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J R Griffiths

Publications and source records attributed to J R Griffiths.

At least 109 records · Page 6Linked to original sources
PubMed1992

An investigation of tumor 1H nuclear magnetic resonance spectra by the application of chemometric techniques.

1H nuclear magnetic resonance (NMR) spectra of tumors and normal tissue include signals from all hydrogen-containing metabolites and can therefore be considered multicomponent multivariate mixtures. We have obtained 1H spectra from perchloric acid extracts of three normal tissues (liver, kidney, and spleen) and five rat tumors (GH3 prolactinoma, Morris hepatomas 7777 and 9618a, LBDS1 fibrosarcoma, and Walker 256 carcinosarcoma). We have applied several different chemometric methods to analyze the data. First, we used principal component analysis, cluster analysis, and an optimized artificial neural network to develop a classification rule from a training set of samples of known origin or class. The classification rule was then assessed using a set of unknown samples. We were able to successfully determine the class of each unknown sample. Second, we used the chemometric techniques of factor analysis followed by target testing to investigate the underlying biochemical differences that are detected between the classes of samples.

Adenocarcinoma↗
PubMed1992

Magnetic resonance neurography.

We have made cross-sectional image "neurograms" in which peripheral nerve has a greater signal intensity than that of other tissue. Neurographic images of the rabbit forelimb were obtained using a spin-echo magnetic resonance imaging (MRI) technique that combines fat suppression and diffusion weighting. After fat suppression the nerve shows up in relative isolation and is brighter than the surrounding tissue due to its longer T2 relaxation time of approximately 50 ms compared to approximately 27 ms for muscle. The addition of pulsed gradients for diffusion weighting of the MR signal further enhances the intensity of the nerve signal relative to that of surrounding muscle tissue. The greater diffusional anisotropy of nerve tissue (D parallel/D perpendicular = 3.1) compared to that of muscle (D parallel/D perpendicular = 1.9) allows further enhancement of the nerve by a subtraction of two diffusion-weighted images, one with the gradients oriented parallel and one with the gradients oriented perpendicular to the nerve orientation. We show that by manipulation of the MRI parameters, either echo time or pulsed gradient strength, the nerves can be made to show up as the most intense feature. This verifies the feasibility of generating three-dimensional "neurographic" images, analogous to angiograms, but which demonstrate the peripheral nerve tracts in apparent isolation.

Adipose Tissue↗
PubMed1992

A two-compartment phosphate-doped gel phantom for localized spectroscopy.

Acrylamide gel loaded with phosphate has been used in two compartment phantoms designed to assess localized spectroscopy techniques. A chemical shift difference of 2.3 ppm was produced by changing the pH from 6 to 8.9. The 31P relaxation times were modified by doping the gels with paramagnetic ions. For a T1 of approximately 1 sec nickel doping gave a T2 of approximately 110 msec and manganese doping gave a T2 of approximately 8 msec. Gel phantoms are more robust than their liquid equivalent and are not prone to leakage. The construction of small compartments with very thin walls is possible, making this type of phantom suitable for small bore imaging/spectroscopy systems.

Acrylic Resins↗
PubMed1992

Enhanced 5-fluorouracil cytotoxicity and elevated 5-fluoronucleotides in the rat Walker carcinosarcoma following methotrexate pre-treatment: a 19F-MRS study in vivo.

