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PubMed2002

Effects of hyperglycemia on oxygenation, radiosensitivity and bioenergetic status of subcutaneous RIF-1 tumors.

Since tissue oxygen tension is a balance between delivery and consumption of oxygen, considerable effort has been directed at increasing the former and/or decreasing the latter. Techniques to decrease the rate of cellular oxygen consumption (increasing the distance oxygen can diffuse into tissues) include increasing glycolysis by administering supra-physiologic levels of glucose. We have examined the effect of hyperglycemia produced by intravenous glucose infusion on the tissue oxygenation and radiation response of subcutaneously implanted murine radiation induced fibrosarcomas (RIF-1). A 0.3 M glucose solution was delivered via tail vein injection according to a protocol that maintained glucose at a plasma concentration of 17+/-1 mM. The effect of this treatment on radiation response (clonogenic and growth delay studies), tumor oxygenation (needle electrode pO2 and 2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF5) binding), and tumor bioenergetics and pH (31P NMR spectroscopy) was examined. Systemic measurements included hematocrit and blood glucose and lactate concentrations. The results of these studies suggest that these subcutaneously implanted RIF-1 tumors are both radiobiologically and metabolically hypoxic and that intravenous glucose infusion is not an effective method of modifying this metabolic state.

Animals↗

PubMed2003

Treatment with the tumor necrosis factor-alpha-inducing drug 5,6-dimethylxanthenone-4-acetic acid enhances the antitumor activity of the photodynamic therapy of RIF-1 mouse tumors.

DMXAA (5,6-dimethylxanthenone-4-acetic acid) is an antivascular agent that exerts its antitumor effect at least partly through the induction of tumor necrosis factor (TNF)-alpha. Photodynamic therapy (PDT), the activation of a photoreactive drug in tumor tissue with visible light, is used clinically to control solid malignancies. PDT has been shown previously to be potentiated, in mice, by the i.p. administration of recombinant human TNF-alpha. Here, we investigated the activity of DMXAA as a modifier of Photofrin-based PDT of implanted murine RIF-1 tumors. The DMXAA dose (20 mg.kg(-1)) used throughout this study had little effect on tumor growth. The combination of DMXAA and PDT led to a reduction in tumor volume and significant delays in regrowth, giving a PDT-dose modification factor of 2.81. This enhancement was found to be strongly schedule dependent. The most pronounced responses were achieved when DMXAA was administered 1-3 h before the local illumination of the tumors; less activity was observed at other intervals within +/-24 h of PDT-light delivery. Using a 2-h DMXAA-light interval, histological examination showed significantly reduced blood vessel counts (CD31 immunostaining) and marked necrosis (H&E) in the tumors given combination therapy compared with the tumors given either agent alone. Conversely, peritumoral tissue was still intact 24 h after the combined therapy. DMXAA did not augment the damage to normal mouse feet after low-dose PDT (1.5 mg.kg(-1) Photofrin); however, there was some enhancement of normal tissue phototoxicity when DMXAA was combined with high-dose PDT. The antitumor effect after DMXAA plus low-dose PDT (1.5 mg.kg(-1) Photofrin) appeared to be dependent on TNF-alpha because neutralizing antibodies to this cytokine reduced the tumor response to control levels. DMXAA by itself induced TNF-alpha in RIF-1 tumors whereas PDT did not. However, the addition of PDT after DMXAA resulted in decreases in TNF-alpha, suggesting that the enhanced antitumor activity of the combination therapy was not attributable simply to an increased induction of the cytokine by PDT over that from DMXAA alone. These observations suggest a promising new combination therapy with considerable therapeutic advantage.

Animals↗

PubMed2003

Cyclophosphamide treatment modifies tumor oxygenation and glycolytic rates of RIF-1 tumors: 13C magnetic resonance spectroscopy, Eppendorf electrode, and redox scanning.

