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At least 109 records · Page 6Linked to original sources
PubMed1991

Tumor bioenergetics and blood flow in RIF-1 murine tumors treated with 5-fluorouracil.

Treatment of RIF-1 solid tumors with 5-fluorouracil (5-FU, 100 or 200 mg/kg, ip) caused substantial regression of the tumors, with regrowth initiated on Day 6 (100 mg/kg) or Day 9 (200 mg/kg). Blood perfusion in the tumor, estimated by uptake of 86Rb+, was significantly increased after treatment with 5-FU, while Rb+ uptake in normal tissues (skin, muscle) was unaffected. The increase in tumor perfusion during the first few days following treatment was significantly greater in animals treated with the higher dose of 5-FU. Perfusion-dependent 86Rb+ uptake returned to control levels by the 9th day after treatment with 100 mg/kg of 5-FU, but remained elevated on Days 9-12 after the higher dose. By the 1st day following treatment with 5-FU, in vivo 31P NMR spectra of treated tumors indicated significantly higher ratios of phosphocreatine to Pi, higher pH, and lower ratios of Pi to nucleoside triphosphates compared to untreated age-matched controls. These changes persisted for 9 days following the lower 5-FU dose and for at least 12 days following the higher dose. Treatment with 5-FU induces profound, dose-dependent changes in tumor bioenergetics, which may result, at least in part, from changes in tumor perfusion after cytoreduction.

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↗
PubMed1995

The effects of isoflurane and halothane on blood flow and 31P NMR spectra in murine RIF-1 tumors.

The principal aim of these studies was to evaluate the utility of isoflurane and halothane for NMR investigations of tumor physiology. In vivo 31P and 2H NMR were used to examine RIF-1 tumors before, during, and (for 31P) after anesthesia. In tumors, halothane decreases blood flow, [PCR]:[NTP], and pH indicated by the Pi chemical shift (pHnmr), while it increases [Pi]:[NTP]; effects consistent with well-established cardiovascular effects of halothane. Isoflurane does not affect tumor blood flow or [PCr]:[NTP], but increases tumor [Pi]:[NTP] and decreases tumor pHnmr. In vivo 31P NMR measurements of normal mouse liver (upper abdomen) indicate that isoflurane has a similar effect in the liver. Although the mechanism for these effects is unknown, observation of a split Pi peak during isoflurane anesthesia suggests that a pool of Pi in a lower pH environment may become evident under isoflurane anesthesia. Regardless of the cause for increased [Pi]:[NTP] and decreased pHnmr, the utility of isoflurane anesthesia for 31P NMR studies of energy metabolism is limited.

Animals↗
PubMed1995

The apparent diffusion constant measured by MRI correlates with pO2 in a RIF-1 tumor.

As tissue oxygen tension (pO2) is an important variable in cancer therapy, it would be of major clinical benefit to be able to measure pO2 noninvasively. Current methods for determining pO2 in clinical settings are limited to superficial tumors. The authors measured the apparent diffusion constant (ADC) in an implanted murine fibrosarcoma (RIF-1) using magnetic resonance imaging and correlated the ADC with tissue pO2 measured by electron paramagnetic resonance oximetry. The ADC correlates significantly with tissue pO2 in this tumor (r = 0.89; n = 14) and so may provide a noninvasive index of pO2 in tumors.

Animals↗
PubMed1989

31P NMR spectroscopic and near infrared spectrophotometric studies of effects of anesthetics on in vivo RIF-1 tumors. Relationship to tumor radiosensitivity.

Mice with subcutaneous RIF-1 tumors were anesthetized with sodium pentobarbital (PB) or ketamine plus acepromazine (KA) before acquisition of in vivo 31P nuclear magnetic resonance (NMR) spectra from tumors. The area of the inorganic phosphate resonance was significantly greater (relative to phosphomonoesters or the alpha-phosphate resonance of nucleoside triphosphate) in spectra obtained under PB anesthesia, suggesting that the hypoxic fraction of the tumor increased following PB anesthesia. In vivo near-infrared laser spectroscopy directly demonstrated that tumor oxyhemoglobin was reduced by more than 20% following PB but was not significantly affected by KA. Total hemoglobin (tumor blood volume) was reduced by 11% following PB anesthesia, but was not significantly affected by KA. Tumor growth delay induced by gamma-irradiation was shorter when tumors were irradiated under PB anesthesia than when irradiated under KA, showing that PB anesthesia had a radioprotective effect. These studies demonstrate that both the 31P NMR and near infrared methods can detect metabolic or physiological changes associated with an increase in tumor radioresistance (i.e., an increase in the radiobiological hypoxic fraction).

Acepromazine↗
PubMed1990

Effect of photodynamic therapy on RIF-1 tumor metabolism and blood flow examined by 31P and 2H NMR spectroscopy.

