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J D Glickson

Publications and source records attributed to J D Glickson.

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

Evaluation of lactate as a 1H nuclear magnetic resonance spectroscopy index for noninvasive prediction and early detection of tumor response to radiation therapy in EMT6 tumors.

In a recent study (Int. J. Radiat. Oncol. Biol. Phys. 36, 635-639, 1996), 1H nuclear magnetic resonance (NMR) spectroscopy was used to demonstrate significant decreases in lactate levels after gamma irradiation of radiosensitive RIF-1 tumors in vitro. For comparison, we have examined the effects of gamma radiation on lactate levels in the more radioresistant EMT6 tumor. Single-slice (5-6 mm thick) localized 1H spectra of subcutaneous RIF-1 (untreated) and EMT6 tumors (pretreatment, 24 and 48 h postirradiation with 4, 10 or 20 Gy of gamma radiation) were measured by the selective multiple quantum coherence transfer method (Sel-MQC, approximately 4 min acquisition time). Both pretreatment lactate levels and pretreatment lactate dehydrogenase (LDH) activities were found to be similar in RIF-1 and EMT6 tumors, suggesting that steady-state lactate levels are unlikely to be reliable indices for predicting response to radiation therapy. After 10 Gy gamma irradiation, EMT6 tumors showed a 21% decrease relative to pretreatment lactate levels at 48 h (1.04 +/- 0.22 to 0.82 +/- 0.16; P = 0.06); after 20 Gy a 40% decrease was observed at 48 h (1.34 +/- 0.27 to 0.81 +/- 0.10; P = 0.07). No significant changes in lactate levels were observed in control EMT6 tumors or in tumors treated with 4 Gy of gamma radiation, in contrast to changes detected previously in RIF-1 tumors, which showed a significant decrease in lactate by 48 h for both 2 and 4 Gy. The decreased effect of radiation on lactate levels in EMT6 compared to RIF-1 tumors may be attributed to the higher hypoxic fraction and lower radiosensitivity of EMT6 tumors (Int. J. Radiat. Oncol. Biol. Phys. 10, 695-712, 1984). The decrease in lactate levels did not, however, strictly reflect the extent of the response to therapy for the high dose of 20 Gy. This study together with our earlier study (Int. J. Radiat. Oncol. Biol. Phys. 36, 635-639, 1996) provides evidence to support the hypothesis that changes in steady-state tumor lactate levels may serve as sensitive early indices of tumor response to gamma radiation at doses of the order of 2 to 4 Gy.

Animals↗
PubMed1997

Diffusion imaging of human breast.

It is shown that diffusion-weighted imaging is possible in the human breast. Diffusion constants were measured in the breast parenchyma of four volunteers with no known breast lesions. The apparent diffusion constant of water measured in regions of interest chosen in normal human breast fibroglandular tissue was 1.64 +/- 0.19 x 10(-5) cm2/S and that measured in the area of fatty breast tissue was 0.32 +/- 0.18 x 10(-5) cm2/S. The resulting images indicate that fibroglandular tissue and fat can be clearly distinguished in diffusion-weighted as well as in absolute diffusion images of the breast. Potential future applications of this technology for the study of breast pathologies are suggested.

Adipose Tissue↗
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↗
PubMed1996

Detection of tumor response to radiation therapy by in vivo proton MR spectroscopy.

PURPOSE: These studies were performed to investigate the effects of radiation on levels of metabolites such as lactate and choline compounds detected by 1H magnetic resonance spectroscopy (MRS). The purpose was to determine the ability of spatially localized 1H MRS to detect tumor response to radiation therapy. METHODS AND MATERIALS: Proton spectroscopic images were obtained from RIF-1 tumors with voxel spatial resolutions of 8-16 mm3 before and at 24 and 48 h following 2, 4, and 20 Gy of gamma-radiation. RESULTS: Lactate levels decreased significantly for all doses by 48 h. Tumors irradiated with 2 and 4 Gy showed a significant decrease by 48 h, but not at 24 h. A group of sham-irradiated control animals demonstrated no significant changes in lactate over the period of observation. CONCLUSIONS: Changes in lactate observed in this study are consistent with an increased blood flow observed in previous studies (15) in the same tumor model following 20 Gy X-irradiation. These studies point to the feasibility of detecting response to clinical doses of fractionated radiation therapy by 1H MRS.

Hydrogen↗
PubMed1996

Inhibition of tumor cell proliferation by dexamethasone: 31P NMR studies of RIF-1 fibrosarcoma cells perfused in vitro.