The effect of cyclophosphamide (Cp) on the glycolytic rate of radiation-induced fibrosarcomas (RIF-1) was measured in vivo in C3H mice by following the production of [3-(13)C]lactate after tail vein infusion of labeled [1-(13)C]glucose. Cp administered i.p. at a dose of 300 mg/kg caused a significant drop in glycolytic rate 24 h after treatment (P < 0.01). This drop was accompanied by an increase in [C-3]/[C-4] glutamate ratio in perchloric acid extracts of the tumors, indicating an increase in the Kreb's cycle activity. Treatment with Cp led to a significant decrease (P < 0.01) in tissue pO(2), measured in vivo with an oxygen Eppendorf electrode. Increases in NADH levels were also observed in rapidly frozen excised tumors examined by three-dimensional optical redox scanning. A significant decrease in tumor pO(2) and an increase in the NADH levels are suggestive of an increase in oxygen consumption by these tumors after Cp treatment. Overall, these data indicate that the reduction in glycolytic rate of Cp-treated RIF-1 tumors is due to an increase in aerobic metabolism.

Animals↗

PubMed2004

[Rifampicin use for potency stabilization in Rif(r) mutants of Streptomyces recifensis subsp. lyticus, an organism producing lytic enzymes].

Rif(r) mutants 1P-92 and 2P-15 were isolated as a result of selection of Streptomyces recifensis subsp. lyticus, an organism producing lytic enzymes. The effect of rifampicin on the biosynthetic potency of the mutants was studied. When added to the medium for cultivation of Rif(r) mutants 1P-92 and 2P-15 in the optimal concentrations (7.5 and 10.0 mcg/ml respectively), the antibiotic showed stabilizing effect on their potency in successive subcultures and recovered the initial potency of the old laboratory strains. Preliminary cultivation of strain 2P-15 after its storage for 6 years at a temperature of -20 degrees C made it possible to increase the efficiency of the initial potency recovery in the analytical selection.

Anti-Bacterial Agents↗

PubMed1989

Comparison between tumor pH and cell sensitivity to heat in RIF-1 tumors.

We have performed a direct comparison between tumor pH and cell survival in heated RIF-1 tumors growing intradermally in thighs of C3H mice. The pH of individual tumors was measured by inserting a microelectrode into the tumor center. After pH measurements, the tumor-bearing legs were heated in a water bath (44.6 degrees C, 30 min). We then excised a small piece of tumor tissue (20-30 mg) from the area where the tip of the microelectrode had been placed and cell survival was determined by in vitro cloning. In some animals, 3 or 5 g/kg of glucose were injected i.p. 1.5 h before heating, to decrease the tumor pH. The average pH before heating was 6.83, 6.68, and 6.51, respectively, for tumors in untreated animals, those given 3 g/kg glucose, or those given 5 g/kg glucose. After heating, the average surviving fractions were 9.91 x 10(-2), 4.72 x 10(-2), and 5.43 x 10(-3), respectively. The cell yield did not differ significantly among the three treatments. As the tumor pH decreased, the surviving fraction also decreased for each treatment group. The correlation coefficient between tumor pH and log surviving fraction was highly significant for heat plus 5 g/kg glucose and all the treatment groups. The slope of the regression line obtained by a least squares method was steepest for all the treatment groups, followed by the heat plus 5 g/kg glucose and heat plus 3 g/kg glucose groups. The smallest slope of the regression line was noted for tumors treated by heat alone. The study shows that the tumor sensitivity to heat is enhanced when the tumor pH is lower and that adaptation of cells to low pH conditions may play a role in determining the relationship between pH and cell kill in RIF-1 tumors.

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PubMed1986

Effect of DL-buthionine-S,R-sulfoximine on the growth of EMT6 and RIF mouse tumors.

The response of murine EMT6 and RIF tumors to DL-buthionine-S, R-sulfoximine (BSO), a glutathione (GSH) depletor, given either as a single dose, continuous oral administration, or in multiple doses, was determined with the use of a tumor-growth-delay assay. BSO consistently caused significant tumor growth delay in EMT6 tumors, which reached 5-7 days (two doubling times) after a single BSO dose (40 mumol/kg or 4 mmol/kg), 3 days (one doubling time) with continuous oral administration (20 mM), and 9 days (three doubling times) with daily BSO administrations (4 mmol/kg) starting at the time of tumor inoculation. Growth inhibition persisted after discontinuation of BSO treatment. Some complete tumor regressions were observed. Only slight tumor growth delay (one doubling time) was observed in RIF tumors at all treatment modes. No direct correlation was observed between tumor GSH content and the effects on tumor growth. In vitro BSO pretreatment (2 mM, 24 hr) of EMT6 tumor cells prior to tumor inoculation, which reduced cellular GSH levels to 34% of controls, did not influence subsequent tumor growth. Pretreatment of mice with BSO (4 mmol/kg, 1 daily sc injection for 7 days) prior to tumor inoculation led to a reduction of tumor takes by 25% when compared to 100% tumor takes in untreated mice. These data imply a BSO-induced change in the host response to tumor development.

