33-2.65). The p21 levels were significantly higher in secretory (mean = 1.99 OD; median = 2.16 OD; range = 0.71-2.65) than in proliferative (mean = 0.97 OD; median = 1.07 OD; range 0.38-1.73) endometrium (P = 0.009) and higher in primary endometrial carcinomas (mean = 2.05 OD; median = 2.04 OD; range 0.21-4.36) than in normal proliferative tissues (P = 0.004). Immunohistochemical analysis showed that most of the tumor cells expressed p21 oncoprotein while the stromal component was unreactive. No correlation between p21 expression and histopathological characteristics of the tumors was observed. Moreover, estrogen receptor (ER)-positive tumors expressed higher p21 levels than did ER-negative tumors (77% vs 33%; P = 0.009). A similar trend, although not statistically significant, was found between p21 values and progesterone receptor expression (74% vs 44%; P = 0.060). On the other side, p21 levels were unrelated to epidermal growth factor receptor levels. Further studies should verify the possible significance of p21 expression in the prognostic characterization of patients with endometrial cancer.

Adult↗
PubMed1992

Cathepsin D in primary squamous laryngeal tumors: correlation with clinico-pathological parameters and receptor status.

Using an immunoradiometric assay, Cathepsin D (Cath D) levels were measured in the cytosol of 23 normal and 39 neoplastic human laryngeal tissues. Scattered Cath D levels (from 2.2 to 17.8 pM/mg protein; median = 7.6) were found in normal mucosa specimens. Cath D concentrations range from 2.0 to 29.3 pM/mg protein (median = 8.5) in laryngeal tumors. When a comparison between Cath D levels in normal and neoplastic tissue specimens from the same patient was done, Cath D levels were significantly higher in laryngeal cancers than in their normal counterparts (P = 0.03). No correlation with clinico-pathological parameters and steroid hormone and epidermal growth factor receptor status was found. Further studies should investigate whether the production of Cath D by laryngeal tumors could have a clinical relevance for this neoplasia.

Adult↗
PubMed1992

EGF receptor expression in primary laryngeal cancer: correlation with clinico-pathological features and prognostic significance.

Epidermal-growth-factor-receptor(EGFR) expression was evaluated in 103 primary laryngeal tumors and in 42 normal laryngeal tissue specimens. Significantly higher EGFR levels were found in cancer specimens than in normal mucosa (p = 0.0053). EGFR expression did not correlate with age, tumor localization, T classification, cervical-lymph-node involvement or type of surgery, whereas it was higher in poorly differentiated tumors (G3) than in well/moderately differentiated (G1-G2) tumors (p < 0.05). Follow-up data were available for 74 patients. When EGFR status and the most important clinico-pathological characteristics were submitted to univariate analysis, tumor localization, type of surgery and EGFR status were found to be significantly correlated with disease-free survival. The 24-month disease-free survival rate was 58% for EGFR+ cancer patients and 82% for EGFR- ones. With multivariate analysis, only EGFR status and tumor localization were identified as significant independent prognostic parameters. Data reported here suggest that high EGFR levels may identify a sub-set of laryngeal-cancer patients with a particularly unfavorable prognosis.

Adult↗
PubMed1989

Assessing fibular length using bimalleolar angular measurements.

Shortening of the fibula after fracture is common and often difficult to appreciate. Loss of lateral malleolar anatomy causes significant biomechanical changes in the ankle and correlates with poor clinical results. We studied angular measurements of distal fibular length to serve as a guide for assessing fibular reduction after ankle fracture. Mortise view X-rays of 50 normal ankles from 25 healthy volunteers were obtained. The average talocrural angle measured 78.5 degrees. However, individual variation was high with values ranging from 75 to 86 degrees. Comparing contralateral ankles demonstrated an average difference of 1.3 degrees (range 0 to 4 degrees). A new, simpler bimalleolar angle was devised which compares the long axis of the fibula with a line drawn between the tips of the malleoli. The average bimalleolar angle measured 77.8 degrees (range 72 to 86 degrees). The contralateral difference averaged 1.2 degrees (range 0 to 3 degrees). This angle was simpler to use and more reproducible. Angular measurements were tolerant of usual radiographic techniques. Internal or external rotation of the ankle up to 5 degrees caused an insignificant change in the angular measurements. One degree change in the talocrural or bimalleolar angle was found to correspond with a 1 mm change in fibular length for the average ankle, calculated radiographically and confirmed in a cadaver study. Abnormal fibular shortening is detected with an angular difference between injured and contralateral sides of 3.0 degrees using the talocrural angle or 2.5 degrees using the bimalleolar angle (95% confidence limits). Thus, a 2.5 to 3.0 degrees contralateral difference should serve as a minimum value required to direct a change in therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