PubMed Health⌕ Search

Biomedical subjects

G Ghanem

Publications and source records attributed to G Ghanem.

At least 55 records · Page 3Linked to original sources
PubMed1994

Receptor-mediated cytotoxicity of alpha-MSH fragments containing melphalan in a human melanoma cell line.

Four alpha-MSH drug conjugates have been synthesized, 2 C-terminal (Pep 3 and 4) and 2 central fragments (Pep 1 and 2), the latter being the 4-10 sequence known to be the main alpha-MSH-receptor-recognition site. Melphalan was introduced into each sequence at different locations. Their ability to recognize alpha-MSH receptors as well as their cytotoxic effects were compared in 3 cell lines: melanoma, carcinoma and fibroblast cells. Pep 1 and 2 were able to specifically bind to MSH receptors on melanoma cells by displacing labelled alpha-MSH from its binding sites at concentrations similar to the 4-10 heptapeptide sequence known to contain the main receptor-recognition site. They subsequently penetrate the cell, most probably by a receptor internalization mechanism, since about half of their effect could be inhibited by competition at the receptor level. Significant and selective cytotoxic effects to melanoma cells could be observed after only 2 hr exposure to the drug conjugates. Interestingly, these 2 conjugates, differing only in melphalan position, showed completely different cytotoxicity in terms of IC50 values, Pep 1 being 24 times more toxic to all cells; but the 2 were equally specific to melanoma cells. However, they both were less toxic to all cells than melphalan itself. Furthermore, Pep 1 and 2 were able to block the receptor and, unlike Pep 3 and 4, their cytotoxic effect could be significantly inhibited by an alpha-MSH agonist. Pep 3 and 4 were 5 to 10 times less toxic than melphalan to melanoma and carcinoma cells and 50 times less to fibroblast cells, and did not show any cell-type selectivity. They were less toxic than Pep 1 to melanoma and carcinoma cells by a factor of 2, but equally toxic to fibroblasts. In contrast, they were more toxic than Pep 2 to fibroblasts, melanoma and carcinoma by a factor of 3, 10 and 24 respectively. Our data strongly suggest a receptor-mediated cytotoxicity mechanism occurring with alpha-MSH central fragments in human melanoma cells due to the presence of alpha-MSH-specific receptors. This mechanism appeared to be both peptide- and cell-type-specific.

Carcinoma, Squamous Cell↗
PubMed1993

TRP-1 expression correlates with eumelanogenesis in human pigment cells in culture.

We have investigated the relationship in human cultured normal and malignant melanocytes between the accumulation of mRNAs encoding tyrosinase and tyrosinase-related protein-1 (TRP-1), the activity of tyrosinase and the presence of melanin. Tyrosinase mRNA correlates with tyrosinase activity and with the presence of pheomelanin, eumelanin or both melanin types. In contrast TRP-1 mRNA is only detectable in cells containing eumelanin, which suggests a role for TRP-1 in the eumelanin synthesis pathway.

Base Sequence↗
PubMed1993

Glutathione depletion increases tyrosinase activity in human melanoma cells.

The aim of the present work was to estimate the effect of intracellular glutathione depletion on melanogenesis in human melanoma cells. We determined tyrosine hydroxylation activity, the rate-limiting step of the pathway, and 14C-melanin formation, an assay reflecting the global eumelanogenic pathway. Intracellular glutathione was depleted by treatment with buthionine-S-sulfoximine, a well-known inhibitor of gamma-glutamylcysteine synthetase. The intracellular depletion of glutathione was substantial after 20 h of incubation with 50 microM buthionine-S-sulfoximine, although a significant effect could be observed after 6 h. Tyrosine hydroxylase activity increased in parallel with glutathione depletion, to reach 160% with respect to the control values during 24 h of buthionine-S-sulfoximine treatment. We have found the response to buthionine-S-sulfoximine to be dose dependent and the two different human cell lines HBL and LND1 to have similar, if not identical, responses. 14C-melanin formation assay revealed even greater activation, up to 400% of the control values. This indicates that glutathione depletion may have two distinct effects: first, a direct one on tyrosinase activity and, second, an effect on the promotion of eumelanogenesis. The stimulation of tyrosine hydroxylase can be explained by a possible inactivation of the enzyme by endogenous thiol compounds rather than by a direct effect of buthionine-S-sulfoximine itself on tyrosinase. The data suggest that thiol compounds may play a role for stimulation of melanogenesis by ultraviolet radiation.

