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Z M Bhujwalla

Publications and source records attributed to Z M Bhujwalla.

At least 37 records · Page 2Linked to original sources
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

Hypoxic cell cytotoxin tirapazamine induces acute changes in tumor energy metabolism and pH: a 31P magnetic resonance spectroscopy study.

Tirapazamine is a hypoxic cell cytotoxin in phase II/III trials. To further understand its mechanism of action in vivo, we examined the effect of tirapazamine on tumor energy metabolism and pH. RIF-1 and SCCVII tumors were grown subcutaneously in the flanks of C3H mice. Tumor energy metabolism, expressed as the ratio of inorganic phosphate to nucleotide triphosphate (Pi/NTP), and intracellular pH (pHi), were measured by 31P magnetic resonance spectroscopy (MRS). In RIF-1 and SCCVII tumors, tirapazamine increased the Pi/NTP ratio by 2.6-fold and 3-fold, respectively, within the first hour after an intraperitoneal dose of 0.3 mmol/kg. A corresponding decrease in pHi from 7.05+/-0.07 to 6.48+/-0.06, and 7.21+/-0.09 to 6.45+/-0.02 in RIF-1 and SCCVII tumors, respectively, was observed. The decrease in tumor 31P bioenergetics and pH was reversible, as exemplified by RIF-1 tumors, which showed a further increase in Pi/NTP ratio of 3.5-fold by 5-8 hr, returning to normal range at 24 hr. Corresponding pHi of RIF-1 tumors was 6.88+/-0.05 at 5-8 hr and 7.16+/-0.05 at 24 hr. We concluded that tirapazamine induces acute changes in tumor energy metabolism and pHi. These findings are relevant to the rational selection and optimal timing of coadministered therapy.

Animals↗
PubMed1998

Estimations of intra- and extracellular volume and pH by 31P magnetic resonance spectroscopy: effect of therapy on RIF-1 tumours.

Quantification of metabolite or drug concentrations in living tissues requires determination of intra- and extracellular volumes. This study demonstrates how this can be achieved non-invasively by 31P magnetic resonance spectroscopy (MRS) employing dimethyl methylphosphonate (DMMP) as a marker of total water space, 3-aminopropylphosphonate (3-APP) as a marker of extracellular space and P and 3-APP as markers of intracellular pH (pH) and extracellular pH (pHe) respectively. The MRS measurements of the tumour volumes were validated by classic radiolabelling methods using 3H2O and [14C]inulin as markers of total and extracellular space respectively. The extracellular volume fraction measured by radiolabelling of RIF-1 tumours was 23 +/- 0.83% (mean +/- s.e.m. n = 9), not significantly different (P > 0.1) from that found by MRS (27 +/- 2.9%, n = 9, London, and 35 +/- 6.7, n = 14, Baltimore). In untreated RIF-1 tumours, pH was about 0.2 units higher than pHe (P < 0.01). 5-Fluorouracil (5FU) treatment (165 mg kg(-1)) caused no significant changes in either pHe or per cent extracellular volume. However significant increases in pH, 48 h after treatment (P < 0.01) correlated with decreased tumour size and improved bioenergetic status [NTP/inorganic phosphate (Pi) ratio]. This study shows the feasibility of an MR method (verified by a 'gold standard') for studying the effects of drug treatment on intra- and extracellular spaces and pH in solid tumours in vivo.

Animals↗
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↗
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

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

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

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↗
PubMed1992

Spatial heterogeneity of the metabolic response of RIF-1 tumors to a vasoactive agent evaluated in vivo by one-dimensional 31P chemical-shift imaging.

Localized 31P NMR spectroscopy was used to evaluate the spatial heterogeneity of the metabolic response of RIF-1 tumors to hydralazine. Volume localized 31P spectra were obtained from subcutaneous RIF-1 tumors using one-dimensional chemical-shift imaging, before and 20 min after treatment with 5 mg/kg hydralazine, administered intravenously. Following treatment all of the tumors showed an overall decrease in the ratio of nucleoside triphosphate (NTP) to inorganic phosphate (Pi) and a decrease in pH. However, spatial localization revealed that the reduction in NTP/Pi was not uniform within some tumors. This was partly due to regional differences in the levels of metabolites existing before treatment. Normal tissue adjacent to the tumor did not show a significant decrease in high-energy metabolites or pH.

Animals↗
PubMed1992

Determination of absolute phosphate metabolite concentrations in RIF-1 tumors in vivo by 31P-1H-2H NMR spectroscopy using water as an internal intensity reference.

