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M Urano

Publications and source records attributed to M Urano.

At least 55 records · Page 3Linked to original sources
PubMed1991

The accelerated repopulation of a murine fibrosarcoma, FSA-II, during the fractionated irradiation and the linear-quadratic model.

Radiation response of a spontaneous mouse fibrosarcoma, FSa-II, to various fractionated doses was studied in vivo together with single dose cell survival curves. Early generation isotransplants were used. Animals were C3Hf/Sed mice derived from our defined flora mouse colony. Lung colony and TD50 assays were used to determine cell survival. Surviving fractions were determined following fractionated irradiations of 1.0 to 5.0 Gy each per fraction with interfractional time intervals of 4 hr. The alpha/beta ratio based on fractionated irradiations was 8.8 Gy for aerobic FSa-II tumor cells and flexure dose was less than 1.3 Gy. Multiple fractions of 5.0 Gy each given with 4, 12, and 24 hr intervals showed an increase in survival with increasing interfractional time interval, suggesting a rapid repopulation of tumor cells between fractions; namely, cell doubling time was shortened between fractions after the first 5.0 Gy doses. These results indicated that tumor cell repopulation is a critical factor in the fractionated radiotherapy. Linear-quadratic model was fitted to single dose survival data. Single dose survival curve of aerobic FSa-II tumor cells following lung colony assays which allowed determination of minimal survival of approximately 3.0 x 10(-3) showed that alpha, beta, and alpha/beta ratios were 0.25 Gy-1, 0.048 Gy-2, and 8.47 Gy, respectively. Single dose survival curve of the same aerobic cells determined by both lung colony and TD50 assays to a survival level of approximately 3.0 x 10(-6) demonstrated that alpha, beta, and alpha/beta ratios were 0.375, 0.0127, and 29.5, respectively. Similar determination for hypoxic FSa-II tumor cells showed that alpha, beta values were smaller whereas the alpha/beta ratio was much larger than for aerobic cells. The oxygen enhancement ratio calculated by the alpha/beta ratios was greater than 3.0.

Animals↗
PubMed1991

Significance of additive heat effect in the therapeutic gain factor in combined hyperthermia and radiotherapy: murine tumor response and foot reaction.

The thermal enhancement ratio (TER) and therapeutic gain factor (TGF) were evaluated for combined hyperthermia and radiation treatments of a murine fibrosarcoma, FSa-II. The TER is the ratio of the radiation dose that induces a given reaction without hyperthermia to that with hyperthermia. The TGF is defined as the ratio of TER for tumor response to TER for normal tissue response. Tumors in the subcutaneous tissue of the right foot were irradiated with graded radiation doses when they reached an average diameter of 6 mm (110 mm3). Hyperthermia was given by immersing animal feet in a constant temperature water bath 10 min before or after irradiation. The tumor growth time to reach 500 mm3 was obtained for each tumor and the median tumor growth time was calculated for each treatment group. For the normal tissue study, the non-tumor bearing murine foot was treated, as was the tumor, and the foot reaction was scored after treatment, according to our numerical score system for radiation damage, until the 35th post-treatment day and averaged. Using the fraction of animals showing a given average foot reaction score in a treatment group, the RD50, or the radiation dose to induce the given foot reaction or greater, was calculated. A single heating at 45.5 degrees C for 10 min and a step-down heating (first heat at 45.5 degrees C for 10 min immediately followed by the second heat at 41.5 degrees C for 60 min) prolonged the tumor growth time, indicating that hyperthermia per se resulted in some cell killing. The prolongation was greater following step-down heating than following single heating. These heat treatments alone induced no noticeable heat damage on the foot, but decreased the threshold dose observed on the radiation dose response curves for the foot reaction. Accordingly, TER and TGF were evaluated with or without normalizing this thermal effect. TER's for both tumor and foot responses without normalization were greater than the TER's after normalization and decreased with increasing radiation dose (between 1.9 and 7.1 or greater for tumor and between 1.3 and 4.3 or greater for foot reaction), whereas the normalized TER's were relatively constant (between 1.6 and 1.7 for tumor and between 0.7 and 1.5 for foot reaction). TGF's without normalization were greater than those obtained after normalization. The former was large at small doses and decreased with increasing radiation dose (between 1.5 and 4.0 or greater), whereas the latter was within 0.8 and 1.3 and relatively independent of radiation dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Tumors growing in irradiated tissue: oxygenation, metabolic state, and pH.

