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F W Hetzel

Publications and source records attributed to F W Hetzel.

At least 37 records · Page 2Linked to original sources
PubMed1991

In vivo 31P NMR study of combined hyperthermia and photodynamic therapies of mammary carcinoma in the mouse.

Although the sequence and time interval effects of combined photodynamic therapy (PDT) and hyperthermia tumor treatments have been studied using survival curves, tumor regrowth, and cloning assays, the metabolic response to combined treatment measured by nuclear magnetic resonance (NMR) spectroscopy has not yet been clarified. In this study, mammary carcinoma in the flank of C3H mice was subjected to PDT (12.5 mg/kg Photofrin II, 632 +/- 1 nm at 200 J/cm2) and water bath hyperthermia (43.5 degrees C, 30 min) with no delay or 4 h delay between treatments. In vivo 31P-NMR spectroscopy was employed to measure energy metabolism and pH of the tumors before and serially after treatment for up to 1 week. The data revealed significant differences in the time course of high energy phosphate levels between treatment combinations, which may reflect the biological effectiveness of the combined treatments. Our observations indicate that 31P-NMR spectroscopy can be used to evaluate the metabolic response of tumors to treatment with combined PDT and hyperthermia.

Animals↗
PubMed1991

Dose-dependent thermal response of tumor pH and energy metabolism evaluated by in vivo 31P NMR spectroscopy and microelectrodes.

In vivo 31P NMR spectroscopy and pH microelectrodes were employed to measure the energy metabolism and pH of a mammary carcinoma in the flank of the C3H mouse before and serially up to a week after various hyperthermia treatments. Water bath hyperthermia was used to treat the tumor at 43.5 degrees C for 30 min (TCD0/30, NMR measurement only), 1 h (TCD10/30), and 2 h (TCD60/30), respectively. The data indicate that, except at 4 h after TCD60/30 treatment, all pH values measured by NMR (pHn) were significantly higher (P less than or equal to 0.001) compared to pH values measured by microelectrodes (pHe) at all treatment levels and times. The magnitude of the difference between pHn and pHe (delta pH) was significantly decreased from the pretreatment level only at 4 h after hyperthermia treatment (0.51 pH units for TCD60/30 and 0.21 pH units for TCD10/30). The ratio of beta-nucleoside triphosphate to inorganic phosphate (beta-NTP/Pi) and pHn were more sensitive to hyperthermia treatment than pHe. The beta-NTP/Pi ratio failed to recover to the pretreatment ratio after 1 or 2 h hyperthermia treatment, while a total recovery was observed within 72 h for 30 min hyperthermia treatment. Our data suggest that the temporal profile of beta-NTP/Pi, pHn, and delta pH may be indicative of the biological outcome of hyperthermia treatment.

Animals↗
PubMed1990

Changes associated with metastasis in B16-F1 melanoma cells surviving heat.

Metastasis to distant sites is mediated by various receptors on the surface of tumor cells. B16-F1 melanomas surviving 43.5 degrees C heat in vitro for 15 minutes and cultured for 10 days bind significantly increased amounts of the basement membrane protein laminin. Motility of heat-resistant B16-F1 cells in vitro toward the chemoattractant laminin is significantly increased. The increased expression of putative laminin receptors may be associated with increased metastasis of melanomas after subcurative hyperthermia.

Cell Survival↗
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

Chronic metabolic measurements of normal brain tissue response to photodynamic therapy.

The metabolic response of normal rat brain to photodynamic therapy (PDT) was studied over a 1 week interval using in vivo 31P-NMR spectroscopy. Rats injected with 12.5 mg/kg Photofrin II were submitted to brain photoactivation 48 h after drug administration with either 140 or 70 J/cm2 light (630 +/- 1 nm) from an Argon dye laser. Control studies, animals not given drug or light, animals submitted only to brain illumination without drug, and animals given drug but no light, were also performed. The data revealed a transient metabolic degradation; a decrease in the ratio of beta-nucleotriphosphate to inorganic phosphate (P less than 0.001) at 24 h after PDT treatment was followed by a return to pretreatment spectral values. Brain tissue alkalosis was also noted, with significant (P less than 0.05) differences in brain tissue pH detected at 72 h post treatment between 70 J/cm2 PDT vs control studies and at 1 week post treatment between 140 J/cm2 vs 70 J/cm2, 140 J/cm2 vs no light-no drug and 140 J/cm2 vs drug only. The data suggest that there is no difinitive metabolic marker from 31P-NMR spectroscopy that can identify necrotic brain tissue caused by PDT. Phosphorus-31 NMR data are also presented which suggest that PDT damage to brain is not solely the result of microvascular occlusion causing ischemic necrosis.