5-fluorouracil (5FU) is activated intracellularly to cytotoxic 5-fluoronucleotides (FNuct). These were detected non-invasively in rats bearing the Walker carcinosarcoma by 19F-magnetic resonance spectroscopy (MRS) following an i.v. bolus dose of 5FU (50 mg kg-1). Pre-treatment of the rats (3 to 24 h earlier) by methotrexate (MTX) (20 or 50 mg kg-1) did not affect the rate of 5FU disappearance but did significantly increase the rate of FNuct formation (P less than 0.002) and the final amount formed (P less than 0.02) as assessed by MRS in vivo. MTX (20 mg kg-1) caused substantially the same effects on FNuct formation (P less than 0.002 for rate and P less than 0.05 for the amount) when 5FU was administered i.p. although higher doses of 5FU (120 mg kg-1) were necessary to observe the 19F-signals. Quantitative analysis by MRS in vitro of extracts from the freeze-clamped tumours treated by 5FU i.v. confirmed that MTX pre-treatment increased FNuct formation 3-fold (P less than 0.05). Hplc quantitative analysis demonstrated that 50% of the FNuct was the cytotoxic nucleotide FUTP which was also increased 3-fold in MTX treated animals (P less than 0.05). Since the Walker tumour is probably sensitive to 5FU action via FUTP incorporation into RNA, these results suggested that drug regimes in which MTX preceded 5FU (MTX-5FU schedule) would be more cytotoxic that 5FU alone. At an MTX dose of 20 mg kg-1 24 h prior to 5FU there was significant inhibition of growth (P less than 0.05) compared to no treatment, MTX alone or the reverse schedule of 5FU-MTX. These results suggest MRS may be of clinical value in optimising chemotherapy using schedules where MTX precedes 5FU.

Animals↗
PubMed1992

Proceedings of a National Cancer Institute workshop: MR spectroscopy and tumor cell biology.

In December 1991, the National Cancer Institute held a workshop to evaluate the role of magnetic resonance (MR) spectroscopy in human cancer biology. The clinical and basic cancer research issues requiring use of MR spectroscopy, the advantages and limitations of MR spectroscopy, and future directions in MR spectroscopy of cancer were discussed. Consensus-building panels were formed on the following four topics: cell membrane biochemistry, tumor therapeutic response or drug resistance, appropriate model systems, and potential clinical applications of MR spectroscopy. The workshop members concluded that large prospective clinical studies as well as in vivo animal and human studies to define prognostic variables should be performed, with correlation between MR spectroscopic results and biochemical and physiologic features. Studies of phospholipid metabolism, the pharmacokinetics of anticancer agents, and effects of new cancer treatments on the tumor vasculature and normal tissues are needed.

Humans↗
PubMed1991

19F nuclear magnetic resonance imaging of drug distribution in vivo: the disposition of an antifolate anticancer drug in mice.

The application of 19F nuclear magnetic resonance imaging to the study of drug distribution in vivo is discussed. CB3988 (C2-desamino-C2-methyl-N10-propargyl-2'-trifluoromethyl-5,8-dideazafolic acid) is a fluorinated representative of a class of quinazoline antifolates which act as inhibitors of thymidylate synthase and which are being evaluated for the treatment of human cancer. 19F images were obtained in vivo from the abdomen of mice following intravenous injection of CB3988 (500 mg/kg). Time resolutions of 4 and 20 min were achieved for two- and three-dimensional imaging, respectively. These images were consistent with the presence of high concentrations of drug (up to 26 mg/ml) in the gall bladder, urinary bladder, and small intestine, as confirmed ex vivo by extraction and HPLC analysis. The results indicate the potential value of 19F NMR imaging in pharmacokinetic studies.

Animals↗
PubMed1991

Detection of differential sensitivity to 5-fluorouracil in Ehrlich ascites tumour cells by 19F NMR spectroscopy.

Quantitative analysis of extracts from two Ehrlich ascites tumour cell lines (Lettre cells) by 19F NMR in vitro demonstrated that one Lettre cell line (designated LLM) metabolized 30-50% less 5-fluorouracil to 5-fluoronucleotides when compared to the other cell line (designated LHM). HPLC analysis of these cellular extracts showed a significant decrease in the concentration of the cytotoxic nucleotide 5-fluorouridine triphosphate in LLM cells compared to LHM cells. No major differences could be observed in the 31P and 1H NMR spectra of the two cell lines. Growth inhibition studies in vitro demonstrated that LLM cells were less sensitive to 5-fluorouracil than LHM cells. These results are consistent with the hypothesis that 19F NMR visible levels of 5-fluoronucleotides can predict the cytotoxicity of the anti-cancer drug 5-fluorouracil.

Adenosine Diphosphate↗
PubMed1991

Differences in vascular response between primary and transplanted tumours.

