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A Cherif

Publications and source records attributed to A Cherif.

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

Intensely potent doxorubicin analogues: structure-activity relationship.

N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b) is an intensely cytotoxic doxorubicin analogue that retains full potency against tumor cells that express elevated levels of P-glycoprotein and are resistant to doxorubicin. 1b was designed to be hydrolyzed in the presence of carboxylate esterases to N-(5-oxypent-1-yl)doxorubicin, an aldehyde capable of existing in equilibrium with a cyclic carbinolamine. To investigate the structural determinants of potency for 1b, we have prepared a series of chemically related compounds in which various omega-[bis(acetoxy)]alkyl or omega-[bis(acetoxy)]alkoxyalkyl groups are substituted at the 3'-amino position of the daunosamine sugar. These groups were selected to assess the effect of chain length, oxygen substitution, and carbinolamine ring size on analogue potency. The compounds were evaluated for their ability to inhibit the in vitro growth of the following cell lines: (a) Chinese hamster ovary (CHO) cells, (b) a CHO cell mutant 100-fold resistant to doxorubicin that expresses elevated levels of P-glycoprotein, (c) a murine ductal cell pancreatic adenocarcinoma (Panc 02), and (d) a murine mammary carcinoma (CA 755). The most potent members of the series were those that could form a straight chain aldehyde intermediate after esterase-mediated hydrolysis of the omega-bis(acetoxy) groups and give rise to 5- or 6-membered ring carbinolamines. Analogues capable of forming 7-, 8-, or 9-membered carbinolamines were markedly less active. The N-methyl derivative of 1b, which cannot give rise to a cyclic carbinolamine, was 2 orders of magnitude less potent than 1b. A branched chain analogue, 1f, which contained a tertiary carbon atom adjacent to the omega-bis(acetoxy) groups, was also substantially less active than its nonbranched counterpart, 1a. These findings suggest that the chain length of the 3'-amino substituents and the ability of the derived aldehydes to form 5- or 6-membered carbinolamines are critical determinants of biologic potency.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Cadmium- and copper-induced changes in tomato membrane lipids.

Cadmium and copper uptake and distribution, as well as their effects on growth and lipid composition were investigated in 17-day-old tomato seedlings (Lycopersicon esculentum Mill. cv. 63/5 F1) grown in culture solution supplied with two concentrations of Cd or Cu (0, 5 and 50 microM). The accumulation of Cd and Cu increased with external metal concentrations, and was considerably higher in roots than in primary leaves. Biomass production of the growing roots and primary leaves was strongly depressed at high metal levels. Also, significant decreases in the content of lipid classes and changes of fatty acid composition were recorded in heavy metal-stressed plants in comparison with controls. Glycolipid contents were decreased more in leaves than in roots by Cd-treatment, but copper decreased both to similar extents in both organs. Likewise, both metals reduced the phospholipid and neutral lipid contents more in roots than in leaves. In almost all lipid classes the proportion of palmitic acid (16:0) increased, and that of linoleic (18:2) or linolenic (18:3) acid decreased, suggesting that heavy metal treatment induced an alteration in the fatty acid desaturation processes. Furthermore, the accumulation of palmitate (16:0) rather than stearate (18:0) indicated an alteration in the ratio of products from the fatty acid synthase. Copper was found to be the most unfavourable for plant growth and lipid metabolism. The possible mechanisms by which heavy metals, especially Cu, induce a strong lipid shift are discussed.

Cadmium↗
PubMed1996

Assessment of tumor cell proliferation using [18F]fluorodeoxyadenosine and[18F]fluoroethyluracil.

This study was to develop radiofluorinated ethyluracil (FEU) and deoxyadenosine analogues (FAD) for noninvasive assessment of tumor proliferative potential by positron emission tomography (PET). 5-(2-Fluoroethyl)uracil ([18F]FEU) was prepared by treating 2,4-dimethoxy-5-(2-hydroxyethyl)pyrimidine with K18F, followed by hydrolysis with HBr. Fluorodeoxyadenosine ([18F]FAD) was prepared by treating a triacetylated analogue of adenosine with K18F. In vitro cell proliferation assay of [18F]-FEU was performed using human peripheral blood mononucleus cells. Tissue distributions were studied in breast tumor-bearing rats at 0.5, 1, 2 and 4 h along with autoradiography at 45 min postinjection. PET imaging studies were conducted in VX-2 tumor-bearing rabbits. In vitro assay indicated that [18F]FEU incorporated into DNA/RNA during cell proliferation. Tumor-to-tissue count density ratios of [18F]FAD and [18F]-FEU increased as a function of time. [18F]FAD had higher tumor-to-nontumor tissue count density ratios than [18F]FEU. Autoradiograms of [18F]FEU and [18F]FAD, and PET images of [18F]FEU, showed that the tumors could be well visualized. The results suggest that [18F]FEU and [18F]FAD have potential use in evaluating tumor cell proliferation by PET.