Experimental tumors growing in irradiated tissue have been used to study the biological differences characteristic of locally recurrent tumors. Animal tumors were early generation isotransplants of a spontaneous fibrosarcoma in a C3Hf/Sed mouse, designated FSa-II. Since the hypoxic cell fraction of tumors growing in irradiated tissue is increased, these tumors are assumed to be metabolically deprived with hypoperfusion and acidosis. In this study we directly measured the oxygen partial pressure (pO2) distribution, metabolic state, and pH of tumors growing in an irradiated tumor bed using oxygen sensitive electrodes and 31P-NMR. The results confirmed a three-fold increase in the number of pO2 readings less than or equal to 2.5 mmHg and also showed increased acidosis with a 0.17 unit decrease in pHNMR. When tumors growing in pre-irradiated tissue reached approximately 100 mm3 in volume, a high frequency of gross and microscopic necrosis and hemorrhage was already observed. Consistent with these observations, the phosphocreatine/inorganic phosphate (PCr/Pi) and nucleoside triphosphate/inorganic phosphate (NTP/Pi) ratios were significantly lower in the tumors in a pre-irradiated bed compared to tumors in a non-irradiated bed (PCr/Pi: 0.51 vs 0.79, p less than 0.05; and NTP/Pi: 0.64 vs 0.93, p less than 0.05). The longitudinal relaxation time (T1) of Pi was numerically shorter in control tumors (consistent with the better tissue oxygenation), but this did not reach statistical significance (2.09 +/- .11 sec vs 2.25 +/- .16 sec).

Animals↗
PubMed1991

The effect of 5-fluorouracil at elevated temperatures on a spontaneous mouse tumour: Arrhenius analysis and tumour response.

In a series of studies to investigate activation energies and thermal enhancements of various chemotherapeutic agents the effect of 5-fluoruracil (5FU), an antimetabolite, on murine tumour cells was studied at elevated temperatures. Animal tumours were early generation isotransplants of a spontaneous fibrosarcoma, FSa-II tumours, and C3Hf/Sed mice were used throughout. Cell survival curves for 5FU were obtained as a function of treatment time by in vitro treatment-in vivo lung colony assay at temperatures between 37.0 and 43.5 degrees C. The D0, or the treatment time to reduce surviving fraction from S to S/e in the exponential portion of the survival curve, decreased slightly from 37 degrees C treatment to 41.5 degrees C treatment. The D0 decreased substantially from 41.5 degrees C to 43.5 degrees C. Arrhenius-plot analysis indicated that the activation energies were 92.9 and 731 kJ/M at temperatures between 37 and 41.5 degrees C, and between 41.5 and 43.5 degrees C, respectively. The activation energy of 92.9 kJ/M for the temperature range from 37 to 41.5 degrees C was the lowest of the other agents, bleomycin, cis-diamminedichloroplatinum and 1,3-bis(2-chloroethyl)-N-nitrosourea, which have been investigated in our laboratory. This indicated that the thermal enhancement was smallest among these agents. In vivo experiments failed to demonstrate thermal enhancement of the anti-tumour effect of 5FU. Namely, combined 5FU and heat treatments at 41.5 and 43.5 degrees C did not prolong the tumour growth time compared with 5FU given at room temperature. No pH effect was found in an in vitro experiment and glucose administration did not enhance the anti-tumour effect of 5FU.

Animals↗
PubMed1991

Regulation of pH in murine tumor and muscle.

The relationship between intracellular and extracellular pH was investigated in a murine tumor and normal tissue, prior to and following glucose injection. Isotransplants of the murine tumor FSa-II in the dorsum of the hind foot and leg muscle, were investigated in nonanesthetized mice. Extracellular pH was measured with a glass microelectrode, with a tip diameter of approximately 80 microns. Intracellular pH was evaluated by 31P-NMR spectroscopy, using a wide-bore NT-150 spectrometer operating at 60.75 MHz. Five grams per kilogram intraperitoneal glucose led to small changes in extracellular pH of muscle (-0.13 unit) measured with a microelectrode, and no change in intracellular pH measured by NMR. In contrast, tumor intracellular pH decreased by 0.34 units and tumor extracellular pH by 1.13 units. The differential effect of glucose on tumor vs normal tissue, and pronounced pH gradient which develops in tumor cells should markedly affect the intracellular:extracellular distribution of drugs which are weak acids or bases.

Animals↗
PubMed1990

Fraction size-dependent acute skin reaction of mice after multiple twice-a-day doses.

