PubMed Health⌕ Search

Biomedical subjects

D Artemov

Publications and source records attributed to D Artemov.

At least 19 recordsLinked to original sources
PubMed2002

Combined vascular and extracellular pH imaging of solid tumors.

The unique physiological environment of solid tumors, frequently characterized by areas of poor flow, hypoxia, high lactate and low extracellular pH (pHe), influences vascularization, invasion and metastasis. Thus, vascularization and the physiological and metabolic environment play permissive (and conversely preventive) roles in invasion and metastasis. By using a multi-parametric approach of combined vascular and spectroscopic imaging, we can begin to evaluate which combinations of vascular, metabolic and physiological regions in a solid tumor represent the highest 'metastatic threat'. Here, we present measurements of pHe, vascular volume and permeability from co-localized regions within a solid tumor. These studies were performed for a group of metastatic (MDA-MB-231) and non-metastatic (MCF-7) human breast cancer xenografts. In this study, we have demonstrated the feasibility of such an approach, and presented methods of analyses to detect differences in patterns of combined parameters obtained from spatially co-registered regions in a solid tumor.

Animals↗
PubMed2001

Magnetic resonance pharmacoangiography to detect and predict chemotherapy delivery to solid tumors.

Detection and prediction of drug delivery to the tumor interstitium are of critical importance in cancer chemotherapy. Prediction of drug delivery derived from standard pharmacokinetic models is frequently inadequate because of the complex nature of tumor blood flow and the microenvironment. Although drug concentrations can be directly sampled with microdialysis or in biopsy samples, we currently lack methods capable of detecting and/or predicting drug delivery to tumors noninvasively. In this study, we describe a novel magnetic resonance (MR) technique to directly detect the drug, and we present the correlation between delivery of drug and the delivery of MR contrast agents to the tumor. Experiments were performed with tumor xenografts in severe combined immunodeficient mice. Three-dimensional maps of the drug distribution within the tumors were obtained with 13C spectroscopic MR imaging with a spatial resolution of 2 x 2 x 2 mm, using signals of the 13C-labeled anticancer agent phenylacetate. Three-dimensional maps of uptake of gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) contrast agent were obtained for the same tumors using dynamic MR imaging. Experimental data were analyzed for correlation between delivery of the drug and the contrast. Histological analysis was performed for excised tumors. Experimental data demonstrated a significant spatial correlation (r = 0.59 with P < 0.001) between the parameter representing delivery of the contrast to tumor interstitium, determined from the kinetic curves of GdDTPA, and integral tissue drug concentrations for two different tumor models. The method is designed to probe extravasation of the drug molecules from the bloodstream into the tumor interstitium. Although therapeutic efficiency of the drug will also depend upon drug retention in the tumor and the ability of the molecules to cross cellular membranes, inefficient drug transfer from plasma to tissue can be a major impediment in achieving effective tumor chemotherapy. The results of this study demonstrate that the uptake kinetics of a low molecular weight MR contrast agent can be used to predict delivery of drug molecules of similar size to the interstitium of solid tumors.

Animals↗
PubMed2001

The physiological environment in cancer vascularization, invasion and metastasis.

One of the most lethal aspects of cancer arises from its ability to invade and metastasize. Determining the factors that promote cancer cell invasion and metastasis is therefore critically important in treating this disease. The tumour physiological environment is uniquely different from normal tissue, and exhibits hypoxia, acidic extracellular pH and high levels of lactate. This environment, dictated largely by abnormal tumour vasculature and metabolism, in turn also promotes angiogenesis. The physiological environment, tumour metabolism, angiogenesis and vascularization are therefore inextricably linked. We have developed and applied non-invasive magnetic resonance (MR) imaging (I) and spectroscopy (S) techniques to understand the role of vascular, physiological and metabolic properties in cancer invasion and metastasis. These MR studies are performed with human breast and prostate cancer cells maintained in culture or grown as solid tumours in immune-suppressed mice. We have detected significant differences in vascular, physiological and metabolic characteristics of metastatic and non-metastatic human breast and prostate cancer models with MRI and MRS. Using a combined MRI/MRS approach we are currently acquiring metabolic, extracellular pH and vascular images from the same localized regions within a solid tumour to further understand the dynamics between these parameters and their role in cancer invasion and metastasis.

Humans↗
PubMed2001

Broadband proton decoupling for in vivo brain spectroscopy in humans.

