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J W Frazer

Publications and source records attributed to J W Frazer.

At least 19 recordsLinked to original sources
PubMed1999

Structure-activity relationships for a class of inhibitors of purine nucleoside phosphorylase.

Values of inhibition constants, Ki, for a family of structurally related, competitive inhibitors of calf spleen purine nucleoside phosphorylase (PNP) have been determined employing both inosine as substrate and a manual assay and 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG) as substrate and a robot-based enzyme kinetics facility. Several of the values determined robotically were confirmed employing the same substrate and a manual assay. Surprisingly, for many of the inhibitors examined, values of Ki determined with MESG as substrate are smaller than those obtained employing inosine as substrate by a factor that varies from less than 2 to 10. Values of concentrations required for 50% inhibition of PNP, IC50, have also been determined for the same family of inhibitors employing inosine as substrate. Values of IC50ino and those for Kiino and Kimesg for subsets of the inhibitors have been employed as training sets to create quantitative structure-activity relationships (QSAR) which have substantial power to predict values of IC50 and Ki for inhibitors outside the training set. These QSAR models should be useful in guiding future medicinal chemistry efforts designed to discover inhibitors of PNP having increased potency.

Animals↗
PubMed1989

Application of MR spectroscopy to the study of tumor biology.

Though MR spectroscopy has long been used to analyze the structure of organic compounds in solution, interest in applying it to the study of biologic systems has been slow in evolving because of past problems with spectral resolution in solids and gels. Renewed interest in this area has been stimulated both by the rapid growth of MR imaging as a clinical tool as well as by improvements in MR spectrometer design and use of sophisticated pulse sequences which have greatly improved the analysis of molecular composition. This review specifically focuses on the application of MR spectroscopy to studying the biology of malignant cells. The bulk of MR studies in this area to date have involved either 1H or 31P spectroscopy. Several investigators have now demonstrated that 1H spectra can be used to distinguish both animal and human tumors of differing metastatic properties. Preliminary data suggest that these spectral differences result in part from differences in cell surface glycoproteins and/or glycolipids between cells of low and high metastatic potential. Many of these molecules can absorb cell water potentially affecting T1 of cell water by their relative concentrations. Prolonged T2 relaxation times have been associated with some spectral peaks which distinguish cells of differing metastatic potential. The findings may partly explain why tumors have the prolonged T1 and T2 relaxation times seen in proton MR imaging. Other 1H MR spectroscopic studies suggest that there are detectable differences in plasma lipids in patients with a variety of malignancies compared to normal controls, suggesting possible utility as a screening test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Proton magnetic resonance spectral patterns of metastasizing and nonmetastasizing human colon cancers.

The spectral features of surgically staged metastasizing (ie, modified Duke's stages C and D) and nonmetastasizing (ie, modified Duke's stages A and B1-2) human colon cancers were studied using 60-MHz continuous wave and 200-MHz pulse Fourier transform proton magnetic resonance spectroscopy. Twenty-one human colon cancers (four nonmetastasizing and 17 metastasizing tumors) collectively contained 24 spectral peaks. A peak at 6.7 to 6.87 parts per million cycles (ppm) was found in three nonmetastasizing tumors but only one metastasizing tumor; the mean area at this peak location was significantly higher in the nonmetastasizing tumors. Mean peak areas at 1.4 to 1.47 ppm, 2.0 to 2.33 ppm, and 8.3 to 8.6 ppm were significantly higher in metastasizing tumors; however, these peaks were observed with only marginally greater frequency in metastasizing vs nonmetastasizing tumors: seven of 17 vs zero of four, 11 of 17 vs one of four, and eight of 17 vs zero of four tumors, respectively. This study suggests that magnetic resonance spectral features may aid in staging human colon cancers and could be used to enhance magnetic resonance imaging of these lesions.

Colonic Neoplasms↗
PubMed1987

Proton NMR examination of tumor cells of high or low metastatic potential.