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PubMed1980

A new mouse tumor model system (RIF-1) for comparison of end-point studies.

A new tumor model system (RIF-1) was developed that is very suitable for studies in which clonogenic survival is compared with growth delay and control probability following various forms of treatment. The tumor was a radiation-induced sarcoma in the inbred female C3H/Km mouse. It had a low median tumor dose, had a satisfactory plating efficiency direct from in vivo to in vitro, was nonimmunogenic or minimally immunogenic, and metastasized only at a relatively advanced stage of growth. The cell line grew either as a monolayer on plastic dishes, as tumor spheroids in spinner culture, as lung nodules following injection of a single-cell suspension into the tail veins of syngeneic mice, or as a solid tumor. Both diploid and tetraploid clonogenic cells were found in monolayer cultures of the RIF-1 line.

Animals↗

PubMed1998

On the correlation between the water diffusion coefficient and oxygen tension in RIF-1 tumors.

Water diffusion-coefficient mapping was used in conjunction with 19F inversion-recovery echo-planar imaging (IR-EPI) of a sequestered perfluorocarbon (PFC) emulsion to investigate the spatial correlation between the diffusion coefficient of water and the tissue oxygen tension (pO2) in radiation-induced fibrosarcoma (RIF-1) tumors (n = 11). The diffusion-time-dependent apparent diffusion coefficient, D(t), was determined by acquiring diffusion coefficient maps at 20 different diffusion times. Maps at four representative time points in different regions of the D(t) curve were selected for final analysis. An intravenously administered PFC emulsion, perfluoro-15-crown-5-ether, was used to generate the PO2 maps. D(t) and PO2 data were acquired with the animal breathing either air or carbogen (95% O2 - 5% CO2) to investigate the effects of increased tumor pO2 on D(t). The average increase in tumor pO2 was 22 torr when the breathing gas was changed from air to carbogen. Correlation plots generated from pixel data for D(t) (air breathing) vs D(t) (carbogen breathing) show little deviation from a slope of unity. Correlation plots of D(t) vs PO2 indicate that no correlation is present between these two parameters. This study also confirmed that necrotic tissue was best differentiated from viable tumor tissue based on D(t) maps at long diffusion times.

Animals↗

PubMed1984

Effects of sequencing of the total course of combined hyperthermia and radiation on the RIF-1 murine tumor.

The optimal sequence for clinical utilization of combined radiotherapy and hyperthermia is not known. The clinical trials have resulted in similar responses whether hyperthermia is given before or after radiation. Moreover, studies addressing the best sequence for an entire course of multifractionated hyperthermia and radiation are lacking. In these experiments, the importance of sequencing of heat and irradiation in a multifractionated treatment regimen in RIF-1 murine tumors was studied. It was observed that a close sequence of heat and irradiation is more beneficial than separate cytotoxic action. When heat and irradiation were given simultaneously, (within 1 hour) 67% to 75% of the tumors were cured. Heat and irradiation given sequentially (the entire course of one following the entire course of the other, each separated by 72 hours) cured 20% of the tumors. No tumors were cured when treated with heat or irradiation alone. The tumor regrowth time (mean tumor doubling time) is much longer in simultaneous treatment than in sequential treatment. It appears that heating first decreases the effectiveness of subsequent irradiation, causing a shorter growth delay than the opposite sequence. Heat alone does not alter the tumor bed permanently, but irradiation seems to do so, resulting in a slower rate of growth upon recurrence.

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PubMed2002

Photodynamic therapy with hypericin induces vascular damage and apoptosis in the RIF-1 mouse tumor model.