A new decoupling sequence, PBAR, is described for broadband heteronuclear decoupling in vivo in humans at 1.5T. The sequence uses non-adiabatic, frequency- and amplitude-modulated inversion pulses designed to minimize decoupling sidebands at low applied gammaB(2) RF field levels and to cover only the narrow range of resonance offsets encountered in practice. The offset dependence of the decoupling efficiency of PBAR is demonstrated and compared to the conventional WALTZ-4 sequence. At the same average power levels, PBAR had slightly reduced bandwidth but significantly less intense decoupling sidebands. Applications of PBAR are shown in vivo in the human brain both for (31)P and natural abundance (13)C spectroscopy using volume decoupling coils. The PBAR sequence allows whole brain [(1)H]-[13]C decoupling to be performed at 1.5T with a standard head coil within FDA guidelines for RF power deposition. Magn Reson Med 45:226-232, 2001.

Brain Chemistry↗
PubMed2001

Real-time measurements of cellular oxygen consumption, pH, and energy metabolism using nuclear magnetic resonance spectroscopy.

Changes in molecular expression or apoptotic behavior, induced by malignant transformation or anticancer treatment, are frequently reflected in cellular metabolism and oxygen consumption. A technique to monitor oxygen consumption, cell physiology, and metabolism noninvasively would provide a better understanding of interactions between molecular changes and metabolism in malignant transformation and following cancer treatment. Such a system was developed in this study by adapting multinuclear MRI and spectroscopic techniques to an isolated cell perfusion system. The system was evaluated by studying the effects of two agents, carbonyl cyanide m-chlorophenylhydrazone (CCCP) which is an uncoupler of oxidative phosphorylation, and antimycin, an inhibitor of oxidative phosphorylation, on the oxygen consumption and metabolism of MCF-7 and MatLyLu cancer cell lines.

Adenosine Triphosphate↗
PubMed2001

'The metabolism of tumours': 70 years later.

Otto Warburg's classic treatise on the reprogramming of tumour metabolism from oxidative to glycolytic metabolism was published in London in 1930. Although the Warburg effect is one of the most universal characteristics of solid tumours, the molecular basis for this phenomenon has only recently been elucidated by studies indicating that increased expression of genes encoding glucose transporters and glycolytic enzymes in tumour cells is mediated by the transcription factors c-MYC and HIF-1. Whereas c-myc is a direct target for oncogenic mutations, expression of hypoxia-inducible factor 1 (HIF-1) is indirectly up-regulated via gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes that result increased HIF-1alpha protein expression and/or increased HIF-1 transcriptional activity in a cell-type-specific manner. As a result of genetic alterations and intratumoral hypoxia, HIF-1alpha is overexpressed in the majority of common human cancers relative to the surrounding normal tissue. In human breast cancer and brain tumours, HIF-1alpha overexpression is strongly correlated with tumour grade and vascularity.

Cell Hypoxia↗
PubMed2000

Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.

The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.

Adenocarcinoma↗
PubMed1999

Switchable multicoil array for MR micro-imaging of breast lesions.

High-resolution breast imaging may improve differentiation between benign and malignant lesions and may be important for refining treatment strategy. This article presents a new, flexible design of a breast-imaging coil capable of providing breast images of a high level of spatial resolution. Referred to as a switchable coil array, the design uses small-diameter surface coils that provide high sensitivity of detection, which, combined with a relatively small field of view, affords a high degree of spatial resolution (up to 200 microm). Remote selection of the coil pair closest to the position of the lesion in the breast permits coverage of the whole breast without changing the position of the coils or the patient. High-resolution MR images of phantom and volunteer patients with benign and malignant breast lesions are presented.

Biopsy, Needle↗
PubMed1999

Dynamics of prostate cancer cell invasion studied in vitro by NMR microscopy.

Understanding the dynamics and pathogenesis of invasion is vital for developing strategies to prevent cancer metastasis. Conventional invasion assays provide information for a single time point. NMR microscopic imaging as used in the current study to measure cell invasion in vitro provides a nondestructive method for scoring cell invasion thus offering a unique possibility to study this process dynamically. An additional advantage is that cells can be retrieved for metabolic and physiological characterization. Two prostate cancer cell lines, DU-145 and Mat-Ly-Lu, preselected for differences in invasive behavior, were studied. Cells were seeded in 12-mm culture plate inserts containing a 15-microm-thick porous membrane with 3.0 microm pore size that was coated with a 100 microm Matrigel layer. Cell invasion in the Matrigel layer was obtained from the profile of intracellular water measured with diffusion-weighted 1D imaging. Additional experiments were also performed with confocal microscopy to validate the NMR results. Significant differences were detected between the invasive behavior of DU-145 and Mat-Ly-Lu cells. The obtained results show that NMR microscopy can be used to dynamically study invasion by cancer cells. The noninvasive nature of NMR microscopy permits determination of cell migration dynamically for any given sample, which is especially important if cell availability is limited to the unique sample, such as for biopsy specimens. Magn Reson Med 42:277-282, 1999.