The impact on tumor cell metabolism of a substantial reduction in cell proliferation rate without acute cytotoxicity was examined in cultured RIF-1 tumor cells following treatment with an antiproliferative steroid, dexamethasone (DEX). After 48 h exposure to 4 mM DEX, acute cell viability was essentially unchanged: cells were 93 +/- 2% trypan blue excluding in both control and treated cultures (all values are mean +/- SD). The fraction of actively proliferating cells in the S phase (as indicated by incorporation of 5-bromodeoxyuridine) was only 4 +/- 3%, compared with 13 +/- 3% in age-matched control cultures (n =4, paired t-test: p < 0.004) and 23 +/- 7% at the beginning of the treatment. Three days of DEX treatment resulted in a limited increase in the level of apoptosis (programmed cell death): cells did not become rounded or detached, but the fraction expressing apoptotic DNA fragmentation (susceptible to nick end labeling by terminal deoxy-nucleotidyl transferase) was 15 +/- 7%, vs 2 +/- 1% in control cultures (p < 0.02). Despite a 75% inhibition of cell proliferation, DEX caused only a modest change in the 31P NMR spectra of RIF-1 cells in vitro. The ratio of phosphocreatine to nucleoside triphosphates (NTP) was 30% higher, on average, in treated than in control cells (n = 8, paired t-test, p < 0.02), even when both treated and control cell densities were low. The level of total phosphomonoester (relative to NTP) was lower at low cell density, but this was independent of whether cells were growing rapidly (control low density) or were growth inhibited by DEX. Neither the ratio of phosphocholine to NTP nor the intracellular pH was significantly different in DEX-treated cells.

Animals↗
PubMed1996

Effects of blood flow modifiers on tumor metabolism observed in vivo by proton magnetic resonance spectroscopic imaging.

Perfusion plays a key role in tumor proliferation and therapeutic response. Tumor heterogeneity necessitates use of the highest spatial resolution to monitor metabolic correlates of blood flow changes. This is best achieved with 1H NMR spectroscopy, which permits noninvasive acquisition of high resolution spectroscopic images (SI) of subcutaneous tumors in a relatively short scan time (e.g., 12-25 microliters voxels with signal-to-noise ratio 7:1 in 30 min at 4.7 T). This study seeks to identify 1H spectroscopic indices of tumor blood flow. Proton SI of subcutaneous murine RIF-1 tumors were recorded (a) before and after administration of nicotinamide (1 g/kg) to increase blood flow, and (b) before and after hydralazine (10 mg/kg) to decrease flow. Nicotinamide produced a significant decrease in the total choline peak amplitudes, which subsequent high resolution NMR spectroscopy of tumor extracts revealed to be due to decreases in phosphocholine and glycerophosphocholine. The deamidation of nicotinamide to nicotinic acid, which is known to have hypolipidemic effects and to stimulate the formation of prostaglandins, may have sufficiently altered lipid metabolism to affect the in vivo concentration of the NMR-visible choline-containing compounds. The main effect of hydralazine was a significant increase of lactate, which is consistent with a reduction of tumor blood flow.

Animals↗
PubMed1996

Proton detection of choline and lactate in EMT6 tumors by spin-echo-enhanced selective multiple-quantum-coherence transfer.

An extension of the Sel-MQC pulse sequence--SEE-SelMQC (spin-echo-enhanced selective multiple-quantum coherence transfer)--that completely suppresses lipid and water in tissues containing mobile lipid in a single scan and detects 1H resonances of multiple metabolites is described. As in the Sel-MQC lactate-editing experiments [Q. He et al., J Magn. Reson. B 106,203 (1995)], SEE-SelMQC acquires lactate from its ZQ --> DQ coherence-transfer pathway; in addition, the method recovers signal from other metabolites by selective generation of additional spin echoes using extra frequency-selective pulses and gradients. This method introduces no loss of lactate signal intensity beyond the 50% that is lost through the multiple-quantum coherence-transfer process. The spatial distributions of choline and lactate with a phantom and in vivo, in subcutaneously implanted murine EMT6 tumors, have been simultaneously mapped.

Animals↗
PubMed1995

Calculation of absolute metabolic flux and the elucidation of the pathways of glutamate labeling in perfused rat heart by 13C NMR spectroscopy and nonlinear least squares analysis.

