RESUMO
Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-ß-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430µM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glioma/tratamento farmacológico , Ouro/química , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Movimento Celular/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Glutationa/metabolismo , Glutationa Redutase/antagonistas & inibidores , Glutationa Redutase/metabolismo , Humanos , Masculino , Ratos , Ratos Wistar , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Células Tumorais CultivadasRESUMO
Fluorescent dyes (e.g., dansyl, fluoresceine isothiocyanate, or naphthalimide groups) are widely used as markers to study biological properties of drugs. In order to evaluate possible mediated cytotoxicity, we attached three molecules each to 1,3,5-tris(3-propylamino)benzene initially synthesized as core molecule for the design of dendrimers. Cytotoxic effects were only observed for the NO(2)-substituted naphthalimide conjugate. The intracellular distribution was visualized via confocal fluorescence microscopy and pointed to an accumulation in the endosome or nucleus, dependent on the cell line used.
Assuntos
Derivados de Benzeno/farmacocinética , Compostos de Dansil/farmacocinética , Dendrímeros/farmacocinética , Fluoresceína-5-Isotiocianato/farmacocinética , Naftalimidas/farmacocinética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Derivados de Benzeno/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Sobrevivência Celular/efeitos dos fármacos , Compostos de Dansil/química , Compostos de Dansil/toxicidade , Dendrímeros/síntese química , Sistemas de Liberação de Medicamentos , Endossomos/efeitos dos fármacos , Endossomos/ultraestrutura , Feminino , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/toxicidade , Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Corantes Fluorescentes/toxicidade , Humanos , Cinética , Microscopia Confocal , Naftalimidas/química , Naftalimidas/toxicidadeRESUMO
Treatment of multiple myeloma, a B-cell cancer, is usually palliative, however, as a result of intensive clinical research there are numerous new treatment options available today. The present review summarizes non-transplant treatment options for multiple myeloma on the basis of available publications. Treatment with new substances, such as immunomodulatory agents, farnesyl transferase inhibitors and apoptosis stimulators, and their mechanisms of action are discussed. In addition to this systematic review of the available evidence on multiple myeloma therapy we have also summarized current recommendations from national and international organizations on aspects of the treatment of multiple myeloma. This should enable readers to see different points of view at a glance and, hopefully, will provide a basis for translation of the available evidence into the best possible therapy.
Assuntos
Mieloma Múltiplo/terapia , Antineoplásicos/uso terapêutico , Humanos , Mieloma Múltiplo/epidemiologiaRESUMO
This study aimed to identify the effects of different bisphosphonates in reducing skeletal-related events, and to determine whether there are any differences in their cost-effectiveness, taking into account their efficacy, safety profile and administration routes. A systematic literature search of databases, such as PubMed and the Cochrane Controlled Trials Register, supplemented by the latest congress abstracts from meetings of the European Hematology Association and the American Society of Clinical Oncology was conducted up to November 2006. Important references in reviews published by peer-reviewed journals were also taken into consideration. Our base-case cost-effectiveness analysis for Germany and the UK showed cost savings for oral clodronate therapy compared with other bisphosphonate therapies. In Germany, costs per patient of treatment with oral clodronate were euro1092.38, euro2360.40 and euro2500.29 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively. The UK results were similar, the costs per patient of treatment with oral clodronate being euro841.79, euro2989.99 and euro3669.19 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/economia , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Administração Oral , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/economia , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Ácido Clodrônico/administração & dosagem , Ácido Clodrônico/economia , Ácido Clodrônico/farmacologia , Ácido Clodrônico/uso terapêutico , Análise Custo-Benefício , Atenção à Saúde/economia , Difosfonatos/economia , Difosfonatos/farmacologia , Feminino , Alemanha , Humanos , Ácido Ibandrônico , Imidazóis/administração & dosagem , Imidazóis/economia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Injeções Intravenosas , Pamidronato , Reino Unido , Ácido ZoledrônicoRESUMO