Animals↗
PubMed1990

Dose-dependent metabolic response of mammary carcinoma to photodynamic therapy.

The metabolic response of mammary carcinoma in the C3H mouse to photodynamic therapy (PDT) was measured using in vivo 31P nuclear magnetic resonance (31P-NMR) spectroscopy and pH microelectrodes. Twenty-four hours after administration of Photofrin II (12.5 mg/kg), the tumor was subjected to photoactivation using an argon dye laser. Optical treatment doses were 200, 400, and 600 J/cm2 and corresponded to the following tumor control doses: TCD10/30, TCD50/30, and TCD90/30, respectively. In vivo 31P-NMR spectra and pH micro-electrode measurements were obtained prior to treatment and at 4, 24, 48, and 72 h and 1 week post-treatment. The data revealed a significant (P less than 0.0002) alkalosis as indicated by the pH measured by NMR compared to pH measured by microelectrodes at all treatment levels and time points. Spectral differences between treatment groups were apparent as early as 4 h after treatment. The ratio of beta-nucleoside triphosphate to inorganic phosphate at 4 h after treatment was significantly (P less than 0.01) smaller for 600 J/cm2 treatment than for 200 J/cm2 treatment. At curative (600 J/cm2) levels, from 48 h on, no phosphate resonances were detected in the spectra. The pH measured by NMR transiently decreased from pretreatment levels after 200 and 400 J/cm2 treatment (P less than 0.002, P less than 0.009, respectively), while no change in pH from pretreatment values was found after 600 J/cm2 treatment. The data suggest that the early metabolic response of mammary carcinoma to PDT, as indicated by 31P-NMR spectroscopy, is dose dependent, and may be a sensitive indicator of biological outcome to treatment.

Animals↗
PubMed1990

Changes in muscle pH following hyperthermia.

Considerable attention has been paid to the modification of intratumor pH in response to hyperthermia. It has been hypothesized that observed reductions in intralesional pH are involved in the ultimate response of tissue to hyperthermia treatment. Further, it has been shown that significant differences exist in hyperthermia-induced changes in blood flow between tumor and normal tissue in many systems. Changes in blood flow are hypothesized to be related to observed changes in pH. Since reduced blood flow is not observed in normal tissue under normal treatment conditions, changes in pH in normal tissue have not been considered significant in their response to hyperthermia treatment. However, this conclusion has not been verified or documented experimentally. The purpose of this study was to examine the distribution of pH in normal tissue (muscle) as a function of time following hyperthermia treatments which in the same animal system resulted in subcurative (TCD 10/30) or curative (TCD 90/30) tumor (mammary adenocarcinoma) responses. The observed distribution of pH in normal tissue was compared with that obtained in tumors under identical conditions. The results indicate that some post-treatment changes in muscle pH do occur following hyperthermia, but that these changes are small compared to those observed in tumors. More importantly, unlike the response observed in tumors, no hyperthermia dose dependency is observed in the muscle response. From these studies it can be concluded that changes in normal muscle pH are probably not associated with normal tissue response to hyperthermia.

Adenocarcinoma↗
PubMed1989

Relationship of spontaneous regional lymph node metastases to dose of local irradiation of primary B16 melanomas.

We evaluated the effects of local X-irradiation on microscopic or small macroscopic primary melanomas in the feet of C57BL/6 mice and the subsequent development of spontaneous femoral lymph node (LN) metastases. Doses of 30, 40, 55, 62.5, or 72.5 Gy often cured the foot tumor and metastases to regional femoral lymph nodes were relatively uncommon. Doses of 3.75, 7.5, 10, 15, and 20 Gy were associated with a dose-dependent regrowth delay of the foot tumor treated at microscopic size. Foot melanomas that were not cured spread to regional femoral LNs more frequently (P less than 0.001). The relative risk of developing femoral LN metastasis increased 2.55 times for each 1-mm increase in the anteroposterior diameter of the primary foot tumor in mice with 20 days of primary tumor exposure and increased 4.87 times for each 1-mm increase in mice with 100 days of primary tumor exposure. Although tumors treated with subcurative doses of irradiation had a longer period of time to metastasize to regional LNs for each 1-mm increase in primary tumor size, this variable alone did not account for the increased incidence of metastasis seen with irradiation.

Animals↗
PubMed1989

Lung metastases after curative or noncurative irradiation of microscopic primary melanomas.

