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J R Griffiths

Publications and source records attributed to J R Griffiths.

At least 127 records · Page 7Linked to original sources
PubMed1989

Potential artefacts from overlying tissues in 31P NMR spectra of subcutaneously implanted rat tumours.

31P spectra of rat tumours obtained with surface coils are shown to include skin signals of varying intensity. As reported previously by Stubbs, M., Rodrigues L. M., and Griffiths, J. R., (NMR in Biomedicine 1, 50-55, 1988) three hepatomas (rapidly growing Morris hepatoma 7777 and slow growing 9618A, and the UA hepatoma) had negligible phosphocreatine (PCr) or creatine (Cr) in acid extracts but frequently had PCr signals in surface coil spectra. Prolactinomas and mammary adenocarcinomas, which had significant PCr and Cr in extracts, showed higher PCr/NTP ratios in spectra taken in vivo than in extracts. A phantom for studying skin signals in vivo is described. A glass sphere of typical tumour size (3-4 mL) is implanted subcutaneously in the rat. Variations in skin signal with pulse duration are demonstrated with this phantom. The factors that could contribute to skin artefact in 31P tumour spectra include: (i) the relative concentrations of metabolites in skin and tumour; (ii) the skin thickness, which depends on the implantation site and rat size; (iii) skin invasion by the tumour; (iv) coil design (solenoid coils and Faraday shields are unlikely to eliminate this problem); (v) pulse repetition times; (vi) pulse duration and other NMR parameters. Careful attention to these factors could reduce skin artefacts.

Adenocarcinoma↗
PubMed1989

19F MRS studies of fluoropyrimidine chemotherapy. A review.

19F NMR spectroscopy (MRS) has been used to follow the metabolism of the fluoropyrimidine anticancer drug 5-fluorouracil and its derivatives non-invasively, both in animals and humans. This review is concerned with the information that has been acquired concerning cytotoxicity and detoxification in relation to studies performed with conventional methods. The potential uses of 19F MRS of fluoropyrimidines in research, particularly concerning combination chemotherapy, and in monitoring therapy, are discussed.

Animals↗
PubMed1989

Phosphorus-31 magnetic resonance spectroscopy and blood perfusion of the RIF-1 tumor following X-irradiation.

Phosphorus-31 magnetic resonance spectra were obtained from the RIF-1 tumor in C3H mice before and up to 2 days after various doses of X rays. Parallel studies were performed to measure relative changes in tumor blood perfusion using [14C]iodo-antipyrine and changes in % tumor necrosis using Chalkley's method. Tumor ratios of phosphocreatine to inorganic phosphate (PCr/Pi) and nucleotide triphosphates to inorganic phosphate (NTP/Pi) as well as pH as measured by 31P-MRS increased significantly at most time points after irradiation with doses of 5, 10, and 20 Gy. Tumor blood perfusion was found to significantly improve after a dose of 20 Gy but not after a dose of 2 Gy. Percent tumor necrosis increased to about 3 times its control level at 1 day after a dose of 20 Gy and then declined to about twice its control value at 2 days. The magnitude of the changes in the 31P-MRS parameters makes it unlikely that any of them are entirely due to radiation-induced changes in the radiobiologically hypoxic fraction of these tumors. Changes in the necrotic fraction did not appear to influence the tumor spectra. However, the observed improvement in tumor blood perfusion may have resulted in an increase in oxidative phosphorylation of the whole tumor population as well as a clearance of inorganic phosphate and acid metabolites, so that 31P-MRS changes may indirectly reflect changes in tumor blood perfusion.

Adenosine Triphosphate↗
PubMed1989

Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by 19F magnetic resonance spectroscopy in vivo.