Stable organogold(iii) compounds of the composition [AuIII(Hdamp)(L1)]Cl are formed from reactions of [AuCl2(damp)] with H2L1 (damp- = dimethylaminomethylphenyl; H2L1 = N'-(diethylcarbamothioyl)benzimidothiosemicarbazides). The cationic complexes can be neutralized by reactions with weak bases under the formation of [AuIII(damp)(L1)] compounds. The structures of the products show interesting features like relatively short AuH contacts between the methylene protons of the Hdamp ligand and the gold(iii) ions. Preliminary biological studies on the uncoordinated compounds H2L1 and their gold complexes indicate considerable cytotoxicity for the [AuIII(Hdamp)(L1)]Cl complexes against MCF-7 cells. The in vitro trypanocidal activity was evaluated against the intracellular form of Trypanosoma cruzi. The organometallic complexes display a remarkable activity, which is dependent on the alkyl substituents of the thiosemicarbazone building blocks of the ligands. One representative of the cationic [AuIII(Hdamp)(L1)]Cl complexes, where H2L1 contains a dimethylthiosemicarbazide building block, shows a trypanocidal activity against the intracellular amastigote form in the same order of magnitude as that of the standard drug benznidazole. Furthermore, no appreciable toxicity to mice spleen cells is observed for this compound resulting in a therapeutic index of about 30, which strongly recommends it as a promising candidate for the development of a future antiparasitic drug.
Assuntos
Ouro/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Tiossemicarbazonas/química , Trypanosoma cruzi/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Ligantes , Células MCF-7 , Modelos Moleculares , Conformação Molecular , Tripanossomicidas/química , Tripanossomicidas/farmacologiaRESUMO
The aim of this study was to prepare different types of paclitaxel-loaded, PLGA-based microparticles and lipidic implants, which can directly be injected into the brain tissue. Releasing the drug in a time-controlled manner over several weeks, these systems are intended to optimize the treatment of brain tumors. The latter is particularly difficult because of the blood-brain barrier (BBB), hindering most drugs to reach the target tissue upon systemic administration. Especially paclitaxel (being effective for the treatment of ovarian, breast, lung and other cancers) is not able to cross the BBB to a notable extent since it is a substrate of the efflux transporter P-glycoprotein. Both, biodegradable microparticles as well as small, cylindrical, glycerol tripalmitate-based implants (which can be injected using standard needles) were prepared with different paclitaxel loadings. The effects of several formulation and processing parameters on the resulting drug release kinetics were investigated in phosphate buffer pH 7.4 as well as in a diethylnicotinamide (DENA)/phosphate buffer mixture. Using DSC, SEM, SEC and optical microscopy deeper insight into the underlying drug release mechanisms could be gained. The presence of DENA in the release medium significantly increased the solubility of paclitaxel, accelerated PLGA degradation, increased the mobility of the polymer and drug molecules and fundamentally altered the geometry of the systems, resulting in increased paclitaxel release rates.
Assuntos
Antineoplásicos Fitogênicos/química , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos , Implantes de Medicamento , Paclitaxel/química , Antineoplásicos Fitogênicos/uso terapêutico , Composição de Medicamentos , Cinética , Ácido Láctico/química , Microesferas , Niquetamida/química , Paclitaxel/uso terapêutico , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polímeros/química , Solubilidade , Tecnologia Farmacêutica , Triglicerídeos/químicaRESUMO
The peroxisome proliferator-activated receptor (PPAR) γ regulates the expression of genes involved in adipogenesis, lipid homeostasis, and glucose metabolism, making it a valuable drug target. However, full activation of the nuclear receptor is associated with unwanted side effects. Research therefore focuses on the discovery of novel partial agonists, which show a distinct protein-ligand interaction pattern compared to full agonists. Within this study, we employed pharmacophore- and shape-based virtual screening and docking independently and in parallel for the identification of novel PPARγ ligands. The ten top-ranked hits retrieved with every method were further investigated with external in silico bioactivity profiling tools. Subsequent biological testing not only confirmed the binding of nine out of the 29 selected test compounds, but enabled the direct comparison of the method performances in a prospective manner. Although all three methods successfully identified novel ligands, they varied in the numbers of active compounds ranked among the top-ten in the virtual hit list. In addition, these compounds were in most cases exclusively predicted as active by the method which initially identified them. This suggests, that the applied programs and methods are highly complementary and cover a distinct chemical space of PPARγ ligands. Further analyses revealed that eight out of the nine active molecules represent novel chemical scaffolds for PPARγ, which can serve as promising starting points for further chemical optimization. In addition, two novel compounds, identified with docking, proved to be partial agonists in the experimental testing.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Agonismo Parcial de Drogas , PPAR gama/agonistas , Animais , Células COS , Chlorocebus aethiops , Simulação de Acoplamento Molecular , PPAR gama/química , PPAR gama/metabolismo , Conformação Proteica , Interface Usuário-ComputadorRESUMO