Photodynamic therapy utilizes the tumor localizing drug dihematoporphyrin ether and red laser light to produce both direct tumor cell destruction via damage to mitochondrial membranes, and also indirect cell kill via destruction of the tumor vasculature. As a first step towards examining the mechanistic relationship between metabolic and vascular effects of photodynamic therapy, murine RIF-1 tumors were treated with a subcurative treatment (500 J/cm2). Tumor metabolic status was monitored using in vivo 31P NMR before, during and after the treatment. The tumor blood flow immediately before and after treatment was measured by direct intratumor injection of D2O saline and observation of the tracer signal clearance from the tumor via 2H NMR. During the photodynamic therapy treatment, significant decreases were observed for the nucleoside triphosphate concentrations, tumor pH and tumor blood flow, while inorganic phosphate concentrations increased. Animals treated with laser light alone and those not given any treatment, demonstrated no significant changes in tumor metabolic status, tumor pH or tumor blood flow. Further studies are required to determine whether tumor blood flow or metabolic status is affected first.

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↗
PubMedDate not supplied

Dynamic heterogeneity: experimental metastasis studies with RIF-1 fibrosarcoma.

We have examined the metastatic behaviour of cells from a series of clones of RIF-1 fibrosarcoma, a recently derived murine tumour. The clones were grown to different sizes (small: 10(5)-10(6) cells and large approximately 2 x 10(7) cells) and their metastatic potential was quantified using an experimental metastasis assay. There was significant variability between the metastatic potential of clones derived from the same population. Furthermore large clones had higher metastatic efficiency (metastases/cell injected) than the small clones derived from the same population. The results from these experiments indicate that metastatic variants are generated during the growth of the clones. The mean effective rate of generation of metastatic variants was estimated using Luria-Delbruck fluctuation analysis to be 1.7 x 10(-5)/cell/generation. The data described are consistent with a dynamic heterogeneity model of metastasis, in which the variant phenotypes are postulated to arise in growing tumour cell populations at a high rate but need not be stable in order to produce metastases. The results thus indicate that the model is applicable to a recently derived tumour as well as the extensively transplanted KHT sarcoma, B16 melanoma and OTF9 embryonal cell carcinoma.

Animals↗
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↗
PubMed1988

Interactions of BCNU, low pH, glucose and hyperthermia in cultured RIF cells.

The interactions of BCNU (1,3-bis[2-chloroethyl]-1-nitrosourea) with low pH, glucose and hyperthermia were studied in cultured RIF tumor cells. The effect of a mild heat treatment of 43 degrees C, 1 h at pH 7.4 on cell killing [surviving fraction (S) = 0.27 +/- 0.05, standard error of the mean (S.E.)] was significantly enhanced by pH 6.5 (S = 0.11 +/- 0.02, S.E.) and 50 mM D-glucose (S = 0.14 +/- 0.01, S.E.). When heat (43 degrees C, 1 h) was added to BCNU, cytotoxicity was increased approximately 14-fold over BCNU alone. Moreover, pH 6.5 increased killing with BCNU and heat by an additional factor of 28. The presence of glucose at 37 degrees C at either pH 6.5 or 7.4 reduced BCNU toxicity in a dose dependent fashion. However, the presence of glucose did not reduce cell killing by BCNU at 43 degrees C. As a result BCNU cytotoxicity was enhanced by approximately 2 orders of magnitude when tumor cell acidification (glucose and low pH) was combined with BCNU and heat.

Carmustine↗
PubMed1995

Accumulation of benzoporphyrin derivative in malignant and host cell populations of the murine RIF tumor.

The accumulation of benzoporphyrin derivative (BPD) in malignant and host cell populations of the mouse RIF tumor was studied by flow cytometry analysis of cells dissociated from the tumor tissue. The highest cellular BPD levels were found in a subpopulation of tumor associated macrophages (TAMs) characterized by a highly elevated expression of interleukin 2 receptor (F4/80+CD25++), but this selectivity was less pronounced than with photofrin. The BPD levels in tumor associated immune cells other than TAMs were lower than in malignant cells. No significant difference in cellular distribution of BPD was observed with the photosensitizer delivered in liposomes compared to the aqueous solution.

Animals↗
PubMedDate not supplied

Radiosensitization of the RIF-1 murine flank tumor by desmethylmisonidazole (Ro 05 9963) during interstitial brachytherapy.

We have investigated the interaction of the nitroimidazole radiosensitizer desmethylmisonidazole (Ro 05 9963) with interstitial radiation using a clonogenic cell assay as the endpoint. Removable I-125 sources were implanted at right angles to the outer surface of globular RIF-1 tumors grown in the flanks of C3H/He mice. Desmethylmisonidazole was administered by continuous intraperitoneal infusion at a rate of 2.7 mg/gm body weight /24 hr. Tumor and serum drug levels were measured by high performance liquid chromatography. Tumor drug levels of 40--100 mugm/gm tumor tissue were achieved consistently. No appreciable cytotoxicity was produced by desmethylmisonidazole alone, but a radiosensitization effect with a dose modifying factor of 1.6 was found.