We have evaluated two fluorinated misonidazole analogues, Ro 07-0741 and CCI-103F, as potential probes for the non-invasive identification of hypoxic tumor cells by 19F magnetic resonance spectroscopy (MRS) in vivo. The equipment used was a 1.9 T Oxford Research Systems TMR-32 spectrometer, fitted with a 15 mm diameter surface coil. Signal was readily detectable, with similar intensity from EMT6 tumor, liver, and brain at early times (1-2 hr) after i.v. injection in BALB/c mice, indicative of an initial uniform biodistribution of parent probes. At later times (5-10 hr) there was a progressive reduction in signal intensity from brain and liver, but tumor levels remained constant or declined more slowly. This is illustrated by tumor/brain ratios at 6-7 hr of 2.9 (Ro 07-0741) and 4.2 (CCI-103F). In 4/5 mice analyzed at 20-24 hr after Ro 07-0741, and 1/2 following CCI-103F, tumor signal remained detectable. This occurred in the absence of parent probe as measured by HPLC, suggesting the involvement of a product of nitroreductive bioactivation. Studies with KHT and RIF-1 tumors in C3H/He mice showed a similar trend but retention in RIF-1 was less dramatic, and this was consistent with the known hypoxic fractions and comparative in vivo nitroreductase activities. These promising results support the continuing development of 19F nitroimidazole probes for non-invasive identification of hypoxic cells in vivo.

Animals↗
PubMed1989

Prediction of 5-fluorouracil cytotoxicity towards the Walker carcinosarcoma using peak integrals of fluoronucleotides measured by MRS in vivo.

19F-magnetic resonance spectroscopy (MRS) can be used to non-invasively monitor metabolism of 5-fluorouracil (5FU) to cytotoxic fluoronucleotides (FNuct). We investigated whether the levels of FNuct formed from 5FU and observed in vivo by MRS in the Walker carcinosarcoma predicted cytotoxicity. Fifty mg kg-1 5FU caused tumour FNuct formation and, when repeated daily for 1 week, significant tumour growth inhibition (P less than 5%). Twenty-five mg kg-1 5FU produced less tumour FNuct (P less than 5%) and did not cause significant tumour regression. Tumour regression and tumour FNuct formation were also suppressed by 50 mg kg-1 5FU combined with a molar equivalent dose of allopurinol (P less than 2%). Tumour extracts were analysed by hplc and MRS confirming the observations in vivo and demonstrating that peak integrals in vivo were directly proportional to 5FU and FNuct concentrations. Hplc analysis of extracts showed that 50% of FNuct in tumours treated with 5FU was the cytotoxic nucleotide FUTP; this was lowered to 5% by a molar equivalent dose of allopurinol (P less than 2%). Twenty-five mg kg-1 5FU also produced significantly less FUTP (36%) than the 50 mg kg-1 dose (P less than 5%). These results suggest that MRS-detectable changes in tumour FNuct (mostly in FUTP) can be used to predict 5FU cytotoxicity.

Animals↗
PubMed1989

Growth studies of subcutaneous rat tumours: comparison of 31P-NMR spectroscopy, acid extracts and histology.

31P-NMP, surface coil spectra of three subcutaneously implanted rat tumours (Morris hepatoma 7777, GH3 prolactinoma, Walker carcinosarcoma) and an N-methyl-N-nitrosourea induced rat mammary adenocarcinoma at different stages of growth were obtained and compared with histological sections taken immediately after NMR acquisitions. Metabolite ratios (phosphocreatine (PCr)/beta nucleoside triphosphate (beta NTP), PCr/Pi, beta NTP/Pi) calculated from the NMR spectra were compared with ratios obtained from acid extracts of tumours of similar size. Measurements of creatine and ADP were also made. Three of the tumours showed positive correlations between increasing tumour size and decreasing metabolite ratios measured both by NMR and in extracts, whereas the Walker carcinosarcoma showed no correlation between size and any parameters measured. Phosphorus metabolite ratios, measured in extracts of skin overlying the tumours, indicated a fall in high energy phosphate when there was histological evidence of skin invasion by the tumour. Surface coil 31P-NMR spectra of subcutaneously grown or induced tumours in the rat represent a slowly changing steady state as the tumour increases in size. We conclude that increasing numbers of hypoxic tumour cells, rather than large areas of necrotic tissue, contribute largely to the NMR spectrum.

Adenocarcinoma↗
PubMed1988

Vasoactive intestinal peptide stimulates glycolysis in pituitary tumours; 1H-NMR detection of lactate in vivo.

1H- and 31P-NMR spectroscopy has been applied to rats carrying implanted tumours in vivo, and used to observe simultaneous changes in intracellular pH (pHi) and lactate concentration during the stimulatory action of vasoactive intestinal polypeptide (VIP). A maximal decrease in pHi to a mean of 0.29 units below basal values was recorded. At the same time, 11 min after VIP, a maximal increase in tumour lactate was found, with a mean value of 150% of the basal concentration. The magnitude of these changes was compatible with in vitro measurements of basal lactate concentration and buffering capacity made on the same tumour line. It is concluded that VIP stimulates glycolysis by the tumour cells, resulting in an accumulation of lactate and a consequent fall in pHi.