INTRODUCTION: Several magnetic resonance (MR) techniques designed to demonstrate the characteristic signal intensity of blood degeneration products of thrombi have been suggested, but the effect of thrombus organization on the MR display, in particular with regard to its temporal evolution, remains to be determined. It is the purpose of this study to develop a stagnation thrombus model in rabbits and to characterize thrombus at different ages with two (MR) imaging techniques, phlebography and histology. MATERIALS AND METHODS: Venous stagnation thrombi were induced in the external jugular veins of rabbits using a minimally invasive radiological technique to produce artificial embolic vascular occlusion and hypercoagulability. Twenty-five animals were divided into 5 groups of 5 animals, and each group underwent 1.5 T MR imaging at 1, 3, 5, 7 and 9 days after thrombus induction using a T1-weighted magnetization-prepared rapid gradient-echo sequence (MP-RAGE: TR 10.4 msec, TE 4.0 msec, FA 15 degrees ) and a T2-weighted fast low-angle shot sequence (FLASH: TR 54 msec, TE 18 msec, FA 15 degrees ). The thrombus length was measured on the T1-weighted images. Thrombus conspicuity, signal intensity, and heterogeneity on T2* weighted images were described using visual scales. Radiographic venography and histology served as reference methods. RESULTS: Thrombi were successfully induced in all animals. The overall thrombus length decreased from 43 +/- 9 (day 1 after induction) to 23 +/- 4 mm (day 9). On 3D-reconstructions of the T1-weighted images, the visible portion of the true thrombus length relative to the overall thrombus length was 0.16 +/- 0.3 (day 1), 0.24 +/- 0.3 (day 3), 0.38 +/- 0.5 (day 5), 0.06 +/- 0.1 (day 7) and 0.00 (day 9). Sixteen of 25 thrombi were detectable with the T2*-weighted technique. The overall thrombus signal intensity decreased with the age of the thrombus from day 1 to day 9. The histological evaluation showed that the rabbit thrombi closely resemble human thrombi morphologically. CONCLUSIONS: The thrombus model closely resembles the human venous stagnation thrombus of different organizational stages. With state-of-the-art MRI techniques, thrombi were only partially displayed with the visibility depending on thrombus age. The model may be suitable for evaluating new and potentially more effective MRI techniques for improved thrombus visualization.
Assuntos
Veias Jugulares , Imageamento por Ressonância Magnética/métodos , Flebografia , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/diagnóstico , Trombose Venosa/patologia , Animais , Meios de Contraste , Interpretação Estatística de Dados , Modelos Animais de Doenças , Imageamento Tridimensional , Veias Jugulares/patologia , Coelhos , Fatores de TempoRESUMO
Heterocyclic derivatives of (R,S)/(S,R)-1-(2-chloro-4-hydroxyphenyl)-2-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (L1) were synthesized and tested for estrogen receptor binding. The selection of the heterocycles was based on theoretical consideration. (2R,3S)/(2S,3R)-2-(2-Chloro-4-hydroxyphenyl)-3-(2,6-dichloro-4-hydroxyphenyl)piperazine 2, (4R,5S)/(4S,5R)-4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline 3, and 4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)imidazole 4 possess a spatial structure with neighboring aromatic rings as is realized in hormonally active [1,2-diphenylethylenediamine]platinum(II) complexes. The 1,2-diphenylethane pharmacophor, however, cannot adapt an antiperiplanar conformation to interact with the estrogen receptor (ER) comparable to synthetic (e.g., diethylstilbestrol (DES)) or steroidal (e.g., estradiol (E2)) estrogens. Due to the different spatial structures, the heterocycles cause only a marginal displacement of E2 from its binding site (relative binding affinity (RBA) < 0.1%). Nevertheless, unequivocally ER mediated gene activation was verified on the MCF-7-2a cell line. Imidazoline 3 as the most active compound reached the maximum effect of E2 (100% activation) in a concentration of 5 x 10(-7) M, while piperazine 2 and imidazole 4 activate luciferase expression only in a small but significant amount of 20% and 27%, respectively. We therefore assigned these heterocyclic compounds to a second class of hormones (type-II-estrogens), which are attached at the ER at different amino acids than DES or E2 (type-I-estrogens).