Antimetabolites, Antineoplastic↗
PubMed1992

Synthesis and cytotoxic properties of new N-substituted 4-aminophenol derivatives with a potential as antimelanoma agents.

New tyrosinase-targeted compounds based on structural variants of the prototype unit 4-aminophenol have been synthesized and screened for their potential as antitumour agents against malignant melanoma. Cytotoxicity assays showed that N-4-hydroxyphenylglycine (NHPG) and its alpha-methyl derivatives methylphenylglycine and dimethylphenylglycine exhibit significant antiproliferative effects on pigmented human melanoma cell lines (HBL), with inhibitory concentrations at 50% (IC50) around 80 micrograms/ml. A marked increase in cytotoxicity was observed with morpholine-containing 4-aminophenols, e.g. N-(2-morpholinoethyl)-4-aminophenol, which showed an IC50 of 20 micrograms/ml of HBL cells. Much more pronounced was the effect of the diacetoxy-derivative, DiAcMoAc, which showed an IC50 of 15 micrograms/ml on HBL cells and as low as 2 micrograms/ml on tyrosinase-containing, non-pigmented human melanoma cells (LND1), with a toxicity response of the same order of magnitude as that of melphalan. These results open interesting perspectives in the design of new targeted pro-drugs against malignant melanoma.

Aminophenols↗
PubMed1992

Acral hyperpigmented macules and longitudinal melanonychia in AIDS patients.

Two patients with AIDS are described who developed acral hyperpigmented macules of the fingers, palms and soles, buccal mucosa and genitalia, associated with longitudinal melanonychia. These pigmentary changes seemed to be independent of zidovudine and were associated in one with diffuse melanoderma and elevated levels of alpha-MSH. Histological and ultrastructural studies showed an increase of the dendrites and pigmentation of the melanocytes and few melanosomes in the keratinocytes.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Immediate and mid-term results of percutaneous mitral commissurotomy.

The results of percutaneous mitral commissurotomy (PMC) were assessed in a series of 600 patients (pts) with mitral stenosis. Their mean age was 43 +/- 15 years (13-86). One hundred and eight had had a previous surgical commissurotomy; 464 were in NYHA class III or IV; atrial fibrillation was present in 188. One hundred and fifty-nine had valvular calcification and angiography disclosed a mild regurgitation (MR) (1/4) in 255. Technical failure occurred in 19 pts. In the remainder, PMC improved valve function: valve area (VA) increased from 1.1 +/- 0.3 cm2 to 2.2 +/- 0.5 cm2 (P less than 0.0001) as assessed by haemodynamics, and from 1 +/- 0.2 to 2 +/- 0.4 cm2 (P less than 0.0001) as assessed by two-dimensional echocardiography. Complications were as follows: death (0.5%), haemopericardium (0.8%), severe MR (3.8%), embolism (3.3%), atrial shunt (14%). Secondary surgery for complications following PMC was necessary in 4.8% of cases. There were poor results (VA less than 1.5 cm2 and/or MR greater than 2/4) in 13%; their predictors being valve anatomy (P less than 0.001), initial valve area (P less than 0.01) and previous surgical commissurotomy (P less than 0.05). Among the 437 pts resident in France, 98% were followed-up 15 +/- 11 months after PMC (range 1-48). After 42 months, the actuarial rates of survival, freedom from need for reoperation and good functional results were respectively: 87 +/- 6%, 81 +/- 3% and 72 +/- 6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Degradation of alpha-melanocyte stimulating hormone (alpha-MSH) by CALLA/endopeptidase 24.11 expressed by human melanoma cells in culture.

The common acute lymphoblastic leukemia antigen (CALLA) is identical to human endopeptidase 24.11 (E-24.11) and is expressed on certain human melanoma lines. This work was conducted in order to investigate whether alpha-melanocyte-stimulating hormone (alpha-MSH) could be a substrate for E-24.11, its degradation leading to the negative alpha-MSH radiobinding assay results observed with some CALLA-positive cell lines. We used 3 human melanoma cell lines (GLL-19, Mel Juso and G361) which lack receptors to alpha-MSH and express CALLA, and, as a control, one CALLA-negative melanoma cell line (HBL) with specific receptors for alpha-MSH. Radioimmunoassays give evidence that alpha-MSH was degraded in the presence of the 4 melanoma cell lines and that disappearance of the peptide was significantly reduced by phosphoramidon in 2 lines (GLL-19 and G361). Upon incubation of alpha-MSH with GLL-19 and G361 cell membranes, 3 degradation products were completely abolished in the presence of phosphoramidon. Amino acid content analysis of alpha-MSH fragments produced by purified E-24.11 permitted identification of 6 peptide bonds in the sequence of alpha-MSH susceptible to cleavage by the enzyme. It is concluded that alpha-MSH is a substrate in vitro for purified E-24.11 and for the enzyme present on the human melanoma cell lines GLL-19 and G361, expressing a high level of endopeptidase activity. However, hydrolysis of alpha-MSH by this enzyme does not seem to represent the main factor responsible for the apparent absence of receptors for the hormone on some cell lines.