Hypericin, a polycyclic quinone obtained from plants of the genus Hypericum, has been proven to be a potent photosensitizer. The mechanism of tumor eradication and mode of cell death induced by in vivo photodynamic therapy (PDT) with hypericin were investigated in the present study using 2 therapeutic protocols. RIF-1 tumors were exposed to laser light at either 0.5 hr or 6 hr after hypericin administration (5 mg/kg, i.v.). A significant reduction in tumor perfusion, as determined by the retention of fluorescein in the tumor tissue, was detected immediately after both PDT treatments. Further decrease in tumor perfusion was observed in the hours after treatment. The re-establishment of tumor perfusion, however, occurred 24 hr after 6 hr-interval PDT, but not after 0.5 hr-interval PDT. The kinetics of tumor cell survival estimated by the in vivo/in vitro clonogenic assay revealed no or limited cell death when tumors were explanted immediately after irradiation, whereas a delayed but progressive cell death was detected when tumors remained in situ after both PDT treatments. The detection of nucleosomal DNA fragmentation by agarose gel electrophoresis or TUNEL assay and the assessment of cell morphology by light microscopy indicated that apoptosis was the most prominent tumor response to hypericin-mediated PDT. Furthermore, immunohistochemical analysis of the tumor tissue showed an increased expression of both Fas and Fas ligand after irradiation, suggesting that this cell death pathway might contribute to the overall PDT-induced apoptotic response. In conclusion, our results demonstrate that apoptosis, likely occurring as a result of vascular damage, is responsible for the tumor eradication by PDT with hypericin in this tumor model.

Animals↗

PubMed2001

Efficacy of antitumoral photodynamic therapy with hypericin: relationship between biodistribution and photodynamic effects in the RIF-1 mouse tumor model.

We investigated the hypericin-mediated PDT effects on the tumor and normal skin and in correlation with its biodistribution. These studies were carried out on C3H mice bearing RIF-1 tumors. The hypericin distribution and PDT effects were recorded at different intervals (0.5-24 hr) after intravenous injection of a 5-mg/kg dose of hypericin. After administration, rapid biphasic exponential decay was observed in the plasma drug concentration. It was found that hypericin was preferentially bound to the plasma lipoproteins. The tumor drug levels increased rapidly over the first few hours and reached a maximum around 6 hr after injection. In contrast, PDT efficacy was maximal when irradiation was performed at 0.5 hr after hypericin administration, which led to 100% cure. The PDT efficacy decreased rapidly as the administration-irradiation interval was prolonged. No tumor cure was obtained at the 6-hr interval, even though it was at this time that the tumor drug level peaked. Fluorescence microscopic studies showed that hypericin was mainly confined within the tumor vasculature at 0.5 hr after injection, whereupon it rapidly diffused to the surrounding tumor tissue. At 6 hr, a strong hypericin fluorescence was observed in the tumor tissue with only faint fluorescence within the vasculature, whereas at 24 hr the fluorescence in the tumor also decreased and became more diffused, and no fluorescence could be seen in the tumor vasculature. Like the tumor response, skin reactions were also found to be much more dramatic at short administration-irradiation intervals. Hypericin distribution and PDT response studies revealed a close correlation between the plasma drug level and the PDT effects, which suggests that vascular damage is the primary effect of hypericin-mediated PDT in this tumor model.

Animals↗

PubMed1992

Microprocessor-controlled Nd:YAG laser for hyperthermia induction in the RIF-1 tumor.

Near-infrared radiation from a Nd:YAG laser at 1,064 nm was used interstitially or superficially to induce hyperthermia in RIF-1 tumors in C3H male mice. A single 600-microns quartz fiber with a 0.5-cm cylindrical diffusor or a weakly diverging microlens at its distal end was used to deliver laser energy to tumors in the hind leg (mean volume = 100 mm3). Two thermocouples were inserted into each tumor. One thermocouple controlled a microprocessor-driven hyperthermia program (maximum output of 3.5 Watts) to maintain the desired temperature. Tumors were exposed to various temperature-time combinations (42-45 degrees C/30 min). Our initial results indicated that excellent temperature control to within 0.2 degrees C of the desired temperature at the feedback thermocouple was achievable during both superficial and interstitial heat treatments. Temperatures at the second thermocouple, however, were found to be lower by as much as 2.3 degrees C (using the cylindrical diffusor) or higher by up to 4.6 degrees C (using the microlens) when compared to the feedback thermocouple temperature. Several correlations were seen between total dose, tumor growth delay, percent skin necrosis, and temperature at the second thermocouple after several superficial and interstitial treatments. Statistically significant improvements in tumor growth delay (at 42 and 45 degrees C) and increased percent skin necrosis at all temperatures were observed after superficial versus interstitial treatment.