Animals↗
PubMed1996

Synthesis, biodistribution, and estrogen receptor scintigraphy of indium-111-diethylenetriaminepentaacetic acid-tamoxifen analogue.

This study was aimed at developing a hydrophilic diethylenetriaminepentaacetic acid-tamoxifen (DTPA-Tam) analogue for use in imaging estrogen receptor positive (ER+) lesions. In rat uterine cytosol, the IC50 of DTPA-Tam conjugate was 1 microM and of tamoxifen, 2 microM. Biodistribution, autoradiography, and radionuclide imaging of 111In-DTPA-Tam in breast-tumor-bearing rats showed that tumor-to-tissue ratios increased steadily between 30 min and 48 h. The in vivo response of MCF-7 breast cancer xenografts to tamoxifen and DTPA-Tam in nude mice demonstrated that DTPA-Tam could reduce tumor growth rate. These results indicate that DTPA-Tam, a new hydrophilic ER+ ligand, might be useful in diagnosing ER+ lesions.

Animals↗
PubMed1996

Positron emission tomography using [18F]fluorotamoxifen to evaluate therapeutic responses in patients with breast cancer: preliminary study.

Positron emission tomography (PET) was used to assess the biodistribution and clinical usefulness of [18F]fluorotamoxifen (FTX) in 10 patients with estrogen-receptor(ER)-positive breast tumors. Ten patients with ER-positive breast cancer were prospectively studied, and the consecutive PET imagings (each takes 15 or 20 min) were obtained for 60 or 80 min after the injection of 88.8-392.2 MBq (2.4-10.6 mCi) of [18F]FTX. Twenty three suspected primary or metastatic lesions in 10 patients were evaluated and the tumor uptakes of [18F]FTX in nineteen tumor lesions were correlated to the response of tamoxifen therapy. Three lesions in three patients were considered to be truly negative for breast cancer on the bases of biopsy specimens and/or clinical course. Five (71.4%) of seven patients and 16 (80.0%) of 20 lesions were interpreted to be truly positive for breast cancer. The mean standardized uptake value (SUV) of the radiotracer in tumor was 3.0 on delayed images. There was no significant correlation between the standardized uptake values of [18F]FTX and the ER concentrations in primary lesions. Nineteen tumor lesions in six patients were evaluable to compare the [18F]FTX uptake with responses to tamoxifen therapy after the PET study. Three patients who had a good response to tamoxifen therapy showed positive lesions on PET images, whereas two of three patients who had a poor response showed negative lesions and one showed mixed results. There was no significant difference of [18F]FTX uptake in bone lesions between good and poor responders. However, when bone lesions were excluded, [18F]FTX uptakes in tumors with good responses were significantly higher than those with poor responses (mean and standard deviation of SUV: 2.46 +/- 0.62 vs 1.37 +/- 0.59, P < 0.05). PET imaging using [18F]FTX provides useful information in predicting the effect of tamoxifen therapy in patients with ER-positive breast cancer. Further study is warranted to confirm the clinical utility of PET using [18F]FTX in breast cancer patients.

Aged↗
PubMed1996

Evaluation of [131I]iodoerythronitroimidazole as a predictor for the radiosensitizing effect.

The aim of this study was to evaluate whether radiolabeled iodoerythronitroimidazole (IETNIM) could predict the radiosensitization effect on tumors. Tumor-bearing mice were irradiated at a dose of 25, 31 and 37 Gy after the injection of IETNIM. They were also exposed to 37 Gy radiation at 35, 70, 140 and 240 min after the i.p. injection of IETNIM. After the irradiation, tumor growth assays were conducted and the effect of IETNIM as a radiosensitizer was estimated as enhancement factor (EF). Tumor uptake was measured at 35, 70, 140 and 240 min after i.p. injection of [131I]IETNIM, which were the same intervals used in the radiosensitization study. EF of IETNIM in mice treated with 25, 30 and 37 Gy irradiation was 0.72, 0.98 and 1.28, respectively. EF of IETNIM in mice irradiated at 35, 70, 140 and 240 min after the injection was 1.50, 1.69, 1.46 and 1.08, which corresponded to the tumor uptake and blood clearance of [131I]IETNIM. [131I]IETNIM may be a suitable radiopharmaceutical to predict the radiosensitization effect of misonidazole analogs on tumors.

Animals↗
PubMed1996

Development of new markers for hypoxic cells: [131I]Iodomisonidazole and [131I]Iodoerythronitroimidazole.

