Distribution in man of 111In-labelled liposomes containing a water-insoluble antimitotic agent.
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Antineoplastic Agents↗
Biomedical subjects
G Ghanem
Publications and source records attributed to G Ghanem.
Dynamic 131I-labelled insulin distribution in rabbits as seen by in-vivo scintigraphic studies.
The kinetics of 131I-labelled insulin distribution in heart, liver, kidneys and urinary bladder of rabbits were studied in vivo by gamma-camera techniques combined with plasma measurements (glucose concentrations and chromatographic separation of insulin and its degradation products). The distribution space of radioiodinated insulin differed from the vascular bed delineated by radioiodinated serum albumin. During a 20-min gamma-camera recording, radioactive degradation products only appeared in the plasma after 10-12 min. Previous administration of a 10 000-fold excess of unlabelled insulin and 5 ml glucose (20%) did not modify the evolution of 131I-labelled insulin cardiac invasion and the subsequent linear decrease of radioactivity. Conversely, wash-out of radioactivity from the liver and kidney was accelerated after preadministration of this excess of unlabelled hormone, binding in these organs accounting for this acceleration. Urinary bladder filling was imaged later than cardiac, hepatic or renal labelling and was only accelerated by polyuria induced by glucose injection, independent of preadministration of unlabelled hormone.
Animals↗
Iv administration of a water-insoluble antimitotic compound entrapped in liposomes. Preliminary report on infusion of large volumes of liposomes to man.
Five patients with advanced multiresistant neoplasms were infused with NSC-251635 (a water-insoluble antimitotic agent) entrapped in egg yolk lecithin, cholesterol, and stearylamine liposomes. The maximum volume injected was 400 ml containing 8 g of lipids, ie, a dose of 135 mg/kg of body weight. Overall tolerance of the treatment was excellent. This study indicates that liposomes may be used safely as carriers for the iv administration of water-insoluble drugs to humans.
Adenocarcinoma↗
Comparison and evaluation of different methods for alpha-MSH labelling.
We have studied the behaviour of 125I-labelled alpha-MSH under different experimental conditions. Until now, the chloramine T method had been used by most investigators with variable results. We have tested three other labelling techniques based on 125I mild oxidation: (1) an enzymatic method with lactoperoxidase, (2) a sparingly soluble chloramine method (T.D.G.U.) and (3) modified chloramine T procedure, 'the iodine volatilization method'. Labelled hormone obtained after each kind of iodination was assayed for immunoreactivity. In addition, time course degradation was measured by classical RIA incubation procedures. Charcoal-dextran was used to separate bound and free antigen. We have found chloramine T-iodinated alpha-MSH to be significantly more damaged than preparations obtained by other methods and to be less stable when stored at -18 degrees C. No differences were found between the differently labelled 125I-labelled alpha-MSH fresh preparations in binding to surface receptors of human melanoma cell lines in culture.
Animals↗
Partial characterization of IR-alpha-MSH peptides found in melanoma tumors.
Our previous work indicated that IR-alpha-MSH (immunoreactive alpha-melanocyte-stimulating hormone) plasma levels are three times as high in melanoma patients with progressing disease than in disease-free patients, and that the melanoma tumor itself may be the source of IR-alpha-MSH. Further identification of the material in tumor extracts has been carried out in this study, and the results presented here show that the immunoreactivity is associated with a major fraction of about 16 kDa and another of 5-9 kDa. Significant amounts of the immunoreactive material were also found in human melanoma cells but not in culture supernatants. The presence of this material may be related to the melanogenic status of the tumor cells. We have estimated the intracellular IR-alpha-MSH to be within a 0.4 to 2.3 nM range in melanoma tumor cells. We have investigated the melanogenic effect of the IR-alpha-MSH material and its relationship to alpha-MSH. Purified extracts both from metastases and cultured cells were found to promote frog skin darkening as well as tyrosinase activity in Cloudman S91 melanoma cells. The IR material could also displace labeled alpha-MSH from its binding sites in human melanoma cells. Our data clearly indicate that melanoma cells engage in an autocrine production of alpha-MSH-like bioactive peptides by melanoma cells, of larger mol.wt., which are able to bind to MSH receptors. These peptides may be involved in the regulation of melanogenesis and possibly in the growth and proliferation of melanoma cells by an autocrine/paracrine mechanism.
Adult↗
Use of an alpha-melanocyte-stimulating hormone analogue to improve alpha-melanocyte-stimulating hormone receptor binding assay in human melanoma.