To study the effect of multiple daily fractions on acute murine foot reaction, the left feet of C3Hf/Sed mice were irradiated by a Cs-137 irradiator at intervals of 6 and 18 hr, alternately. Fraction sizes ranged from 1 to 12 Gy, and various numbers of fractions were given. At the end of fractionation, a top-up dose of 20 Gy was administered. The overall treatment time ranged from 2 to 21 days. The average skin reaction from 10 to 35 days after completion of irradiations was determined. The skin reactions started from 8 to 27 days following the completion of irradiations. The skin reaction after fraction sizes of 3.5 and 5 Gy was dependent on the total dose. The skin reaction after fraction sizes of 1.5 and 2 Gy showed a biphasic response; at lower total doses, the skin reaction was proportional to the total dose, but at higher total dose, the skin reaction reached a plateau. The average skin reaction at the plateau with fraction sizes of 1, 1.5, and 2 Gy were 0.79 +/- 0.03, 1.12 +/- 0.13, and 1.37 +/- 0.06, respectively. The alpha/beta ratio for acute skin reaction following the twice a day scheme was 9.09 Gy (at dose/fraction greater than or equal to 3.5 Gy). The plateau may be attributed to the effect of accelerated proliferation and a balance between cell depletion and proliferation during twice-a-day irradiations. It is also suggested that twice-a-day irradiations induce more proliferation in skin than once a day treatments.

Animals↗
PubMed1990

Regeneration in cervix cancer after 252Cf neutron brachytherapy.

Regeneration of clonogens in human cervical cancer was assessed by the pathological evaluation of the hysterectomy specimen after intracavitary 252Cf neutron brachytherapy implants separated by varying time intervals followed by extrafascial hysterectomy. In this study, patients with bulky/barrel shaped Stage IB cervical cancers received 252Cf implants plus approximately 45 Gy of whole pelvis linear accelerator radiotherapy in approximately 25 fractions in 5 weeks followed by hysterectomy 4-6 weeks after radiotherapy. The specimens were studied grossly and microscopically for residual tumor. It was found that the fraction of positive specimens increased with elapsed time interval between implants. These findings support the hypothesis that there is repopulation of surviving clonogens with increased time interval between the implants. The observation also supports current concerns that rapid depopulation of tumor can lead to rapid repopulation, that is, rapid shrinkage of tumor can alter the physiological environment such that clonogens can rapidly regenerate.

Brachytherapy↗
PubMed1990

[Thermal radiosensitization in vitro and its implication to radiotherapy].

Thermal radiosensitization and the possible mechanism are reviewed. In vitro studies suggest that hyperthermia can enhance cell killing by radiation resulting in a steeper slope and smaller shoulder of the cell survival curve, compared to the survival were following radiation clone. Molecular studies suggest that inhibition of DNA synthesis and or repair of DNA damage by hyperthermia might be major causes of the thermal radiosensitization. When the curve is fitted by linar quadratic (L-Q) model, a increased number of beta, while relatively stable amount of alpha values are shown for survival curve to radiation combined with hyperthermia. This implies that when a larger radiation dose (greater than or equal to 4 Gy) is combined with hyperthermia, the enhancement would be greater in thermal radiotherapy.

Cell Survival↗
PubMed1989

The effect of hyperthermia on the early- and late-appearing mouse foot reactions and on radiation carcinogenesis: Part II. Effect on radiation carcinogenesis (thermal enhancement and oxygen enhancement).

The effect of hyperthermia on radiation carcinogenesis was investigated in the C3Hf/Sed mouse foot. The foot was irradiated under hypoxic conditions, in air, or under hyperbaric oxygen conditions to evaluate the oxygen effect. Hyperthermia at 43.5 degrees C for 45 min was given by immersing the animal foot into a constant temperature water bath. A malignant tumor in the irradiated foot was first observed congruent to 250 days after irradiation. Tumors developed in the irradiated area until day 850. RCD50, or 50% radiation carcinogenesis dose was the endpoint and was calculated based on the tumor incidence 650 days after irradiation. RCD50 following radiation given alone under hypoxic conditions was 66.3 (60.0-73.2) Gy, and the oxygen enhancement ratio (hypoxic/hyperbaric oxygen) was 3.0 (2.5-3.5). Radiation carcinogenesis was enhanced by hyperthermia given with a 20 min treatment interval with no significant alteration in the oxygen effect. Thermal enhancement was greatest when hyperthermia was given 20 min prior to irradiation (2.5 [2.2-2.9] under hypoxia). No thermal enhancement was observed when two treatments were given with a treatment interval of 2 days. The median time to develop a malignant tumor decreased with increasing radiation dose. This median time was shorter following combined hyperthermia and irradiation (423 days) than following radiation alone (504 days). Histological studies revealed that more than 80% of tumors were soft tissue sarcomas, and the most common tumor was fibrosarcoma. Squamous cell carcinoma was found in 7% of all tumors.