Animals↗
PubMed1999

Tumor angiogenesis, vascularization, and contrast-enhanced magnetic resonance imaging.

Angiogenesis, the process by which new blood vessels are generated, occurs during wound healing, in the female reproductive system during ovulation and gestation, and during embryonic development. The process is carefully controlled with positive and negative regulators, because several vital physiological functions require angiogenesis. The consequences of abnormal angiogenesis are either excessive or insufficient blood vessel growth. Ulcers, strokes, and heart attacks can result from the absence of angiogenesis normally required for natural healing, whereas excessive blood vessel proliferation may favor tumor growth and dissemination, blindness, and arthritis. In this review, the process of angiogenesis and the characteristics of the resulting tumor vasculature are outlined. Contrast-enhanced magnetic resonance imaging techniques that currently are available for basic research and clinical applications to study various aspects of tumor angiogenesis and neovascularization are discussed.

Angiogenesis Inducing Agents↗
PubMed1998

Intratumoral conversion of 5-fluorocytosine to 5-fluorouracil by monoclonal antibody-cytosine deaminase conjugates: noninvasive detection of prodrug activation by magnetic resonance spectroscopy and spectroscopic imaging.

The monitoring of antibody-directed enzyme-prodrug therapies requires evaluation of drug activation within the tissues of interest. We have demonstrated the feasibility of noninvasive magnetic resonance spectroscopy and spectroscopic imaging (chemical shift imaging) to detect activation of the prodrug 5-fluorocytosine (5-FCyt) to the cytotoxic species 5-fluorouracil (5-FU) by monoclonal antibody-cytosine deaminase (CD) conjugates. In vitro, L6-CD but not 1F5-CD selectively metabolized 5-FCyt to 5-FU on H2981 human lung adenocarcinoma cells because of the presence and absence of cell surface L6 and CD20 antigens, respectively. After pretreatment of H2981 tumor-bearing mice with L6-CD, in vivo metabolism of 5-FCyt to 5-FU within the tumors was detected by 19F magnetic resonance spectroscopy; the chemical shift separation between 5-FCyt and 5-FU resonances was approximately 1.2 ppm. 5-FU levels were 50-100% of 5-FCyt levels in tumors 10-60 min after 5-FCyt administration. Whole body 19F chemical shift imaging (6 x 6 mm in-plane resolution) of tumor-bearing mice demonstrated the highest signal intensity of 5-FU within the tumor region. This study supports further development of noninvasive magnetic resonance methods for preclinical and clinical monitoring of CD enzyme-prodrug therapies.

Animals↗
PubMed1998

Two-compartment model for determination of glycolytic rates of solid tumors by in vivo 13C NMR spectroscopy.

Carbon-13 NMR spectroscopy of 13C enriched substrates is useful for non-invasively determining metabolic fluxes of cells and tissues. Our study demonstrates that for RIF-1 tumor cells, examined under monolayer culture with continuous perfusion and also grown as solid subcutaneously (sc) implanted tumors in vivo, the levels of intracellular glucose and intermediates of the glycolytic pathway are below the level of detection by NMR spectroscopy. For these tumors, glucose transport into the cell is the most probable rate limiting step of the glycolytic pathway. Under these limiting conditions a simple two-compartment model of glycolysis applies. This model yields two parameters: the average rate of glycolysis and the rate of lactate clearance through the vasculature. For the RIF-1 tumor these parameters were 0.022 +/- 0.01 and 0.034 +/- 0.006 min(-1), respectively.

Animals↗
PubMed1998

Characterization of a major permeability barrier in the zebrafish embryo.