Animals↗
PubMedDate not supplied

The effect of radiosensitizer pretreatment on the response of the RIF-1 mouse sarcoma to cytotoxic drugs.

We have studied the effect of misonidazole (MISO) or metronidazole (MET) pretreatment upon the response of the RIF-1 mouse tumor to cytotoxic drugs. The response to melphalan was unchanged and that to cyclophosphamide only marginally affected by pretreatment. For CCNU and chlorambucil, the dose modifying factors (DMFs) were 1.3 and 2.0 respectively for MISO and 1.0 and 1.4 respectively for MET. The acute LD50 of CCNU was reduced by MISO (DMF approximately 1.2) but depression of white blood cells was unchanged. For chlorambucil, modification of normal tissue response was similar to that seen in the tumor. Other radiosensitizers (Ro 07-1902, Benznidazole) were more effective than MISO in enhancing tumor response to chlorambucil. Compounds which do not contain nitro groups, and which are not electron-affinic, (imidazole, SKF 525A) can also produce the effect.

Animals↗
PubMed1984

Reoxygenation in the RIF-1 tumor.

The proportion of hypoxic cells in the RIF-1 tumor was examined for 13 days following a 15 Gy conditioning dose. The paired survival curve technique indicated that 100% of the surviving cells were hypoxic immediately following this treatment. However, within 1 hour, only about 50% remained hypoxic; this proportion continued to drop to about 10% but did not reach the pretreatment level of 1.1% for the duration of the study.

Animals↗
PubMed1985

The effect of treatment in fractionated schedules with the combination of X-irradiation and six cytotoxic drugs on the RIF-1 tumor and normal mouse skin.

RIF-1 tumors, implanted syngeneically in the gastrocnemius muscles of the right hind legs of C3H/Km mice, were treated either with X ray alone, drug alone, or drug and X ray combined. The drugs tested were bleomycin, BCNU, cis-diamminedichloro platinum, adriamycin, cyclophosphamide, and actinomycin-D. All drugs were administered either in the maximum tolerated dose or a dose that causes minimal tumor growth delay. Both drugs and X rays were administered either as a single dose or in five daily fractions. In addition to the single modality controls, seven different schedules of combined modalities were tested. Tumors were measured periodically after treatment in order that the day at which each tumor reached 4 times its initial cross-sectional area, i.e., its size at the time of treatment, could be determined. The effect of treatment on tumors was based upon excess growth delay (GD), i.e., T400% (treated)-T400% (untreated control). Treatment effects for the same combined modality schedules were also determined for normal skin, using the early skin reaction as an endpoint. Dose effect factors (DEF) were computed for all combined modality schedules and were based upon calculated radiation dose equivalents. We also calculated supra-additivity ratios, SRI and SRII, therapeutic gain factors and adjusted therapeutic gain factors. The only drugs to produce significant supra-additivity with X rays were cis-Pt and cyclo. Maximum supra-additivity for cis-Pt was afforded by divided doses of the drug (5 X 2.4 mg/kg/day) given immediately before X ray (5 X 1000 rad/day) on 5 consecutive days, although 3 other schedules also produced significant supra-additivity. Maximum supra-additivity for cyclo was seen for a single dose of 100 mg/kg followed 1 day later by a course of 5 daily X ray doses (5 X 1000 rad/day), and at least one other schedule produced almost as great an effect.

Animals↗
PubMed1986

The effects of purine nucleoside analogs on the response of the RIF-1 tumor to melphalan in vivo.

The effect of several purine nucleoside analogs on the cytotoxicity of melphalan (L-PAM) in the RIF-1 tumor in vivo was investigated. All the analogs tested--3'-deoxyguanosine (3'-dG), 3'-deoxyadenosine (3'-dA), and N6-butyryl-3'-deoxyadenosine (N6-BC)--at a dose of 100 mg/kg, enhanced the tumor cell killing by L-PAM as measured by an in vivo/in vitro procedure. This enhancement was maximal when the drugs were given simultaneously. The mean enhancement ratios (ER's) determined from the L-PAM dose response curves were 1.4 for 3'-dG, 1.3 for 3'-dA, and 1.4 for N6-BC. A similar modification of the L-PAM-induced depression of white blood cell counts was not obtained. A large single dose of L-PAM (8 mg/kg) produced a transient drop in mouse body temperature. The analog 3'-dG (100 mg/kg) increased and prolonged this hypothermic effect. In addition 3'-dG also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 28 minutes to 35 minutes. The enhancement of the efficacy of L-PAM by these analogs probably results from this pharmacokinetic effect.

Animals↗