Animals↗
PubMed1989

Relationship between energy status, hypoxic cell fraction, and hyperthermic sensitivity in a murine fibrosarcoma.

The energy status, radiobiological hypoxic cell fraction, and hyperthermic sensitivity of a spontaneous murine fibrosarcoma, FSa-II, have been evaluated as a function of tumor size. Tumors were evaluated over the size range of 70 to 800 mm3. The concentration of the high-energy phosphate reservoir creatine phosphate progressively decreased by a factor of 5 with increasing tumor volume, and was matched by an increase in creatine. The concentration of ATP also decreased with increasing tumor size, although this decrease was substantially less pronounced. The sum of ATP, ADP, and AMP did not vary with tumor size, suggesting that the necrotic fraction remained constant. The decrease in energy status occurred in parallel with an increase in the size of the hypoxic cell fraction and with increasing thermal sensitivity. The results suggest that energy status may be an important modifier of hyperthermic sensitivity in vivo and reflect tissue oxygen concentration.

Adaptation, Physiological↗
PubMed1988

Effect of bleomycin on murine tumor cells at elevated temperatures and two different pH values.

The cytotoxic effect of bleomycin, an antibiotic chemotherapeutic agent, at elevated temperatures was investigated. Single cell suspensions of FSa-II tumor cells were treated at elevated temperatures with or without bleomycin either at pH 7.4 or 6.7. Immediately after treatment, cells were cooled and diluted for lung colony assay. Cyclophosphamide of 200 mg/kg was injected i.p. into the recipient mice 48 h before i.v. injection of tumor cells. Lungs were removed 13 days thereafter and fixed in Bouin's solution. Colonies formed on the surface of each lobe were counted, and the surviving fractions were calculated. Cell survival was determined as a function of treatment time at various temperatures. Survival curves following bleomycin treatment at various temperatures were biphasic. Initial steep portion was followed by a resistant tail. The surviving fractions were reduced to 0.1 within 20 min of treatment at pH 7.4 in the temperature range from 39.0 degrees-43.5 degrees C, and 10 min at pH 6.7. The slope of the resistant tail becomes steeper with increasing temperature, indicating that the cytotoxic effect of bleomycin was enhanced at elevated temperatures. The reciprocal of D0 (treatment time to reduce surviving fraction from 1.0 to 0.37 on the exponential portion of survival curve) of the resistant tail was plotted as a function of the treatment temperature, and activation energy was calculated. This analysis indicates that the enhancement of the cytotoxic effect increases with increasing temperature. However, above 42.5 degrees C, this enhancement appears to be dominated by lethal thermal damage.

Animals↗
PubMed1988

The effect of hyperthermia on the early and late appearing mouse foot reactions and on the radiation carcinogenesis: effect on the early and late appearing reactions.

The effect of hyperthermia on radiation-induced early- and late-appearing foot reactions was studied in C3Hf/Sed mice derived from our defined flora mouse colony. The animal foot was irradiated with 137Cs gamma-rays under hypoxic, air, or hyperbaric oxygen (O2 30 psi) conditions. Hyperthermia of 43.5 degrees C for 45 min was given locally in a water bath where a constant temperature +/- 0.1 degrees C was maintained. Treatment intervals between the 2 treatments were 20 min and 2 days. For the early-appearing reactions scores taken between the 14th and 35th post-irradiation days were averaged. Late-appearing reactions became apparent after approximately the 200th post-treatment day and increased with time. The foot reaction was enhanced by hyperthermia given 20 min before or after irradiation. Dose response curves for radiation given 20 min after hyperthermia for acute-appearing reactions lacked shoulders, whereas those following the same treatment schedule for late-appearing reactions showed significant shoulders. The thermal enhancement ratios (TER) for score 2.0 (complete epilation) early- and late-appearing reactions depended on the treatment interval and sequence. The TER values were greater for a short treatment interval (20 min.) than for a long treatment interval (2 days). Thermal enhancement was greater for hyperthermia given before irradiation compared to the reverse sequence. The TER values were always smaller for the late-appearing reactions than for the acute-appearing reactions. The relationships between early reaction scores and late reaction scores showed that the late reactions following combined heat and radiation are less extensive than those following radiation alone if they were compared at radiation doses which induced an equal level of early reactions. This difference was most significant at low early reaction scores and decreased with increasing score level.

Aerobiosis↗