Adenoma↗
PubMed1988

31P-nuclear magnetic resonance spectroscopy studies of the response of rat mammary tumors to endocrine therapy.

We have used 31P-nuclear magnetic resonance spectroscopy to detect the metabolic changes that occur in estrogen-sensitive, N-methyl-N-nitrosourea-induced rat mammary tumors as they regress following ovariectomy. In untreated animals the spectra of the tumors showed a steady loss of high energy phosphates (phosphocreatine and nucleoside triphosphates) and an increase in inorganic phosphate. This was reversed after ovariectomy. Spectral changes occurred before detectable regression of the tumor. Estrogen-insensitive tumors, grown from implanted Rama 600 and 622 cells, did not regress in response to ovariectomy, and their high energy phosphates continued to fall; estrogen-sensitive tumors also failed to respond to sham ovariectomy. These effects are probably due to the reduction in cellular energy requirements that occurs when the hormonal stimulus to growth is removed. Because the nuclear magnetic resonance method is noninvasive, this technique should be applicable clinically as a means of predicting the response of a tumor to endocrine therapy.

Adenosine Triphosphate↗
PubMed1988

Phosphate metabolites in rat skin.

A model for studying the 31P NMR spectrum of rat skin without contribution from other tissue signals has been developed by creating a skin pedicle. 31P NMR spectra were obtained with a solenoidal coil, which was separated from the flank of the rat by a Faraday shield. Phosphomonoesters, inorganic phosphate (Pi) (1.63 +/- 0.12 mumols per g wet wt), phosphodiesters, phosphocreatine (PCr) (1.4 +/- 0.12 mumols per g wet wt) and ATP (1.35 +/- 0.22 mumols per g wet wt) were observed, superimposed on broader signals, probably due to phospholipids. Extracts of freeze-clamped pedicles contained concentrations of phosphorus metabolites similar to those seen by NMR. The exception was Pi which was twofold higher in the extract. The presence of the broader phospholipid contribution suggests that the signals did not arise solely from the panniculus carnosus muscle of rat skin, although this muscle was evident on histological examination of the pedicles. In extracts of normal rat skin levels of creatine, ATP, ADP and Pi were similar to those of pedicles, whereas PCr was about twofold higher. Signals from rat skin are likely to contribute to spectra of subcutaneous organs and tumours. Two kinds of rat hepatoma that contained no PCr frequently gave PCr signals from the overlying skin, whereas in three other subcutaneous tumours the contribution from skin was negligible.

Adenosine Diphosphate↗
PubMed1986

Activation of hepatic glycogen phosphorylase b in vivo by sodium sulphate in normal (Wistar) and phosphorylase b kinase-deficient (gsd/gsd) rats.

Sulphate ions have been known for some years to enhance the activity of hepatic glycogen phosphorylase b in vitro. Here we report that intravenous injections of 4.92 mmol of Na2SO4/kg body wt. to rats induced marked hepatic glycogenolysis in vivo, accompanied by polyuria, glycosuria and a mild hyperglycaemia. These effects were observed both in normal (Wistar) rats and in gsd/gsd rats that lacked hepatic phosphorylase kinase. In both rat strains the activity of glycogen phosphorylase in liver extracts was enhanced by pretreatment of the animals with Na2SO4, but in phosphorylase kinase-deficient livers the enhancement was solely in phosphorylase b activity, whereas both the a and b forms of the enzyme were activated in normal livers. Hepatic glycogenolysis was also induced by perfusing rat livers, both normal and gsd/gsd, with 25 mM-Na2SO4. Under these conditions both the rat strains showed only enhanced activities of glycogen phosphorylase b. This suggested that the increased activity of phosphorylase a in the extracts of normal livers after Na2SO4 administration in vivo was due to a hormonally mediated conversion of the b form into the a form. The activation of glycogen phosphorylase b was stable to dilution and appeared to be due to a long-lasting structural change in the enzyme or very tight binding of an activator.