This study was aimed at developing ligands to evaluate tumor hypoxia by planar scintigraphy. Two 2-nitroimidazole analogues were developed as precursor compounds to image hypoxic tumors. Both tosylmisonidazole (Ts MISO) and tosylerythronitroimidazole (Ts ETNIM) were labeled with 131I. The biodistribution and autoradiographic evaluations by planar scintigraphy of 131I-IMISO and 131I-IETNIM were conducted at 1, 2 and 4 hours after administration to rats bearing 13762 breast tumors. Biodistribution of 131I-IMISO was also evaluated in Madison lung tumor-bearing mice. Intratumoral oxygen tension was measured by the Eppendorf system. Biodistribution showed similar tumor/blood and tumor/muscle count density ratios for both compounds. The thyroid uptake of both analogues was increased with time, suggesting in vivo deiodination probably occurred. Autoradiographs of 131I-IMISO and 131I-IETNIM revealed good visualization of the neoplasms. The tumor oxygen tension was 3-6 mmHg as compared to the normal tissue oxygenation of 30-40 mmHg. The findings indicate that these analogues can localize in the hypoxic region of solid tumors and may assist with quantitation of the hypoxic fraction of tumor for proper selection and evaluation of appropriate radiotherapy and chemotherapy.

Animals↗
PubMed1996

[Complications of percutaneous mitral commissurotomy. Personal experience and review of the literature].

Percutaneous mitral commissurotomy was performed in 484 patients by the double balloon technique and by Inoue's technique in 33 patients. The average age of the patients was 33.6 +/- 13 years (range: 8 to 72 years); 30% were in atrial fibrillation. A primary failure was observed in 10 patients (2%). The acute mortality was 0.4% and first month mortality 0.6%, the main cause being perforation of the left ventricle. The incidence of systemic embolism was 2%, related to atrial fibrillation (p < 0.016); this complication disappeared after systematic utilisation of transoesophageal echocardiography. Grade 4+ mitral regurgitation was created in 5 patients (1%) and grade 3+ in 20 others (3.9%). A score > 8 (p < 0.006) and preexisting grade 1+ mitral regurgitation (p < 0.005) were predictive factors of these severe regurgitations. They were also more frequent with Inoue's technique (10.5%; p < 0.05). Surgical intervention was necessary during the first month in 5 patients and at long-term (38 +/- 24 months) in 15 others. A tear in the anterior leaflet and ruptured chordae tendinae were the main mechanisms. The most common minor complication was the creation of a small interatrial shunt (16%) without any immediate or long-term complications. With a major complication rate of 4.2%, the mitral surface area increased from 0.97 to 2.2 cm2 and the cardiac index from 3 to 3.6 l/min/m2; left atrial pressure fell from 27 to 15 mmHg (p < 0.0001): the incidence of residual stenosis was only 2%. Seventy nine per cent of patients were asymptomatic and 16% were paucisymptomatic (class II) at long-term. Systematic transoesophageal echocardiography to detect thrombi, the use of pig-tail or Inoue catherters, effective heparinisation during a prolonged procedure and improved experience of the medical teams, should result in a further reduction of the risks of percutaneous mitral commissurotomy.

Adolescent↗
PubMed1995

Results of percutaneous double-balloon mitral commissurotomy in one medical center in Tunisia.

Percutaneous balloon mitral commissurotomy was attempted in Tunisia, where rheumatic fever is still endemic, in 463 consecutive patients with severe rheumatic mitral valve stenosis. Their mean age +/- SD was 33 +/- 12 years (range 8 to 68), 324 patients (70%) were women, and 327 (71%) were in sinus rhythm. Valvotomy was technically successful in 454 patients (98%). The mean mitral valve gradient decreased from 20 +/- 7 to 6 +/- 4 mm Hg, mean left atrial pressure decreased from 27 +/- 8 to 15 +/- 6 mm Hg, cardiac index increased from 3.0 +/- 0.7 to 3.6 +/- 0.8 L/min/m2, and Gorlin mitral valve area, from 0.97 +/- 0.19 to 2.2 +/- 0.4 cm2 (all p < 0.001). Two-dimensional echocardiographic mitral valve area increased from 1.03 +/- 0.18 to 2.15 +/- 0.36 cm2 (p < 0.00001). A final valve area of > or = 1.5 cm2 was achieved in 98% of patients. Multivariate analysis identified a pre-mitral valve area < 0.8 cm2 and an echocardiographic score (echo score) > or = 12 as the strongest predictors of residual stenosis (final mitral valve area < 1.5 cm2). Major procedural complications included mortality (0.4%), tamponade (0.7%), thromboembolism (2.0%), severe mitral regurgitation (4.6%), significant (pulmonary to systemic flow ratio > or = 1.5) interatrial shunt (4.8%). Four hundred thirty patients were followed up between 6 and 82 months (mean 37 +/- 22): 95% were in functional class I to II without reintervention, and 7 patients died (1.6%); restenosis (echocardiographic mitral valve area < 1.5 cm2) occurred in 10.4% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia.