Assuntos
Compostos Heterocíclicos/síntese química , Imidazóis/síntese química , Piperazinas/síntese química , Receptores de Estrogênio/metabolismo , Ligação Competitiva , Neoplasias da Mama , Dietilestilbestrol/farmacocinética , Dietilestilbestrol/farmacologia , Desenho de Fármacos , Estradiol/metabolismo , Receptor alfa de Estrogênio , Feminino , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Cinética , Luciferases/genética , Modelos Moleculares , Conformação Molecular , Piperazinas/química , Piperazinas/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Proteínas Recombinantes/biossíntese , Relação Estrutura-Atividade , Transfecção , Células Tumorais CultivadasRESUMO
N-Monoalkylated (Et) and N,N'-dialkylated (Me and Et) 1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamines and their dichloroplatinum(II) complexes were synthesized, and their configuration and conformational behavior were 1H-NMR spectroscopically clarified. The latter was brought in relation to their relative binding affinity (RBA) to the estrogen receptor as well as to their estrogenic potency. In contrast to the RR/SS-configurated diamines, the R/S-configurated ones showed marked estrogenic properties which correlate with the RBA's. In the related R/S-configurated complexes the estrogenic activity is determined by the same structural requirements as in the diamine series. However, a correlation between RBA's and estrogenic potencies is missing. The connection between spatial structure and activity is discussed by use of a drug-receptor model recently proposed by Höltje and Dall.
Assuntos
Etilenodiaminas/farmacologia , Compostos Organoplatínicos/farmacologia , Receptores de Estrogênio/metabolismo , Animais , Sítios de Ligação , Bovinos , Etilenodiaminas/química , Etilenodiaminas/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Compostos Organoplatínicos/química , Compostos Organoplatínicos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Erythro- and threo-configurated aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2- phenylethylenediamine](sulfato)platinum(II) complexes with variable substituents in the 2-phenyl ring (2-PtSO4 to 9-PtSO4: H, 4-F, 3-OH, 4-OH, 2,6-F2, 2,6-Cl2, 2-F/4-OH, 2-Cl/4-OH) were synthesized and tested for estrogenic and antitumor activities. The ligands were obtained by a three-step reaction. The stilbenes were reacted with a mixture of IN3 and NaN3 to yield the respective 1,2-diazido-1,2-diphenylethanes. The subsequent reduction with LiAlH4 led to the corresponding 1,2-diphenyl-ethylenediamines. The (sulfato)platinum(II) complexes were synthesized by reaction of Ag2SO4 with the diiodo complexes, which had been obtained by coordination of the diamines with K2PtI4. Two complexes, erythro-8-PtSO4 and erythro-9-PtSO4, possess antitumor and estrogenic effects and are therefore of interest for the therapy of breast cancer.