In order to optimize the detection and measurement of alpha-melanocyte-stimulating hormone (alpha-MSH) receptivity in human melanoma cells, and the authors replaced the natural hormone by [Nle4,D-Phe7]-alpha-MSH, a more stable and potent analogue in the receptor binding assay commonly performed with alpha-MSH. The following parameters were investigated: temperature, incubation time, number of cells, and ratio of labelled to unlabelled hormone. Optimal conditions for each assay were determined. The results demonstrate that the analogue has identical binding sites to alpha-MSH, as similar reciprocal displacements of each labelled (125I) hormone by serial dilutions of unlabelled alpha-MSH or [Nle4,D-Phe7]-alpha-MSH (10(-12) M to 10(-6) M) were obtained. To further compare the two hormones, we performed a screening of various human cell lines: ten melanomas and five nonmelanomas. The assay with [Nle4,D-Phe7]-alpha-MSH yielded more receptor expression on six of ten melanoma lines against only four of ten with the natural hormone. In conclusion, the use of radiolabelled [Nle4,D-Phe7]-alpha-MSH analogue instead of labelled alpha-MSH improved both sensitivity and reproducibility in this receptor binding assay on human melanoma lines.
Humans↗
Alpha-melanocyte-stimulating hormone immunoreactivity in human melanoma metastases extracts.
Seven human melanoma metastases were extracted in order to check the possible presence of any alpha-melanocyte stimulating hormone (MSH) immunoreactivity. The aim of that study was to provide some explanation for, mainly, two observations that we have already made and reported: 1) increased plasma alpha-MSH levels in melanoma of tumour-bearing patients as compared with tumour-free patients; 2) the presence of specific alpha-MSH receptors on human melanoma cells in culture. We could measure large amounts of immunoreactive alpha-MSH in all tumours ranging from 0.31 to 4.27 pmoles per g of wet tissue. Further identification of the extracted material by high-performance liquid chromatography revealed compounds of higher molecular weight and more hydrophobic than synthetic alpha-MSH. In addition, purified extracts could also displace 125I-labelled alpha-MSH from its cellular binding sites in an alpha-MSH specific radio-receptor binding assay. Our findings would suggest a possible presence of some hormone precursor(s) inside the melanoma tumours.
Aged↗
Popliteal cyst in a patient with total knee arthroplasty: a case report and review of the literature.
We report a case of total knee arthroplasty (TKA) failure presenting initially as a large popliteal cyst without bony destruction in a 66-year-old woman. A foreign body gigantocellular inflammatory reaction against polyethylene wear particles was found on histology. The size of the cyst and the absence of bony destruction can be due to an exclusive early intramuscular granulomatous reaction. Progressive loosening of the femoral component and narrowing of the joint space heralded the TKA failure.
Aged↗
In vitro cytotoxicity of hexamethylmelamine (HMM) and its derivatives.
The cytotoxicity of hexamethylmelamine (HMM) and its metabolites was investigated in three murine cell lines: one in vitro naturally sensitive to HMM (RC) and two in vivo naturally resistant (P388 and P388D1). The percentage of viable cells was determined both by the in situ reduction of a tetrazolium salt (MTT assay) and by the uptake of labelled thymidine into DNA (3HTdR assay). Short (1h) and long (48h) exposures of cells to drugs were considered. In all experimental conditions used, HMM was found to be inactive, whereas its hydroxylated metabolite hydroxymethylpentamethylmelamine (HMPMM) and one analog N, N 'dihydroxymethyltetramethylmelamine (DHTMM) were found to be cytotoxic. The results further indicated that HMM must be metabolized before it can exert its cytotoxic effect. The activity of HMPMM and DHTMM was found unlikely to be related to extracellular or intracellular release of formaldehyde.
Altretamine↗
Comparison of two cytotoxicity assays--tetrazolium derivative reduction (MTT) and tritiated thymidine uptake--on three malignant mouse cell lines using chemotherapeutic agents and investigational drugs.