The absolute metabolite quantification method of Thulborn and Ackerman [J. Magn. Reson. 55, 357 (1983)] in which the tissue water proton signal is used as an internal intensity standard and its more recent variation in which NMR peak intensities are referenced to that of the natural abundance deuterium signal of water [Li et al., SMRM Abstr. 2, 825 (1988); Song et al., Magn. Reson. Med. 25, 45 (1992) have been implemented to obtain absolute phosphate metabolite concentrations in subcutaneous RIF-1 tumors during untreated growth and following treatment with 5-fluorouracil. The equivalence of these two hydrogen isotopes as intensity standards and the validity of their use in the determination of absolute metabolite concentrations in vivo by NMR has been demonstrated. On matched in vivo and extract tumor samples (n = 5), excellent agreement has been obtained between nucleoside triphosphate concentrations determined by NMR and those derived by HPLC analysis for the control tumors. Following 3 days of untreated growth, absolute concentrations of phosphate metabolites in RIF-1 tumors (n = 10) decreased significantly, except for the Pi concentration which did not vary. For the treated tumors (n = 10) there were no changes in metabolite concentrations except for a decrease in the PCr and, possibly, Pi concentrations. The PCr/Pi ratio in the latter tumors did not change. These observations suggest that changes in absolute metabolite concentrations may be more sensitive indices of response to therapy than changes in metabolite peak amplitude ratios, a parameter commonly used to express in vivo NMR data.

Animals↗
PubMed1992

Energy metabolism, pH changes, and lactate production in RIF-1 tumors following intratumoral injection of glucose.

The metabolic consequences of increased glucose availability were examined in subcutaneous RIF-1 tumors in vivo, using 13C and 31P NMR spectroscopy. Significant increases in the levels of nucleotide triphosphates and phosphocreatine relative to low energy phosphates and in tumor pH were observed within 30 min following injection of 1 g/kg of glucose directly into the tumor. These changes did not occur following an equivalent intratumoral dose of the non-metabolizable sugar alcohol, mannitol. When [1-13C]-glucose was administered, [3-13C]-lactate and [3-13C]-alanine were the only labeled metabolites detected in the in vivo 13C NMR spectra during the period of bioenergetic improvement. Biochemical analysis revealed a substantial increase in tumor and plasma glucose concentration, but no increase in either tumor or plasma lactate, consistent with the absence of acidosis. Evaluation of the distribution of glucose in the tumor by quantitative autoradiography of [1-14C]-2-deoxyglucose administered with the glucose indicated that, on average, 7 mM of the added glucose distributed over the entire tumor within 10 min. The significant improvement in overall metabolic status of the tumors following glucose administration is attributed to the existence of substrate limited regions within the tumor.

Animals↗
PubMed1990

The combined measurement of blood flow and metabolism in RIF-1 tumours in vivo. A study using H2 flow and 31P NMR spectroscopy.

Blood flow and phosphorus metabolites have been measured simultaneously in the murine RIF-1 tumour in vivo. Blood flow was measured using the H2 washout technique and 31P NMR spectroscopy was used to measure high energy phosphates, inorganic phosphate and intracellular pH within the tumour. Following NMR and flow measurements, hydralazine was administered and the measurements repeated. There was always a decrease in blood flow, and a fall in nucleoside triphosphate detected by NMR, after administration of hydralazine. At blood flows in excess of 15 mL 100 g-1 min-1, the nucleoside triphosphate/inorganic phosphate ratio was 1.0 or greater, whereas at flows in the range of 5-12 mL 100 g-1 min-1 the ratio fell to below 0.5, and at flows below 5 mL 100 g-1 min-1 there was no detectable resonance from nucleoside triphosphate.

Animals↗
PubMed1990

Metabolic heterogeneity in RIF-1 tumours detected in vivo by 31P NMR spectroscopy.

The spatial distribution of phosphate metabolites and pH within subcutaneously implanted RIF-1 tumours was determined by 1-dimensional phosphorus chemical shift imaging. 31P spectra from two to three 4 mm thick cross-sectional slices were obtained for each tumour. Quantitative morphometry was used to estimate the amount of necrosis within those slices. A spatially heterogeneous distribution of phosphate metabolites and pH was detected in most of the tumours. Levels of necrosis ranged from 0-24% for the tumours in this study. There was no significant correlation between the extent of necrosis over this range and levels of metabolites or pH, suggesting that factors besides necrosis can contribute to spectral heterogeneity.

Animals↗