The vast majority of studies on tumour vasculature are performed on transplanted tumours in rodents. However, it is known that there may be differences between primary and transplanted lesions. The purpose of this study is to test whether a specific vascular response is similar in primary tumours and in transplanted tumours derived from them. The technique used was to give an intraperitoneal injection of 5 mg kg-1 hydralazine, which is known to result in hypoxia in transplanted tumours. Changes in perfusion were indicated by changes in metabolism, monitored using 31P Magnetic Resonance Spectroscopy. The primary tumours were induced by local irradiation many months previously and only 4/11 (36%) of these responded to hydralazine. One of the non responders was subsequently transplanted into isogeneic mice to produce a tumour line which was histologically very similar to the primary. Of these 16/17 (94%) responded. The difference is statistically significant (P = 0.001). The reasons for this difference are not known. A number of possibilities are discussed and in the authors' opinion, the most likely cause is that it results from an artefact of transplantation.

Animals↗
PubMed1991

Monitoring therapeutic response to tamoxifen in NMU-induced rat mammary tumours by 31P MRS.

Tamoxifen injections were given once a week for 4 weeks to 19 rats bearing N-methyl-N-nitrosourea (NMU)-induced mammary carcinomas. NMR spectra were collected on days 2, 7, 14, 21 and 28. Only 42% of the tumours responded to the tamoxifen in that they regressed significantly; another 21% did not change in size and 37% grew significantly. In the ones that did subsequently regress there were significant changes in the NTP/Pi ratio as early as 2 days after treatment, before any detectable change in volume was recorded, and continuing up to 21 days. The significance of these findings and the possible mechanisms underlying the changes are discussed.

Animals↗
PubMed1991

The potential for prazosin and calcitonin gene-related peptide (CGRP) in causing hypoxia in tumours.

Using 31P NMR spectroscopy, changes in tumour metabolic status were studied in a transplanted rat fibrosarcoma following the administration of vasodilators. Mean Arterial Blood Pressure (MABP) was monitored simultaneously. Two vasodilators were studied, prazosin and CGRP, which altered the NMR parameters Pi/sigma P, beta NTP,Pi, PCr/Pi and PME/Pi in a dose dependent manner. There was a good correlation between the various NMR parameters; for analysis, Pi/sigma P was used for convenience. With increasing doses of vasodilator, Pi/sigma P increased and the MABP decreased. Reduction in pHNMR showed a correlation with decreasing MABP following the administration of prazosin but not after CGRP. Both prazosin and CGRP produced changes in 31P NMR spectra consistent with a reduction in tumour blood flow. The results for prazosin and CGRP were comparable and showed a 15-20% increase in Pi/sigma P for a 20% reduction in MABP. These results were compared with those from hydralazine. With hydralazine an acceptable reduction in blood pressure (up to approximately 25%) has little effect and may even alter NMR parameters consistent with an increase in blood flow, a reduction of approximately 40% is required for a significant decrease in flow. Both prazosin and CGRP are shown to be far more effective than hydralazine in causing tumour hypoxia at a clinically acceptable reduction in blood pressure. CGRP may be the more suitable for clinical use because of its short half life, its capability to achieve controlled hypotension and the relatively few side effects associated with its use.

Animals↗
PubMed1990

In vivo 19F NMR spectroscopy of the antimetabolite 5-fluorouracil and its analogues. An assessment of drug metabolism.

The metabolism of 5-fluorouracil (5FU) and its analogues 2'-deoxy-5-fluorouridine (2'FdURD), 5'-deoxy-5-fluorouridine (5'FdURD) and R,S-1-(tetrahydro-2-furyl)-5-fluorouracil (Ftorafur) has been studied by 19F NMR in rat liver and the rat S. G. Prolactinoma. In experiments using i.v. bolus injections of 0.46 mmol/kg 5FU was cleared more rapidly from the liver than 5'FdURD (t1/2 of 4.7 +/- 0.6 vs 15.8 +/- 0.8 min, P less than 0.001). Alphafluoro-beta-alanine (FBALA) production was almost identical after 5FU or 2'FdURD but slower and more sustained after 5'FdURD and still slower after Ftorafur. Both 5FU and 2'FdURD caused formation of toxic fluoronucleotides in S.G. Prolactinomas when administered i.v. (0.92 mmol/kg bolus). After i.v. infusion (0.23 mmol/kg/hr for 4 hr) 5FU produced fluoronucleotides whereas 2'FdURD did not; however, both 5FU and 2'FdURD (0.19 mmol/kg daily i.p. for 7 days) suppressed tumour growth. FBALA was observed in tumors following 5FU and 2'FdURD. Infusion of FBALA itself (0.17 mmol/kg/hr for 4 hr i.v.) led to signal in the tumour, so this compound could have been formed in the liver. These data demonstrate that 19F NMR can monitor drug metabolism in vivo.