Aluminum Silicates↗

PubMed2003

High-resolution assessment of blood flow in murine RIF-1 tumors by monitoring uptake of H(2)(17)O with proton T(1rho)-weighted imaging.

Perfusion parameters, such as blood flow, are critical properties of tumors related to angiogenesis, drug delivery, radiosensitivity, bioenergetic status, and steady state levels of metabolites, such as lactate, that have been proposed as indices of tumor response to therapy. The existing MR methods for measuring tumor blood flow (TBF) have limitations related to sensitivity, spatial resolution, or dependence on other physiological properties such as vascular permeability. To address many of these difficulties, this study introduces the use of an (17)O-enriched tracer in conjunction with high-resolution, indirect MRI to measure TBF. To demonstrate the advantages of this technique, relative TBF was measured in subcutaneous RIF-1 tumors in C3H mice by monitoring the uptake of H(2) (17)O with a resolution of 0.16 x 0.31 x 3 mm in 13 sec. At this resolution, tumor heterogeneity with respect to blood flow is clearly visible. Measurement of the tracer arterial input function, which is necessary for determination of absolute blood flow, may be facilitated with improved temporal resolution.

Animals↗

PubMed2003

Comparison of the return-to-the-origin probability and the apparent diffusion coefficient of water as indicators of necrosis in RIF-1 tumors.

Two model-independent measures of diffusion, the apparent diffusion coefficient (ADC) and return-to-the-origin probability enhancement (R) were compared for their ability to detect tissue necrosis in RIF-1 murine tumors. Both reflect the degree of restriction experienced by the endogenous water molecules; however, the ADC is calculated from the initial linear slope of the diffusion attenuation curve, while R is calculated from data that includes the non-monoexponential part of the curve. In spectroscopic studies (n = 9), neither the ADC nor R showed a strong correlation with tumor volume. In imaging studies (n = 14), ADC, R, and T(2) were calculated on a pixel-by-pixel basis. There, the mean ADC and mean R for the entire imaging slice showed reasonable correlation with necrotic tumor fraction (r(2) = 0.679 and -0.665, respectively). The mean T(2) value yielded a poor correlation (r(2) = 0.436). Regions-of-interest were chosen from areas identified as either necrotic or viable and the resulting sets of ADC and R-values were subjected to discriminant analysis to determine the identification error rate. The error was greater for R than for the ADC (P < 0.001). Therefore, in this application, the use of the non-monoexponential part of the diffusion attenuation curve does not provide additional identification power.

Animals↗

PubMed1988

Multicompartment analysis of blood flow and tissue perfusion employing D2O as a freely diffusible tracer: a novel deuterium NMR technique demonstrated via application with murine RIF-1 tumors.

Deuterium NMR is employed in concert with multicompartment kinetic analysis for measurement of tissue blood flow and perfusion through a bolus administration of D2O as a freely diffusible tracer. The traditional single-compartment and two-compartment in-parallel flow models with no tracer recirculation are briefly discussed. The two-compartment in-series flow model with recirculation is developed to account for reflow of the stable (slowly excreted) deuterium tracer. With this model a monoexponential tracer washout curve is predicted. The rate of blood flow and tissue perfusion is readily extracted by three-parameter monoexponential analysis of the residue decay curve. A three-compartment model with recirculation, incorporating one compartment in-series with two compartments in-parallel, is developed for analysis of biexponential tracer washout curves. With this model the flow rates through the two in-parallel compartments (i.e., fast and slow) and the volume fractions of these two compartments are obtained by five-parameter biexponential analysis of the residue decay curve. Application of these multicompartment tracer-recirculation flow models is demonstrated with in situ determinations of murine RIF-1 tumor blood flow and tissue perfusion. The blood flow rates determined by deuterium NMR and analyzed by the multicompartment flow models agree well with those determined by others using radiolabels. A companion article (S.-G. Kim and J.J.H. Ackerman, Cancer Res. 48, 3449-3453, 1988) discusses in more depth the practical aspects of applying these multicompartment models to tumor blood flow measurement.