Three rat 13762NF mammary adenocarcinoma clones and cell lines of different metastatic potentials (MTLn3, MTC, and MTPa) were studied for their proton nuclear magnetic resonance spectral characteristics as intact cells in vitro and after chloroform/methanol, neuraminidase, or ethanol treatments. The intact-cell spectral characteristics of the highly metastatic tumor cell clone MTLn3 were clearly distinguished from the less metastatic clone MTC or the parental MTPa cell line on the basis of spectral peaks in the range of 0.9 to 1.45 p.p.m. broad peaks near 2.0 p.p.m., and peaks in the range of 2.75 to 3.2 p.p.m. Glycoproteins are among the molecules known to have resonances in these upfield spectral regions, and these tumor cell subpopulations have previously been shown to possess characteristic quantitative differences in cell surface, metastasis-associated glycoproteins. Treatment of the cells with neuraminidase or ethanol, or extraction with chloroform/methanol increased spectral detail and also revealed characteristic differences in spectral peaks between the tumor cell subpopulations. The identity of the cellular components responsible for these spectral characteristics are unknown, but some clearly arise from differences in the extractable lipids present in the tumor cell subpopulations. Further study will be required to determine if the spectral differences described in this preliminary report are directly related to the known biochemical characteristics of the highly metastatic clone, and if the observations have general relevance to metastatic potential or are a singular feature of these cells. However, these initial results suggest that manipulation of factors which allow unmasking of spectral detail combined with the use of prescribed tumor cell subpopulations may aid in using proton NMR to identify and define biochemical or structural differences related to the metastatic potential of tumor cells.

Adenocarcinoma↗
PubMed1986

Mechanisms of synergism between arteriolar embolization and hyperthermia in a rabbit V-2 model of solitary hepatic metastasis.

In a V-2 model of solitary hepatic metastasis, residual tumor was histologically identified in the treatment field in only three of 14 (21%) animals subjected to microsphere embolization of tumor arterioles plus focal (43 degrees C, 40 min) hyperthermia compared with seven of ten (70%) subjected to focal (43 degrees C, 40 min) hyperthermia alone (P less than or equal to 0.05), five of seven (71%) (P less than or equal to 0.05) treated by occlusion plus sham heating, and five of five (100%) (P less than or equal to 0.01) sham-treated controls. Prior occlusion tended to reduce the radiofrequency power required for heat up and steady-state temperature maintenance of tumors (P less than or equal to 0.09 and P less than or equal to 0.06, respectively) and reduced the cooling rate after heating compared to unoccluded tumors (P less than or equal to 0.02) but did not affect mean time to temperature, maximum and minimum temperature measured at the tumor-normal tissue interface, and animal core temperature compared with that of the hyperthermia alone treatment group. In ten other animals with hepatic V-2 tumors of comparable size subjected to focal hyperthermia plus or minus arteriolar embolization, temperatures were continuously monitored at four additional intratumor sites in a fixed geometric orientation around the heating probe. No significant differences were noted in maximum and minimum temperatures in comparably oriented probes over a 40-min heating period between the hyperthermia and the occlusion-hyperthermia treatment groups. In five other animals with solitary V-2 hepatic implants, comparable microembolization plus or minus focal tumor heating to 43 degrees C, 40 min, did not significantly reduce tumor interstitial pH compared with pretreatment values. This study reproduces previously observed synergism between arteriolar embolization and hyperthermia but suggests the mechanism may be unrelated to observable differences in intratumor pH and thermal profile and may result from other mechanisms, perhaps by mimicking the angioocclusive effects of hyperthermia itself.

Animals↗
PubMed1985

Focal heating of V-2 tumors with a hybrid radiofrequency applicator.

A hybrid radiofrequency heating system previously reported to produce highly focused heating patterns at less than or equal to 10 cm depth in phantom models was utilized to selectively heat hypervascular, heat resistant rabbit V-2 tumors implanted in the left hindlimb. Spheroidal heating patterns 3 to 4 cm in diameter with minimal temperatures of 43 degrees C to 46 degrees C in two non-field perturbing probes at opposing edges of the tumor were consistently produced; however, temperature maxima 0.5 +/- 0.4 to 8.6 +/- 5.9 degrees C above minimum target temperatures of 43 degrees C and 46 degrees C, respectively, were observed. This led to both tumor regressions and adjacent normal tissue damage in some animals. These findings suggest this system may have application to selective heating of deep seated tumors, but that problems related to accurate thermal mapping and to intratumor temperature distribution must first be resolved.

Animals↗
PubMed1985

Differences in NMR spectra between tumor clones of defined metastatic potential.