Animals↗
PubMed1986

Energy metabolism in rat pituitary tumors during stimulation of prolactin by vasoactive intestinal polypeptide and thyrotropin-releasing hormone: a study with nuclear magnetic resonance spectroscopy.

The effect of the peptides TRH and vasoactive intestinal polypeptide (VIP) on phosphate-bound energy of GH3 tumor cells in vivo was investigated using the noninvasive technique of topical 31P-nuclear magnetic resonance spectroscopy. VIP (4.0 micrograms/100 g BW) caused a reduction in the high energy metabolite phosphocreatine and an increase in inorganic phosphate. In the same experiments (n = 9), VIP stimulated PRL secretion to a value of 146% +/- 13 of basal concentrations. The change in the inorganic phosphate-phosphocreatinine ratio had a positive correlation with the increase in PRL secretion (P less than 0.001), indicating a VIP-induced energy consumption for a process related to PRL secretion. In separate experiments, in vitro, it was confirmed that VIP increased energy consumption by demonstrating an increase in glycogenolysis by the pituitary tumor cells. TRH also increased PRL secretion to 145% +/- 23 of basal values but, in contrast, did not induce changes in energy metabolites detectable by nuclear magnetic resonance. It is concluded that VIP and TRH promote PRL release through different stages in the secretion process.

Adenine Nucleotides↗
PubMed1985

Phosphorylation status of liver by 31P-n.m.r. spectroscopy, and its implications for metabolic control. A comparison of 31P-n.m.r. spectroscopy (in vivo and in vitro) with chemical and enzymic determinations of ATP, ADP and Pi.

An investigation into the measurement of Pi and ADP in rat liver in vivo and in freeze-clamped extracts by 31P-n.m.r. spectroscopy was carried out. The concentration of Pi estimated in vivo is less than 25% [1 mM (mumol/ml of cell water)] of the value obtained from freeze-clamped liver (4 mM), whereas ADP in vivo is undetectable (1.4 mM in vitro). At 5 min after infusion of 750 mg of fructose/kg, the Pi content of liver extracts fell to 1.3 mM, whereas Pi is undetectable in vivo under these conditions [Griffiths, Stevens, Gadian, Iles & Porteous (1980) Biochem. Soc. Trans. 8, 641]. The results indicate that the lower Pi and ADP concentrations found in vivo may be due to compartmentation or binding rather than to degradation of labile organic phosphates during extraction. The results are discussed with reference to previous measurements of liver phosphates and investigations of compartmentation in the liver, as are some of the possible consequences for metabolic control in the liver of low ADP and Pi concentrations.

Adenosine Diphosphate↗
PubMed1985

31P-Nuclear magnetic resonance spectroscopy of rat pituitary tumours in vivo.

31P-Nuclear magnetic resonance (NMR) spectra were obtained in the living rat from 19 implanted prolactin-secreted pituitary tumours. Seven major peaks were found including those arising from the high energy phosphorus metabolites ATP and phosphocreatine. Intracellular pH of the tumours was measured and a relationship with prolactin secretion was observed, the highest plasma prolactin concentrations being associated with an intracellular pH greater than 7.18. Repeated NMR measurements in three tumours over periods of up to 21 days revealed progressive changes with age, shown by an increase in inorganic phosphate, a decrease in high energy phosphorus metabolites and a decrease in prolactin secretion. It is concluded that NMR spectroscopy provides a useful method of studying intracellular events which accompany hormone secretion in vivo.

Animals↗
PubMed1984

VIP enhances TRH-stimulated prolactin secretion of pituitary tumours. Studies with 31P NMR.

Intravenous thyrotrophin releasing hormone (TRH) caused a 6.5-fold increase in plasma prolactin (PRL) in rats carrying implanted pituitary tumours. Vasoactive intestinal polypeptide (VIP) had no effect, but TRH given after VIP raised TRH stimulated secretion 13-fold above basal. 31P NMR spectroscopy showed that VIP caused a decrease in high energy metabolites (depleted phosphocreatine, elevated inorganic phosphate and lowered intracellular pH). TRH alone caused a similar but smaller effect; given after VIP, it caused no detectable depletion. We suggest that the changes in high energy metabolite concentrations reflect increased cellular energy consumption consistent with a priming process (stage 1) in PRL secretion, followed by hormone release (stage 2). VIP induces stage 1 whereas RTH induced both stages.

Animals↗