Animals↗

PubMed1990

Phosphorus metabolites and the distribution of cell cycle phase of RIF-1 tumors in response to 14 Gy irradiation.

Simultaneous measurements of DNA cell phase cycle distributions and in vivo 31P NMR spectroscopy were performed on 40 RIF-1 murine tumors irradiated with 14 Gy of X-radiation. Diploid and tetraploid tumor populations were observed. The cells blocked in G2/M phase were measured as a function of the ratios of tetraploid cell number in G2/M phase versus total cell population measured. The G2/M population reached a maximum at 32 h post irradiation, dropping to control values by 72 h, while the ratio of inorganic phosphate to beta-nucleotide triphosphate dropped significantly at 32 h and remained significantly lower than control up to 72 h post irradiation. Measurements of PME, PDE, PCr, and pH showed no significant variations at any time point. No significant change in host cell population could be observed. Since the measured G2/M population never increased to more than 3% of the total cell population, the change observed in the 31P NMR spectra were not simply the result of possible differences in NMR profiles of the different cell phase populations but were more likely due to a change in the metabolic characteristics or environment of a majority of the cells.

Animals↗

PubMed1991

Multinuclear MR investigation of the metabolic response of the murine RIF-1 tumor to 5-fluorouracil chemotherapy.

The metabolic response of the RIF-1 tumor to 5-fluorouracil (a single dose of 260 mg 5FU/kg, ip) was monitored in 10 mice using 19F and 31P MR spectroscopy. 19F MRS revealed a continuous drop in tumor 5FU level and an increase in the fluoronucleotide (Fnuc) signal to a plateau value of 50% of the initial 5FU level, during the first 2 h after chemotherapy. Although the 31P MR spectra of the tumors showed no significant initial changes, the total level of MR visible tumor phosphate decreased and tumor pH increased during the subsequent days. The changes in phosphate metabolism and tumor pH did not correlate with the detected fluorine levels or tumor response. However, the pretreatment Pi level, the plateau Fnuc level, and the 5FU induced decrease in tumor volume showed significant correlation. This indicates that both 19F and 31P MR spectroscopy have potential for predicting response to 5FU chemotherapy.

Animals↗

PubMed1991

In vivo 13CNMR spectroscopy of glucose metabolism of RIF-1 tumors.

An efficient method for measuring in vivo 13C NMR spectra of tumors has been developed and employed to monitor glucose metabolism in radiation-induced fibrosarcomas (RIF-1) subcutaneously implanted in C3H/HeN mice. [1-13C]Glucose was injected directly into the tumors at a dose of 1 g/kg body wt. Spectra were obtained with a Bruker AM 360-WB spectrometer (8.4 T/8.9 cm bore) employing a homebuilt probe equipped with a four-turn solenoidal coil (1.5 cm outer diameter) for detection of 13C signals and a Helmholtz coil (two 3-cm turns separated by a 3-cm gap, oriented orthogonally to the 13C coil) for 1H decoupling. In addition to the natural abundance 13C resonances of the tumors, signals were detected from the alpha- and beta-anomers of labeled glucose. Within 15 min following injection of labeled glucose [3-13C]lactate and [3-13C]alanine were detected. Lactate labeling approached steady state levels within about 50 min after glucose injection: in contrast, alanine labeling increased continuously over the duration of the experiment (70 min). Sixty minutes after glucose injection, the ratio of the intensity of [3-13C]lactate to the principal lipid methylene resonance (30 ppm from external tetramethylsilane), which served as an internal intensity reference, was correlated with tumor size, whereas the corresponding ratio of the [3-13C]alanine resonance was not. Labeling of glutamate was below the level of detection in the in vivo spectra; however, labeling of C4-glutamate at a level approximately 50-fold lower than the level of [3-13C]lactate was detected in perchloric acid extracts. Incorporation of 13C label into C2- and C3-glutamate and C2-lactate was also observed.

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