Animals↗
PubMed1990

Monitoring tumor growth and regression by 31P magnetic resonance spectroscopy.

Magnetic resonance spectroscopy (MRS) uniquely provides noninvasive access to chemistry in vivo. 31P MRS can be used to monitor the high energy phosphates--phosphocreatine (PCr) and ATP, and their breakdown product--Pi, in situ in animals or patients. In several experimental tumor lines in animals it has been shown that the PCr/ATP and other related ratios steadily decline as the tumor increases in size, and that this effect is reversed when the tumor is treated with a therapeutic modality to which it responds. Acid extracts of freeze-clamped tumors at different stages of growth have confirmed these MRS observations and give additional information on related compounds such as creatine and ADP. Results show that, in the tumors studied, at least 80% of the ADP and about 40% of the Pi are bound and not in solution in the cytosol. Histological sections have indicated that the MRS response to endocrine therapy, in an NMU-induced estrogen-sensitive mammary tumor model, precedes any histological changes or any measurable regression. If these findings can be translated into a clinical setting, this may mean that MRS can be used in the clinic as an early predictor of tumor responsiveness to treatment. In untreated tumor growth, the cause of the decrease in PCr and ATP relative to Pi is probably due to the tumors outgrowing their blood supply and the cells becoming increasingly hypoxic. The PCr is lost more rapidly than ATP, indicating that the equilibrium in the creatine kinase reaction is maintained in these tumors. When the tumor is treated, cellular growth ceases and the requirement for oxygen and other nutrients is greatly reduced. This would allow the cellular energy reserves to be repleted and thus lead to the paradoxical improvement in the high energy phosphate status of a tumor that is about to regress.

Adenine Nucleotides↗
PubMed1990

The energy metabolism of RIF-1 tumours following hydralazine.

Phosphorus-31 Magnetic Resonance Spectroscopy (MRS) was used to observe the effect of two doses of the vasodilator hydralazine on the energy status of RIF-1 tumours. An intravenous dose of 5 mg/kg hydralazine reduced the high energy phosphate metabolites PCr and ATP, lowered pHMRS and raised the levels of inorganic phosphate of tumours within 20 min of administering the drug. The levels of high energy metabolites continued to decrease for at least 24 h. Normal muscle spectra obtained up to 1 h after drug administration remained unchanged. An intravenous dose of 0.5 mg/kg hydralazine also reduced NTP/Pi and PCr/Pi levels of tumours up to at least 5 h after drug administration, but the effect was smaller than for the higher dose. Blood flow measurements and measurements of systemic blood pressure demonstrated that 5 mg/kg of hydralazine produced a reduction in both systemic blood pressure and tumour blood flow relative to most normal tissues investigated. It is concluded that the changes in the P-31 MRS spectra of tumours were due to a reduction in tumour vascular perfusion following administration of hydralazine.

Animals↗
PubMed1990

Modification of the 31P magnetic resonance spectra of a rat tumour using vasodilators and its relationship to hypotension.

The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS1 fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment (an increase in inorganic phosphate, a reduction in nucleotide triphosphates and a reduction in pH) were consistent with nutrient deprivation. These changes were dose dependent. Changes in MABP and heart rate were consistent with vasodilatation in normal tissues. However, for the same fall in MABP, hydralazine produced a greater rise in tumour inorganic phosphate (Pi) and a greater fall in tumour pH than did prostacyclin. Controlled bleeding was effective in reducing MABP. It also reduced tumour pH but had no significant effect on tumour Pi. The clinical application of the two drugs for reducing tumour blood flow and pH for therapy is likely to be limited by the large degree of hypotension necessary to produce an effect. The differential effect of the two drugs for the same fall in MABP may be related to different degrees of direct tumour vasodilatation or to a direct effect of hydralazine on tumour energy metabolism. The observation that controlled bleeding does not change tumour Pi is further evidence indicating that the degree of arterial hypotension is not the sole factor in determining tumour energy status.