Absolute metabolic fluxes in isolated perfused hearts have been determined by a nonlinear least squares analysis of glutamate labeling kinetics from [1-13C]glucose, [4-13C]beta-hydroxybutyrate, or [2-13C]acetate using 13C NMR spectroscopy. With glucose as substrate, the malate-aspartate shuttle flux was too slow to account for the reducing equivalents generated by glycolysis and to predict the observed oxygen consumption rate. For acetate and beta-hydroxybutyrate, the malate-aspartate shuttle had to be reversed for the network to agree with the observed oxygen consumption and glutamate labeling. Thus, an additional redox shuttle was required to reoxidize the NADH produced by cytoplasmic malate dehydrogenase. Using this model there was good agreement between the experimentally determined oxygen consumption and glutamate labeling and the calculated values of these parameters from the model for all substrates. The contribution of exogenous substrate to the overall tricarboxylic acid (TCA) cycle flux, 89.6 +/- 6.5% (mean +/- S.D.) as measured in the tissue extracts compared well with 91.4 +/- 4.2% calculated by the model. The ratio of TCA cycle flux to oxygen consumption for acetate, was 2.2 +/- 0.1, indicating that NADH production is principally accounted for by TCA cycle flux. For glucose or beta-hydroxybutyrate, this ratio was 2.9 +/- 0.2, consistent with the existence of other NADH producing reactions (e.g. glycolysis, beta-hydroxybutyrate oxidation).

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

Proton NMR observation of the antineoplastic agent Iproplatin in vivo by selective multiple quantum coherence transfer (Sel-MQC).

We have noninvasively detected the proton signal of an antineoplastic agent Iproplatin in vivo by selective multiple quantum coherence transfer (Sel-MQC). Without isotopic labeling or chemical modification, the Sel-MQC method labels Iproplatin by its intrinsic proton multiple quantum coherences and, hence, differentiates the Iproplatin signal from the intensive overlapping resonances of lipid and lactate. This proton NMR method should also be applicable to study other drugs with appropriate spin coupling patterns.

Animals↗
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↗
PubMed1995

Single-scan in vivo lactate editing with complete lipid and water suppression by selective multiple-quantum-coherence transfer (Sel-MQC) with application to tumors.

A novel single-scan selective homonuclear multiple-quantum coherence-transfer technique, Sel-MQC, is presented that achieves lactate editing with complete lipid and water suppression. The method is suitable for studying tissues with high fat content and those subject to substantial motion. Frequency-selective excitation is employed to selectively prepare lactate into its multiple-quantum states; lipid and water are left in the single-quantum modes and eliminated by the multiple-quantum selection gradients. The efficiency of lipid suppression is monitored by a 2D Sel-MQC experiment which separates lipid and lactate along the multiple-quantum-evolution dimension. The spatial distribution of lactate can be imaged by the spectroscopic imaging version of Sel-MQC. Sel-MQC sequences were demonstrated both in phantoms and in vivo, using subcutaneously implanted murine EMT6 tumors.

Animals↗
PubMed1994

31P NMR spectroscopic studies of the effects of cyclophosphamide on perfused RIF-1 tumor cells.

To determine whether direct cellular effects of chemotherapy are responsible for 31P NMR spectral changes observed in treated tumors in vivo, RIF-1 fibrosarcoma cells were examined in vitro before, during, and after treatment with 4-hydroperoxycyclophosphamide (4-HC), an activated form of cyclophosphamide. When RIF-1 cells were treated with 4-HC in a metabolically stable but nonproliferating state, the 31P NMR spectra were identical with those of untreated cells for up to 70 h. When actively proliferating RIF-1 cells were treated with 4-HC, the intensities of the nucleotide triphosphate resonances, which increased linearly during control cell growth, remained constant for 50 h or longer. These studies demonstrate that the bioenergetic improvement observed following treatment of RIF-1 tumors in vivo [S.-J. Li, J.P. Wehrle, S.S. Rajan, R.G. Steen, J.D. Glickson, and J. Hilton, Cancer Res. 48, 4736 (1988)] does not result from direct effects of cyclophosphamide metabolites on RIF-1 cell metabolism, but rather from indirect effects of treatment on tumor or host physiology.

Animals↗
PubMed1994

Measurement of the intracellular concentration of oxygen in a cell perfusion system.