PURPOSE: To develop a hydrophilic ligand to image tumor hypoxia at positron emission tomography (PET). MATERIALS AND METHODS: Biodistribution of fluorine-18-labeled fluoroerythronitroimidazole (FETNIM) and F-18-labeled fluoromisonidazole (FMISO) was determined at PET and autoradiography in three mammary-tumor-bearing rats. The partition coefficient of FETNIM, FMISO, and misonidazole was determined. RESULTS: Biodistribution of F-18-labeled FETNIM at 1, 2, and 4 hours showed tumor-to-blood ratios of 2.29 +/- 0.599, 2.41 +/- 0.567 and 8.02 +/- 2.420, respectively, and tumor-to-muscle ratios of 0.66 +/- 0.267, 2.11 +/- 0.347, and 5.92 +/- 2.240, respectively. The tumor-to-blood count density ratio with F-18-labeled FETNIM at 4 hours after injection was significantly higher than with F-18-labeled FMISO. Autoradiographs indicated that both agents could help differentiate hypoxic versus necrotic region in the tumor. CONCLUSION: F-18-labeled FETNIM can help detect tumor hypoxia and is easier to prepare, less costly, and more hydrophilic than F-18-labeled FMISO.

Animals↗
PubMed1994

Imaging, biodistribution and therapy potential of halogenated tamoxifen analogues.

Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT). [18F]-Labeled tamoxifen analogue ([18F]FTX) was prepared in 30-40% yield and [131I]-labeled tamoxifen analogue ([131I]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [18F]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41 +/- 0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24 +/- 0.017. [131I]ITX at 6 h showed a tumor uptake value of 0.26 +/- 0.166; when rats were pretreated with DES, the value changed to 0.22 +/- 0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [131I]ITX was increased to 0.48 +/- 0.107 at 6 h. In the [3H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [131I]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodo-tamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 micrograms in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.

Animals↗
PubMed1993

Synthesis of [18F]fluoroalanine and [18F]fluorotamoxifen for imaging breast tumors.

To develop ligands for imaging breast tumors, [18F]fluoro analogue of tamoxifen and [18F]fluoroalanine were radiosynthesized. In vivo biodistribution studies were performed in mammary tumor-bearing rats. In studies on the biodistribution of an [18F]fluoro analogue of tamoxifen, tumor uptake decreased when rats were pretreated with diethylstilbestrol (DES), suggesting that tracer uptake in tumors was receptor-mediated. An estrogen receptor assay indicated that tumors have a receptor density of 7.5 fmol/mg protein. Studies of the distribution of [18F]fluoroalanine in tissue showed that the tumor-to-tissue ratio increases as a function of time. Positron emission tomography (PET) images of tumor-bearing rats demonstrated that tumors can be visualized 1 h after rats are injected with an [18F]fluoro analogue of tamoxifen. PET imaging of pigs after injection of 10 mCi of [18F]fluoro analogue of tamoxifen showed uterine uptake that could be blocked by DES (50 mg). The findings suggest that both radiotracers are useful for imaging breast tumors.

Alanine↗
PubMed1992

N-(5,5-diacetoxypent-1-yl)doxorubicin: a new intensely potent doxorubicin analogue.

N-(5,5-Diacetoxypent-1-yl)doxorubicin (DAPDOX) (3), a new, water-soluble analogue of doxorubicin, has been synthesized by coupling doxorubicin with 5-oxopentane-1,1-diacetate in the presence of NaBH3CN. This analogue was designed to be converted to the corresponding aldehyde, N-(5-oxopent-1-yl)doxorubicin, in the presence of carboxylate hydrolases, enzymes that are ubiquitous in tissue. DAPDOX had a half-life of several days in 0.05 M phosphate or 0.05 M acetate buffer solution at pH 4.0. However, in 0.05 M phosphate buffer at pH 7.4 in the presence of 20 unit equiv of porcine liver carboxylate esterase, the half-life of DAPDOX was less than 1 min. N-(5-acetoxypent-1-yl)doxorubicin (4), which should give rise to N-(5-hydroxypent-1-yl)doxorubicin on esterase-mediated hydrolysis, and N-(pent-1-yl)doxorubicin (5), were also prepared for comparative biological studies. DAPDOX was 150 times more potent than doxorubicin at inhibiting the growth of Chinese hamster ovary (CHO) cells in culture. The compound retained the same degree of potency against a CHO subline 100-fold resistant to doxorubicin (CHO/DOX) that expressed elevated levels of P-glycoprotein. Compounds 4 and 5, on the other hand, were no more effective than doxorubicin at inhibiting the growth of CHO cells and were 4-7-fold less potent against the CHO/DOX subline. DAPDOX is representative of a new structural class of doxorubicin analogues with unique chemical and biological properties.

ATP Binding Cassette Transporter, Subfamily B, Mem↗