NMR can discriminate between malignant and normal tissues. This study attempts to determine if NMR can discriminate between tumor clones of differing metastatic potential derived from the same parent tumor. Rat 13762NF mammary adenocarcinoma clones of either high (MTLn3), intermediate (MTC), or low (MTPa) metastatic potential were grown in roller-bottle tissue culture, harvested during exponential growth phase, centrifuged to form a 0.75-cm3 pellet, and analyzed in a Varian 360L spectrometer operating at 60.0 MHz. Dimethyl sulfoxide (10%) was used as an internal standard at 3.1 ppm downfield from tetramethyl silane (TMS). NMR spectra of replicate samples were analyzed and compared. The position of the water peak for MTLn3 (n = 7) was 5.14 +/- 0.0301 vs 5.07 +/- 0.0207 for MTC (n = 5) and 5.05 +/- 0.009 for MTPa (n = 5) (P less than or equal to 0.001). Integrated area of upfield peaks (where glycoproteins residues are expected to resonate) was 47.43 +/- 7.17 for MTLn3 (n = 6) and 40.95 +/- 5.48 for MTC (n = 4) vs 32.06 +/- 10.1 for MTPa (n = 5) (P less than or equal to 0.05). Previous work with these tumor clones suggests quantitative changes in surface glycoproteins are associated with differences in metastatic behavior. This study demonstrates differences in water peaks between cells of high, intermediate, and low metastatic potential and differences in the integrated area of upfield spectral peaks. How these observations relate to the biologic properties of the cells is uncertain. If they prove to have general validity, NMR could be used to profile biologic potential of human malignancies.

Adenocarcinoma↗
PubMed1985

Selective occlusion and focal hyperthermia therapy of V-2 tumors in the rabbit hindlimb.

Utilizing technology recently developed in our laboratory, hypervascular, heat-resistant V-2 tumors growing in the rabbit hindlimb were variously subjected to selective vascular occlusion by embolization with Dextran M microspheres and focal hyperthermia to minimum intratumor temperatures of 43 degrees C X 40 minutes (OH), focal 43 degrees C X 40 minutes hyperthermia alone (H), selective occlusion plus sham hyperthermia (O), and sham treatment. Regional toxicity observed consisted of skin burns and muscle fibrosis in the H and OH groups and peripheral embolization in the O alone group. Tumors subjected to a single OH treatment had significantly reduced growth rate over a 28-day period of observation compared with all other treatment groups and sham-treated controls (P less than or equal to .05). Our findings suggest that the combination of selective vascular embolization and focused hyperthermia may be useful in therapy of hypervascular, heat-resistant human tumors in anatomic locations where selective occlusion and relatively intense focal heating can be performed. The regional toxicity encountered in this model reemphasizes the need for extensive thermal mapping over the heated region.

Animals↗
PubMed1985

Dependence of magnetic resonance image (MRI) intensity values on relaxation times, pulse intervals and other signal attenuation factors.

Magnetic resonance image (MRI) pixel intensities were investigated using a phantom containing several uniform size chambers filled with solutions of known relaxation times, as well as head scans of patients and volunteers. Intensities were measured with a variety of pulse intervals typically used for imaging with spin echo, (SE) and inversion recovery (IR) sequences at 0.15 Tesla using the back projection (R-THETA) method, and at 0.27 Tesla using the 2-dimensional Fourier transform (2DFT) technique. The results were compared with the calculated dependence of MRI signal intensity on relaxation times and pulse interval parameters using the well known functions containing exponential forms. The experimental and the calculated pixel intensity time dependence did not always agree. We infer that factors other than the conventional functions for T1 and T2 signal decay are important. These factors may include the attenuation of the radiofrequency (RF) signals through inhomogenious lossy dielectric materials (e.g., tissues and organs), the location (coordinate) of the portion of the sample to be imaged relative to the RF coils, and the timing and amplitude of gradient pulses relative to the RF input and the detected signals. The flow velocity and diffusions are also important determinants of the signal from blood vessels and body fluids. We point out the necessity for further investigation toward more comprehensive understanding of MRI intensities.

Adenoma↗
PubMed1977

Microwave fixation of brain tissue as a neurochemical technique- a review.

Microwave devices have been developed for rapidly inactivating brain enzymes by focusing the power output into the heads of small laboratory animals. The rapid inactivation achieved prevents postmortem changes and permits the measurement of neurochemicals such as acetylcholine at concentrations close to those obtained in vivo. The technique promises the assay of neurochemical parameters not possible before.

5-Hydroxytryptophan↗
PubMed1976

Metal ion content of specific areas of the rat brain after 1600 MHz radiofrequency irradiation.

Rats were exposed to a hyperthermal environment or 1600 MHz radiation for 10 minutes to achieve equivalent rectal temperature increase (4 degrees C). Brain areas were quantitatively assayed for changes in magnesium, calcium, copper, zinc, iron, sodium, and potassium. Iron was increased in several brain regions of both hyperthermal and irradiated animals. Copper content of the cortex was also increased in both experimental groups, whereas zinc was decreased in the hypothalamus. Magnesium was increased in the cortex and medulla of the irradiated rats.

Animals↗