Assuntos
Antineoplásicos/síntese química , Etilenodiaminas/síntese química , Compostos Organoplatínicos/síntese química , Animais , Antineoplásicos/uso terapêutico , Fenômenos Químicos , Química , Etilenodiaminas/uso terapêutico , Feminino , Leucemia P388/tratamento farmacológico , Camundongos , Camundongos Endogâmicos DBA , Compostos Organoplatínicos/uso terapêutico , Receptores de Estradiol/efeitos dos fármacos , Receptores de Estradiol/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
[1,2-Bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum (II) complexes with one substituent in the 2-position (CH3, CF3, F, Cl, Br, I: meso- and d,l-1-PtCl2, meso-(3-5)-PtCl2, meso-(7 and 8)-PtCl2) or two substituents in the 2,6-positions (CH3, Cl: meso-2-PtCl2, meso- and d,l-6-PtCl2) in both benzene rings were synthesized and tested for estrogenic and cytotoxic activities. Two complexes (meso-6-PtCl2 and meso-7-PtCl2) possess both effects. In comparative tests on estrogen receptor positive and negative mammary tumors in cell culture (MCF 7, ER+ and MDA-MB 231, ER-) and in animals (MXT, ER+ and MXT, ER-, mouse), meso-6-PtCl2 shows a selective effect on the estrogen receptor positive mammary carcinoma. A further increase of efficacy was achieved with the water-soluble (sulfato)platinum(II) derivative (meso-6-PtSO4). On the DMBA-induced hormone dependent mammary carcinoma of the SD rat, meso-6-PtSO4 is significantly more active than its ligand (meso-6) and cisplatin.
Assuntos
Neoplasias Mamárias Experimentais/tratamento farmacológico , Compostos Organoplatínicos/síntese química , Animais , Neoplasias da Mama , Linhagem Celular , Cisplatino/uso terapêutico , Feminino , Humanos , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
INTRODUCTION: Contrast-enhanced magnetic resonance (MR) imaging using ultra small superparamagnetic iron oxide (USPIO) particles is a new noninvasive modality for imaging inflammatory atherosclerotic plaques. We determined the accuracy, interobserver agreement, and potential sources of error of this technique by means of postmortem MR imaging of aortic preparations. MATERIAL AND METHODS: Anesthetized atherosclerotic Watanabe heritable hyperlipidemic (WHHL) rabbits were studied after administration of different dosages of intravenous USPIO (DDM 43/34, IDF Berlin, Germany) and different postcontrast time intervals. A (n = 5) received 0 micromol Fe/kg. B (n = 5) received 50 micromol Fe/kg, 8-hour postcontrast interval. C (n = 5) received 50 micromol, 24 hours. D received 200 micromol, 48 hours. The aortas were removed and 3-mm segments prepared for postmortem examination by MR imaging using a T2-weighted gradient-echo sequence (TR/TE/FA; 41 milliseconds/11 milliseconds/15 degrees ), radiography (mammography), and histology (iron staining). USPIO accumulation was defined as the presence of 20 iron-positive cells per microscopic view (x100 magnification). Two independent readers analyzed the MR images and rated their confidence level for a positive MRI finding, defined as a focal signal loss, on a 5-point scale. The results were evaluated by receiver-operator characteristic (ROC) analysis. RESULTS: Of a total of 621 vessel segments technically acceptable for evaluation, 534 were histologically negative and 87 positive. Accuracy, expressed as the area under the ROC curve, was 0.85 for reader 1 and 0.88 for reader 2. Interobserver agreement was 0.67. False-positive findings were established by at least one reader for 121 of the 621 segments, false-negative findings for only 15 segments. Calcifications and mural thrombi were identified as potential sources of error of the method. CONCLUSION: Postmortem USPIO-enhanced MR imaging of atherosclerotic plaques showed a high accuracy and good interobserver agreement in the animal model used here. Further optimization of the method should aim at reducing the rather high percentage of false-positive results.