Amino Acid Sequence↗
PubMed1989

Surgical treatment of bone metastases of the peripheral skeleton--a review of 33 cases.

Out of a total of 31 patients (26 females and five males) there were 24 complete and nine impending pathological fractures. These, treated from October 1985 to September 1987 at the Bordet Institute, were evaluated. Breast cancer was the most frequent underlying disease (66%) followed by lung cancer (12%). Eighteen lesions were treated by endoprosthetic replacement and 15 by an intramedullary fixation device. Bone cement was added to either of these. Satisfactory pain relief was obtained in 82% of the treated areas and restoration of function in 76%. Complications were rare but included one easily resolved superficial wound infection, four deep venous thromboses, movement limited to 21% (seven joints), and the changing of two fixation or reconstruction devices. Median survival time was 6 months; 35% of the patients were still alive after 12 months and 10% after 24 months.

Adult↗
PubMed1988

Mitral calcification in aortic stenosis.

To appreciate the incidence, the promoting factors and the consequences of mitral calcification in aortic stenosis (AS), the data from 675 patients operated on for AS were reviewed. Mitral calcification was revealed by fluoroscopy, echocardiography and/or surgery. Mitral annular calcification (MAC) was observed in 169 patients (25%). In patients with MAC, females were more frequent (42.3 vs. 17.9%, P less than 0.0001), age was greater (64 vs. 58 years, P less than 10(-7)), AS was more severe (0.6 vs. 0.7 cm2, P less than 0.002), and LV walls were thicker (interventricular septum 13.5 vs. 12 mm, P less than 0.0003 posterior wall 12.8 vs. 11.9 mm, P less than 0.004). First-degree AV block was more frequent in patients with MAC but did not lead to more frequent pacemaker implantation. Mitral anterior leaflet calcification was noted in 215 patients (31.8%). When massive, it created mitral stenosis which, in one case, required later mitral replacement. Five- and ten-year actuarial survival rates were not different in patients with or without mitral calcification. We conclude that mitral calcification is frequent in AS. Promoting factors for MAC are age, severity of AS, and female gender.

Adult↗
PubMed1987

Combined aortic, mitral and tricuspid surgery: results in 78 patients.

Between 1968 and 1984, 78 patients (mean age 43, range 14 to 65 years) underwent combined aortic, mitral and tricuspid surgery (22 triple valve replacements, 56 aortic valve replacements with tricuspid conservative surgery and mitral valve replacement (N = 48), or commissuroplasty (N = 8). Pre-operative consequences of valvular disease (mainly mixed valve disease) were severe as assessed by functional class (72 pts in III or IV NYHA), cardiomegaly (CTR: 62 +/- 6%), increase of mean pulmonary arterial and wedge pressures (respectively 30 +/- 12 and 19 +/- 6 mmHg) decrease in cardiac index (2.1 +/- 0.5 l min-1 m-2), LV dilatation (LV end diastolic volume: 184 +/- 86 ml m-2) and impairment of LV systolic function (LV ejection fraction: 50 +/- 12%). Operative mortality rate was 11.5%. The 69 survivors were all followed up, for a mean of 56 months (2 to 207). 16 late deaths occurred. Actuarial survival rate at 10 years was 58.4%, and greatly influenced by pre-operative NYHA class. Linearized rates of thromboembolic events, valve thrombosis and haemorrhage were respectively 6.4, 1.5 and 1.2% pt-1 yr-1. Those of infective endocarditis, periprosthetic leak, reoperation and valve failure were 0.6, 3.3 and 4.9% pt-1 yr-1 respectively. At 9 years, 42% of the patients were in NYHA class I or II and free from complications.

Adolescent↗