Animals↗
PubMed1990

Pharmacokinetic studies with the antifolate C2-desamino-C2-methyl-N10-propargyl-2'-trifluoromethyl-5,8-dideazafolic acid (CB3988) in mice and rats using in vivo 19F-NMR spectroscopy.

In vivo 19F-NMR spectroscopy has been used to study the pharmacokinetics of the experimental antifolate drug CB3988 (C2-desamino-C2-methyl-N10-propargyl-2'trifluoromethyl-5,8-dideazafolic acid) in mice and rats. NMR results have been compared to those obtained by HPLC and the effect of the inclusion of the CF3 group evaluated by comparing the pharmacokinetics of CB3988 and ICI 198583 (C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid) in rats. In mice, following the administration of CB3988 (500 mg kg-1 i.v.), drug could be detected in both the upper and the lower abdomen. NMR signal from the upper abdomen reached maximum intensity 10-40 min after administration, declining thereafter with a half life of 28 min. Signal detected in the lower abdomen reached maximum intensity 60-90 min after treatment. HPLC analyses indicated that CB3988 was present at appreciable concentrations (about 20-30 mg ml-1) in both bile and urine which is consistent with the signal from the upper and lower abdomen being derived from the gall bladder and urinary bladder, respectively. Studies in rats also indicated that CB3988 (100 mg kg-1 i.v.) rapidly entered and was cleared from the upper abdomen. Comparison of data from rats with intact and cannulated bile ducts suggested that 19F-NMR could detect CB3988 undergoing enterohepatic circulation. Furthermore, comparison of the plasma half life of CB3988 with the half life for the decline of the NMR signal from the upper abdomen suggested that NMR measurements may reflect the plasma clearance of CB3988. When the pharmacokinetics of CB3988 and ICI 198583 were compared the only significant difference was in the alpha phase half life which was 2-fold faster for CB3988. These data demonstrate that CB3988 is cleared rapidly by both biliary and urinary excretion. This is in contrast to N10-propargyl-5,8-dideazafolic acid, where delayed excretion is associated with hepatic and renal toxicities. The ability to study CB3988 pharmacokinetics non-invasively by 19F-NMR spectroscopy confirms the utility of the technique and, since 19F-NMR can be applied directly to clinical investigations, it may be possible to obtain similar information in humans.

Animals↗
PubMed1990

31P-NMR spectroscopy and histological studies of the response of rat mammary tumours to endocrine therapy.

We have shown by 31P-NMR spectroscopy that ovariectomy, in N-methyl-N-nitrosourea induced mammary adenocarcinomas, increases signals from phosphocreatine (PCr) relative to nucleoside triphosphate (NTP) before measurable regression (2 days) and for at least a further 13 days. The present study correlates the NMR changes with histological changes in the regressing tumour. Mammary tumours were examined by NMR before, and 2 and 14 days after, ovariectomy or sham-ovariectomy. Sections were taken from five tumours at each time point after operation for histology and for immunocytochemical staining of myoepithelial cells, luminal cells and basement membrane material. The histology showed typical cribriform papillary type mammary adenocarcinomas. The luminal cell population had a high mitotic activity and there was a prominent myoepithelial layer. At 2 days post-ovariectomy no significant change in mitotic activity was observed and no cytological characteristics attributable to ovariectomy could be seen. At 14 days postovariectomy the tumour was indistinguishable from a tubular adenoma, had significantly reduced mitotic activity, a relative increase in myoepithelial cells and basement membrane material. The changes detected by NMR must reflect early metabolic events, perhaps related to the histological changes observed at 14 days after ovariectomy. 31P-NMR spectroscopy may permit early monitoring of endocrine therapy for mammary cancer.

Adenocarcinoma↗