Fish embryos represent a class of multicompartmental biological systems that have not been successfully cryopreserved, primarily because of the lack of understanding of how water and cryoprotectants permeate the compartments. We are using the zebrafish embryo as a model to understand these kinetics. Zebrafish embryos have two major compartments, the blastoderm and the yolk, which is surrounded by the multinucleated yolk syncytial layer (YSL). We determined the water and cryoprotectant permeability in these compartments using two methods. First, we measured shrink/swell dynamics in optical volumetric experiments. Zebrafish embryos shrank over time and did not re-expand while immersed in dimethyl sulfoxide (DMSO) or propylene glycol. Second, we measured DMSO uptake with diffusion-weighted nuclear magnetic resonance spectroscopy. DMSO uptake was rapid during the first few minutes, then gradual thereafter. We used one- and two-compartment models to analyze the data and to determine the permeability parameters. We found that the two-compartment model provided a better fit to the data. On the basis of this model and in the presence of DMSO, the yolk and blastoderm had very similar water permeabilities (i.e., 0.01 and 0. 005 micron x min-1atm-1, respectively), but they had different DMSO permeabilities separated by three orders of magnitude (i.e., </= 5 x 10(-6) and 1.5 x 10(-3) cm/min, respectively). The low solute permeability of the yolk predicted that the yolk/YSL compartment should be more susceptible to cryodamage. To test this, the yolk, blastoderm, and YSL were examined at the ultrastructural level after vitrification. Only the YSL incurred significant damage after freezing and thawing (p </= 0.05).

Animals↗
PubMed1997

Intracellular volume and apparent diffusion constants of perfused cancer cell cultures, as measured by NMR.

Diffusion NMR spectroscopy was used to study intracellular volume and apparent water diffusion constants in different cell lines (DU145, human prostate cancer; AT3, rat prostate cancer; MCF-7, human breast cancer; RIF-1, mouse fibrosacroma). The cells were grown on various matrices (collagen sponge, collagen beads, polystyrene beads) which enabled continuous growth in perfused high density cell culture suitable for NMR studies. In perfused cell systems, the attenuation of the water signal versus the squared gradient strength was fitted by the sum of two decaying exponentials. For the slowly decaying component the apparent water diffusion constant at 37 degrees C was 0.22 (+/-0.02) x 10(-9) s/m2 for all cell lines at diffusion times > 100 ms. It continuously increased up to 0.47 (+/-0.05) x 10(-9) s/m2 when the diffusion time was decreased to 8 ms, indicating restricted diffusion. No significant effect of the matrices was observed. The fractional volume of the slow component as determined from the biexponential diffusion curve correlated with the relative intracellular volume, as obtained from the cell density in the sample and the cell size as measured by light microscopy. Therefore, this simple NMR approach can be used to determine intracellular volume in perfused cell cultures suitable for NMR studies. Using this information in combination with spectroscopic data, changes in intracellular metabolite concentration can be detected even when the cellular volume is changing during the experiment. The apparent diffusion constant for the fast diffusing component varied with growth matrix, cell density and cell type and also showed the typical characteristics of restricted diffusion (increase of apparent diffusion constant with time).

Animals↗
PubMed1995

In vivo selective measurement of (1-13C)-glucose metabolism in tumors by heteronuclear cross polarization.

Selective detection of (1-13C)-glucose and its glycolytic product, (3-13C)-lactate, was achieved by selective 13C NMR spectroscopy with 1H cross polarization. The total sensitivity of conventional broadband experiments was retained, and peak intensities were at least equivalent to those obtained with the inverse detection technique (i.e., 1H(13C)) for single proton resonances. A key advantage of the method is that it maintains the specific absorption rate (SAR) within FDA limits of 5 W/kg by reducing power deposition during decoupling. In this study we have monitored the kinetics of metabolism of 13C-labeled glucose to lactate following intravenous infusion of 0.55 ml of 0.18 M labeled glucose. Physiological effects were minimized by a) maintaining total plasma glucose concentrations below 20 mM throughout the course of NMR experiment and b) by avoiding significant heating of the tumor.

Absorption↗
PubMed1995

Pharmacokinetics of the 13C labeled anticancer agent temozolomide detected in vivo by selective cross-polarization transfer.

The anticancer agent temozolomide labeled with 13C (8-Carbamoyl-3-13C-methylimidazo-[5,1-d]-1,2,3,5-tetrazin-4-(3H)-o ne), was noninvasively detected in subcutaneous RIF-1 tumors by a selective cross polarization 13C NMR method, at a field strength of 9.4T. Pharmacokinetics of the drug, at a dose of 150 mg/kg, were determined for intravenous and intraperitoneal models of administration (three animals per mode). The half-life of the drug in the tumors was approximately 60 min. The uptake and clearance of the drug, however, varied significantly between individual hosts, for both modes of administration. These results demonstrate the feasibility of obtaining pharmacokinetics of anticancer agents for individual tumors without the need for a label that might modify drug activity (e.g., fluorine). The variability of the in vivo measurements, even within the same tumor model, demonstrates the necessity of directly monitoring the tumor to evaluate drug pharmacokinetics.

Animals↗