Assuntos
Arteriosclerose/patologia , Meios de Contraste , Ferro , Imageamento por Ressonância Magnética , Óxidos , Animais , Dextranos , Feminino , Óxido Ferroso-Férrico , Nanopartículas de Magnetita , Masculino , Variações Dependentes do Observador , Curva ROC , CoelhosRESUMO
RATIONALE AND OBJECTIVES: Inflammatory atherosclerotic plaques are characterized by increased endothelial permeability and multiple macrophages. Blood-pool MRI contrast agents like superparamagnetic iron oxide (SPIO) have an affinity for the monocyte-macrophage system and thus, may label inflammatory plaques. The objective was to demonstrate SPIO uptake in plaques of atherosclerotic rabbits by MRI and histology. METHODS: Aortas of anesthetized Watanabe hereditable hyperlipidemic rabbits were studied with a moderately T2*-weighted gradient-echo sequence at 1.5 T. Four groups of five animals each were studied: (1) without ultrasmall SPIO (carboxydextran coating; particle size, 25 nm; estimated plasma half-life, 6 hours) or with imaging after intravenous injection of SPIO at a dose (micromol Fe/kg) and postcontrast time delay (hours) of 50/8 (2), 50/24 (3), or 200/48 (4). In vivo MRI was compared with corresponding ex vivo histological iron stains. RESULTS: Animals receiving 200 micromol Fe/kg demonstrated areas of focal signal loss clearly confined to the aortic wall on a mean of 24 +/- 9 (31% +/- 11%) of 76 +/- 5 images compared with 0 +/- 0 of 76 +/- 5 images in controls (P = 0.009). The number of images with this finding in groups 2 and 3 was not significantly different compared with controls. By microscopy, SPIO-iron was seen in the endothelial cells and subendothelial intimal macrophages of atherosclerosis-prone aortic wall segments. Atherosclerotic lesions demonstrating iron uptake also showed a high macrophage content. CONCLUSIONS: SPIO accumulates in aortic plaques of atherosclerotic rabbits, producing a characteristic MRI finding. As SPIO accumulates in plaques with increased endothelial permeability and a high macrophage content, two established features of plaque inflammation, it may have a potential for noninvasive assessment of inflammatory atherosclerotic plaques.
Assuntos
Doenças da Aorta/diagnóstico , Arteriosclerose/diagnóstico , Meios de Contraste , Ferro , Imageamento por Ressonância Magnética , Óxidos , Animais , Doenças da Aorta/patologia , Arteriosclerose/patologia , Interpretação Estatística de Dados , Feminino , Hiperlipidemias/diagnóstico , Hiperlipidemias/patologia , Masculino , CoelhosRESUMO
In the search for new anti-breast cancer compounds a series of diastereomeric aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfato platinum(II) complexes was tested on the hormone-sensitive MXT-M-3.2 breast cancer of the mouse. By simultaneous determination of tumor and uterine weights at the end of the experiment we obtained an insight into the mode of action. Changes in the uterine weights indicate whether the anti-breast cancer effect of the test substance is caused either by its capability to reduce the endogenous estrogen level via inhibition of estrogen biosynthesis (mechanism B), or by its estrogenic side effects which enhance the immune defense in the host animals (mechanism C). Studies on the [3H]thymidine incorporation into DNA of MDAMB-231 breast cancer cells showed that all test compounds inhibit deoxyribonucleic acid synthesis, like cisplatin (mechanism A). However, in comparison to the standard cisplatin, their activities were low. The three most effective test compounds threo-2-PtSO4 (2-phenyl-residue), threo-5-PtSO4 (2-(4-hydroxyphenyl)-residue), and threo-8-PtSO4 (2-(2-fluoro-4-hydroxyphenyl)-residue) seem to exert their anti-breast cancer effect by mechanism B. Moreover, threo-5-PtSO4 was moderately active on the hormone- insensitive MXT-M-3.2 (Ovex) breast cancer of the mouse. Aqua[erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-chloro-4-hydroxypheny l) ethylenediamine]sulfato-platinum(II) (erythro-9-PtSO4) was the only breast cancer inhibiting compound of the series acting mainly according to mechanism C. A minor contribution of mechanism A, impairment of the DNA function in the tumor cell, to the anti-breast cancer activity of these aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfato platinum(II) complexes cannot be excluded, since such effects are apparent in the MDA-MB-231 as well as in the MCF-7 breast cancer cell line at higher drug concentrations. In this test series which was performed with the crystal violet chemosensitivity assay, the MCF-7 cells proved to be somewhat more sensitive.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Animais , Neoplasias da Mama/metabolismo , DNA de Neoplasias/biossíntese , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Transplante de Neoplasias , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Receptores de Estrogênio/fisiologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Diastereomeric para-substituted dichloro(1,2-diphenylethylenediamine)platinum(II) complexes were synthesized and tested for their antitumor activity on the human MDA-MB 231 breast cancer cell line and the P 388 leukemia of the mouse. An interaction with the DNA was demonstrated by UV difference spectroscopy. The D,L configurated, 4-fluoro-substituted complex was the most active.
Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Animais , Neoplasias da Mama/patologia , Carcinoma de Ehrlich/patologia , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia P388/patologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The platinum complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)- ethylenediamine]dichloroplatinum(II),K, was tested for its antitumor activity on hormone-sensitive tumor models under peroral administration. The resorption from the gastrointestinal tract was proved by determining the estrogenic effect of K in a dose/activity study using the immature-mouse uterine weight test. In comparison to the subcutaneous injection, a tenfold peroral dose was administered to achieve identical effects. By peroral treatment of the hormone-sensitive MXT(M3.2) mammary carcinoma of the mouse with K an almost complete inhibition of the tumor growth was obtained. This effect was superior to that of subcutaneously applied cisplatin and significantly better than that obtained by perorally administered ligand L at an equimolar dose, indicating that the antitumor effect is caused by the intact complex K and not by the liberated ligand L. The strong antitumor activity of perorally applied K was also demonstrated on the hormone-sensitive Noble Nb-R prostatic carcinoma of the rat. Histological examinations showed that the platinum complex K did not cause cisplatin-like kidney damage or irritations of gastric or intestinal mucosa when given perorally.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/toxicidade , Feminino , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Biológicos , Tamanho do Órgão/efeitos dos fármacos , Compostos Organoplatínicos/toxicidade , Ratos , Ratos Sprague-Dawley , Útero/efeitos dos fármacosRESUMO
The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)ethylenediamine][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F-Pt(CBDC), the evaluation of their structures, their tumor-inhibiting properties and their stability in physiological environment are described (reference complexes: the dichloro- and sulfatoplatinum(II) analogues, carboplatin and cisplatin). The most interesting diastereomer, rac-4F-Pt(CBDC), equals cisplatin and surpasses carboplatin in its effect on human breast cancer cell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive against attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stability in vivo and for fewer side effects. In accordance with this, in vitro studies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protein, show that the free, non-protein-bound fraction is relatively high, coming close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experiments to in vivo conditions. The distinctly better anti-breast cancer activity of rac-4F-Pt(CBDC) than of carboplatin has been attributed to its ability to accumulate in the tumor cells. The human ovarian cancer cell line NIH-OVCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).
Assuntos
Carboplatina/análogos & derivados , Neoplasias da Mama , Carboplatina/química , Carboplatina/farmacologia , Tamanho Celular , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Neoplasias Ovarianas , Platina/análise , Albumina Sérica/metabolismo , Solubilidade , Células Tumorais CultivadasRESUMO
The enantiomeric [1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) complexes were synthesized and tested on the hormone-sensitive human MCF7 breast cancer cell line and on the P388 leukemia of the mouse. They showed a strong and comparable activity on both tumor models.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Cisplatino/uso terapêutico , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos DBARESUMO
The synthesis of diastereoisomeric [1,2-bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes, DL-3-PtCl2 and meso-3-PtCl2, and their evaluation on the hormone-independent, human MDA-MB231 breast cancer cell line, on the cisplatin-sensitive and -resistant L1210 leukemia cell line, on the cisplatin-resistant human NIH:OVCAR 3 ovarian cancer cell line, on the P-388 leukemia of the mouse and on the cisplatin-sensitive and -resistant Ehrlich ascites tumor of the mouse are described. On all tumor models DL-3-PtCl2 produces a marked inhibitory effect. The diastereoisomer meso-3-PtCl2 is less active and more toxic. It is striking that DL-3-PtCl2 leads to a pronounced inhibition of all cisplatin-resistant tumors. At non-toxic concentrations DL-3-PtCl2 produces cytocidal effects on the NIH:OV-CAR 3 cell line. Therefore DL-3-PtCl2 is of interest for further evaluation for the therapy of ovarian cancer.