[O2] was measured in the embedding material (alginate) in a typical apparatus for conducting studies of viable cells with NMR, using low frequency EPR. In suspension cultures respiration was independent of [O2] in the perfusing media down to about 1 microM while in alginate beads, the comparable value was 70 microM, indicating that the alginate was a very substantial barrier to the free diffusion of oxygen. With knowledge of [O2] in the various compartments, [O2] in the perfusing medium can be increased and the full power of NMR can be used to provide information on metabolism under various conditions. These results also provide evidence supporting the feasibility and usefulness of EPR techniques using nitroxides to measure [O2] in macroscopic samples such as NMR perfusion tubes. This technique is rapid, apparently nonperturbing, and enables one to differentiate between the concentrations of oxygen in different compartments.

Alginates↗
PubMed1994

Band-selective spin echoes for in vivo localized 1H NMR spectroscopy.

This study describes a new single spin-echo spatial localization sequence, BASSALE or BAnd-Selective Spin echo Acquisition for Localized Editing, that overcomes a number of the limitations of the STEAM and PRESS volume selection pulse sequences. It achieves conformal volume localization in a single shot by spatially tailored suppression of all magnetization outside a 2D region of interest followed by selection of a single orthogonal slice. This separation of spatial localization from the echo formation process has permitted use of a spectrally selective cosine-modulated sinc refocusing pulse to acquire localized 1H spectra with the water suppression efficiency of STEAM and the sensitivity of PRESS. Echoes formed by such spectrally selective pulses have been termed band-selective spin echoes. The BASSALE sequence attains shorter echo times than PRESS, inhibits scalar spin-spin interactions to permit localized editing and T2 relaxometry of metabolites with J-coupled spins (e.g., lactate), is insensitive to homonuclear multiple-quantum and polarization transfer effects, and can be made sensitive or insensitive to spin displacement effects. Applications are shown both with phantoms and in situ in the rat brain.

Amino Acids↗
PubMed1994

Glucose metabolism in RIF-1 tumors after reduction in blood flow: an in vivo 13C and 31P NMR study.

Low pH appears to enhance the effectiveness of therapeutic hyperthermia. 13C and 31P NMR spectroscopy have been employed to examine the possibility that elevating glucose in a solid tumor while simultaneously reducing tumor blood flow would induce a more profound acidosis than either treatment alone. When blood flow in RIF-1 tumors was acutely reduced by administration of hydralazine and additional glucose was delivered locally by intratumoral injection, tumor acidosis (as determined by 31P NMR spectroscopy) during the period of reduced blood flow was not enhanced, relative to administration of hydralazine alone. Tumor NTP/P1 ratios decreased significantly within 20 min of hydralazine administration, whether or not glucose was injected, although NTP/P1 ratios were slightly higher in tumors that received extra glucose. Tumor lactate concentrations were not significantly different in glucose-supplemented tumors, despite glucose concentrations that were 4 to 5 times higher. When the added glucose was labeled with 13C, no correlation was detected between the pH in an individual tumor and the intensity of the 3-[13C]-lactate resonance in the same tumor.

Acidosis↗
PubMed1993

Gel-entrapment of perfluorocarbons: a fluorine-19 NMR spectroscopic method for monitoring oxygen concentration in cell perfusion systems.

Oxygenation is a major determinant of the physiological state of cultured cells. 19F NMR can be used to determine the oxygen concentration available to cells immobilized in a gel matrix by measuring the relaxation rate (1/T1) of perfluorocarbons (PFC) incorporated into the gel matrix. In calcium alginate gel beads without cells the relaxation rate (1/T1) of the trifluoromethyl group of perfluorotripropylamine (FTPA) varies linearly with oxygen concentration, with a slope of 1.26 +/- 0.15 x 10(-3) s-1 microM-1 and an intercept of 0.50 +/- 0.04 s-1. During perfusion with medium equilibrated with 95%/5% O2/CO2, changes in PFC T1s indicate that the average oxygen concentration was reduced from 894 +/- 102 microM in the absence of cells to 476 +/- 65 microM and 475 +/- 50 microM in the presence of 0.7 x 10(8) EMT6/Ro and RIF-1 murine tumor cells per milliliter of gel, respectively. The presence of 0.2 microliters of FTPA/ml of gel had no effect on the energy status of the cells as indicated by 31P NMR spectra. To calculate oxygen gradients within the beads from the average PFC T1 of the sample, a mathematical model was used assuming that oxygen is the limiting nutrient for cell metabolism and that the cellular oxygen consumption rate is independent of oxygen concentration. Data for EMT6/Ro cells were fit using experimentally determined perfusion parameters together with literature values for cell volume and oxygen consumption rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Alginates↗