Two different techniques [reduction of a tetrazolium derivative (MTT) and 3HTdR uptake assays] were compared in order to evaluate the cytotoxic effects of different chemotherapeutic agents in vitro. The cytotoxicities of Melphalan, hexamethylmelamine and seven derivatives, and daunorubicin were measured on P388D1 mouse macrophage-like cell line, RC mouse renal carcinoma cell line, and B16 mouse melanoma cell lines. Growth inhibition was determined after one hour as well as after continuous (48 hours) exposure to drugs. The IC50 was calculated using an appropriate algorithm (FADHA) which allowed within and between run variabilities to be taken into account. Optimal conditions had to be elucidated for culture conditions before assay: number of cells/well and assay duration for each line. The MTT and 3HTdR uptake assays were found to be similar in terms of sensitivity and reproducibility, both for adherent and floating cell lines. However, the MTT assay has the advantages of low cost and time saving. It also avoids problems related to radioactivity manipulation and counting. Both techniques rank the same chemicals as active or inactive. The algorithm Fadha was found to be a very powerful mathematical tool for comparing the IC50 values obtained by both assays.
Animals↗
Compared cytotoxicity effects of five anticancer drugs on human (HBL) and mouse (B16) melanoma cells in vitro.
In order to assess the potential interest of replacing the murine cell lines by human cell lines for in vitro cytotoxic assays, the sensitivity and the selectivity of the murine B16 and the human HBL melanomas to five chemotherapeutic drugs were investigated in vitro. The cytotoxicities of Melphalan, Daunorubicin (DNR), Hexamethylmelamine (HMM), Hydroxymethylpentamethylmelamine (HMPMM), and Dihydroxymethyltetramethylmelamine (DHTMM), 2 HMM derivatives, were measured in the two cell lines using two different techniques: reduction of a tetrazolium derivative (MTT) and tritiated thymidine uptake into DNA. The cytotoxicity at inhibitory concentration 50 (IC50) was determined after one hour as well as after 2 days exposure of cell after one hour as well as after 2 days exposure of cells to each drug. The results indicate that the HBL human melanoma was generally more sensitive to Melphalan and DHTMM than the B16 murine melanoma cells as far as the IC50 was concerned. In contrast, no difference of sensitivity was found to DNR and DHTMM. HMM was found to be inactive in both cell lines. The analysis of variance on IC50 values showed that the sensitivity of murine and human melanoma cell lines to drugs was statistically different. Despite the identical selectivity of the two cell lines, two promising observations can be made as far as the comparison of the two cell lines is concerned: 1) the higher sensitivity of HBL human cell line to Melphalan in the in vitro assays and 2) the slightly lower sensitivity of HBL to DNR, a drug without clinical activity against human melanoma.
Analysis of Variance↗
Studies on factors influencing human plasma alpha-MSH.
The various physiological effects of alpha-MSH, mainly on the CNS and on pigmentation in animal models, are well documented in the literature. Only a few investigators have confirmed similar properties in the human. However, the possible physiopathological role played by this hormone in human melanoma is still poorly defined. In order to approach this subject in a manner as complete as possible, we have performed, during the past four years, three different series of experiments: 1) alpha-MSH measurements in plasma samples from: a. melanoma and other cancer patients, b. whole body UVA irradiated healthy adults, c. circadian rhythm determinations in melanoma patients and in healthy male adults; 2) alpha-MSH measurements in human melanoma tumours; 3) alpha-MSH receptor expression on human melanoma cells in culture involving: a. alpha-MSH radio-binding assays and b. tyrosinase assay. Our results so far show 1) increased alpha-MSH levels in melanoma patients' plasma, alpha-MSH responsiveness to UVA stimulated skin, large immunoreactive alpha-MSH content in melanoma metastases and an alpha-MSH circadian rhythm in some individuals different from cortisol; 2) alpha-MSH receptor expression in melanoma cells could be increased by various effectors able to stimulate melanogenesis.
Aged↗
Production of interleukin 1 by activated blood monocytes and alveolar macrophages from melanoma patients.
The production of Interleukin 1 (Il1) by circulating blood monocytes and alveolar macrophages was studied in melanoma patients. There were 144 patients in the monocytes study and 5 patients in the alveolar macrophages study. The Il1 activity was tested by a bioassay and reported in units based on the integration of the area under the curve. This was shown to be preferable to the standard method, i.e. probit analysis. Results showed that there was no depression of Il1 activity in melanoma patients as compared to control (98 + 32 units, versus 100 units). There was no difference when the values were compared according to sex, age and stage of the disease. However, a significant difference was found between phototype I and phototype IV. Alveolar macrophages, in all experiments (n = 5), had a significantly lower Il1 activity than the autologous monocytes. It is concluded that we can question the relevance of Il1 production by peripheral blood monocytes to the state of the immunity of melanoma patients.
Adult↗
Monoclonal antibodies to human melanoma associated antigens: study of their specificity and visualization at the cellular level of the antigenic distribution.
Six monoclonal antibodies(Mabs) including 4 anti-melanoma, one anti-glioma, and one anti-HLA-DR have been tested in a 125I-protein A antibody binding assay using a panel of 34 different cell lines. This panel included 19 melanomas from different clinical and geographical origins, 10 fibroblast lines out of which 9 were established from melanoma patients, 2 glial cell lines, 1 osteosarcoma, 1 teratocarcinoma, and 1 murine melanoma. The reactivity pattern of the 4 anti-melanoma Mabs showed that they were not directed against antigens strictly restricted to melanoma, but rather against antigenic structures preferentially expressed on melanoma cells. These Mabs were found to crossreact with gliomas, thus they seem to recognize neuroectoderm associated differentiation antigens. The high crossreactivity of the anti-glioma Mab for melanoma was confirmed in this study. As expected from the literature, HLA-DR antigens were found to be expressed on more than 50% of the melanoma lines tested. The cellular distribution of the antigens recognized by two anti-melanoma Mabs on melanoma cells could be visualized by an autoradiographic procedure. From the labeling pattern it was concluded that only a proportion of the cells, varying from 13 to 38%, expressed the relevant antigen.
Antibodies, Monoclonal↗
Electrospray mass spectrometric analysis of new alpha-MSH analogues carrying nitrogen mustard at their amino terminus.
Two different chlorinated drugs, chlorambucil and melphalan, have been linked to the carrier alpha-melanocyte-stimulating hormone at the end of the solid-phase peptide synthesis of the hormone. The [Nle4, D-Phe7] and the [Nle4, L-Phe7] derivatives of the hormone have both been used. It was found by electrospray mass spectrometric analysis that the products undergo hydrolysis of the chlorinated moiety of the drugs, most likely due to the acidic conditions necessary for cleavage of the peptide from the resin. Only the melphalan-O(ethyl)-N(succinyl)-derivative of alpha-melanocyte-stimulating hormone [Nle4, L-Phe7] did not show a bis-hydroxylated form. It was proven by blank experiments with commercially available melphalan that this mustard occurs for some 45%-50% in the mono-hydroxylated form, which is known to be pharmacologically poorly active.
Amino Acid Sequence↗
First results of a clinical pilot study on intraarterial chemotherapy with haemofiltration of locally advanced gastrointestinal cancers.
Intra-arterial chemotherapy combined with haemofiltration enables the administration of drugs to confined neoplastic tissue while limiting the systemic drug exposure. During the procedure, the cytotoxic drugs are injected into the arterial supply of the tumour and the venous blood coming from the tumour bed is pumped out and filtered trough haemofiltration unit in order to extract the cytotoxic drug not fixed on the tumour. The patients selected for such treatment failed previous intravenous chemotherapy. Thirteen patients underwent intra-arterial chemotherapy injections combined with haemofiltration procedures: 8 unresectable liver metastases from colorectal cancer and 5 pelvic recurrences from rectal cancer. Fluorouracil, mitomycin C and doxorubicin were infused. One out of thirteen patients presented a complete regression of his liver metastases, 5/13 presented a partial regression, 2/13 patients did not show any significant modification of the size of their lesions and were classified as stable disease, 5/13 patients showed a progression of their neoplastic disease. No nephrotoxicity or major gastrointestinal side effects were observed. Intra-arterial chemotherapy combined with haemofiltration procedure is a therapeutic modality that could be considered in patients with locally advanced cancer who failed previous first line intravenous chemotherapy.
Aged↗
[Value of transesophageal echocardiography in the diagnosis of peripheral embolic event].
Ischemic cerebro-vascular events are in 15% of cases secondary to a cardiac embolus. The prevalence of echocardiographic anomalies, susceptible of being at the origin of a cerebral embolus may reach 50%. Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE) in the detection of a thrombus of the left atrial appendage, spontaneous echocontrast, intra-aortic atherosclerotic plaque lesion, patent foramen ovale or an atrial septal aneurysm. The high prevalence of these anomalies in a population who presented an ischemic cerebrovascular accident does not suffice to establish a causal relationship between the anomaly and the cerebral event. Further studies seem to be necessary to establish the responsibility of these different anomalies and determine their embolic risk, by defining certain risk factors. Pending the results of such studies, TEE should be indicated more systematically in the case of an ischemic cerebrovascular accident of the young patient without a clinically evident cardiopathy, independently of the results of TTE.
Aortic Diseases↗