Melanomas growing in the feet of syngeneic C57BL/6 mice were treated with a single dose of X-irradiation. After doses of 0, 3.75, 7.5, 10, 20, or 30 Gy the tumor-bearing limb was amputated at tumor sizes 1, 2, 3, 4, or 5 mm. After doses of 40, 50, 62.5, or 72.5 Gy, progressive tumor growth did not occur, and amputation of tumor-bearing limbs was done when controls were 1, 2, 3, 4, or 5 mm in size. Eighteen days after amputation the mice were killed, and pulmonary metastases were documented at autopsy. None of the mice developed pulmonary metastases after curative irradiation of the primary foot tumor. After subcurative irradiation there was a significant increase (P less than .003) in pulmonary metastases. The size of the primary melanoma is important in the prediction of these metastases. In this model melanomas can be cured by an adequate dose of irradiation, but in those not cured the incidence of lung metastases is increased. The impact of this biologic phenomenon on survival is unclear.

Animals↗
PubMed1989

Hyperthermic "dose" dependent changes in intralesional pH.

Following hyperthermia a dramatic drop in intra-lesional pH has occurred in a variety of experimental tumor systems. To date, no direct observations have been made that document the time course of such changes or the recovery from such changes over prolonged periods of time. These experiments were designed to measure intralesional pH as a function of time following "doses" of hyperthermia related to specific biological end points. All studies were conducted in the C3H-mammary carcinoma tumor model system. Intralesional temperature was continuously monitored throughout treatment and post treatment pH was measured with microelectrodes at several specific time points ranging from 4 hrs to 7 days. The pretreatment control value of mean pH was 6.73. At the TCD90 "dose" level the mean value of pH dropped to a level of 6.22 +/- .095 while following the TCD10 "dose" the value obtained was 6.55 +/- .148. Recovery of the pH to higher values followed similar time courses returning to maximum values approximately 3 days post treatment. The recovery, plateau levels of pH were however, separated by approximately .3 pH units with the higher "dose" curve always at lower values than that achieved following the lower "dose".

Adenocarcinoma↗
PubMed1989

Normal brain tissue response to photodynamic therapy: histology, vascular permeability and specific gravity.

The response of photodynamic therapy on normal brain was investigated in 140 Fisher rats. The rats were injected i.p. with Photofrin II (12.5 mg/kg) and 48 h later the dural area over the frontal cortex was photoactivated with red light (630 +/- 1 nm) from an argon dye laser. Treatment was performed with optical energy densities of 140 and 70 J/cm2. Histopathology, vascular permeability and specific gravity measurements were conducted on different populations of rats at 4 h, 24 h, 72 h and 1 week after photodynamic therapy (PDT). Histopathology revealed similar gross and microscopic pathology associated with light energies of 70 and 140 J/cm2 after all time points. A large cerebral infarct approximately the size of the brain surface area treated, evolved 24 h following treatment. Evans blue extravasation indicated a small area of vascular permeability evident as early as 4 h following PDT treatment at both energy levels, with increasing permeability evident at later time points. Specific gravity measurements taken on a representative area of the lesion indicated a significant (P less than 0.01) amount of edema present at 24 h post treatment with a gradual reduction approaching control values over the time period of 1 week. The data indicate a significant amount of damage to normal brain from low PDT treatment doses.

Animals↗
PubMed1989

Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat.

We heated Wistar rats (n = 10) to 41.5 +/- 0.2 degrees C for 15 minutes, 24 hours before the induction of forebrain cerebral ischemia. We subjected 23 rats to forebrain ischemia without prior heating. Ischemic cell damage in the medial, lateral, and overall CA 1/2 hippocampus, inferior frontal cortex, and dorsal-lateral striatum was significantly (p less than 0.05) less severe in heated animals than in nonheated animals.

Animals↗
PubMed1989

Biologic rationale for hyperthermia.

This article discusses the basic biologic data relative to the use of hyperthermia as an adjuvant to ionizing radiation in the treatment of solid tumors. The cytotoxic effects of hyperthermia are presented, as are parameters that modify cellular sensitivity. In vivo physiologic changes associated with hyperthermia are also considered. Finally, the in vitro and in vivo interactions between hyperthermia and radiation are discussed, particularly as they relate to improved tumor response.

Animals↗
PubMed1987

Photodynamic therapy of normal cerebral tissue in the cat: a noninvasive model for cerebrovascular thrombosis.

The early neuropathological response of normal cat brain to photodynamic therapy was investigated. Photofrin II was injected (IV) into a cat and photoactivated with red light from a filtered incandescent lamp. Animals were subjected to phototherapy either through the intact skull or with energy deposition onto the intact dura. Following photoactivation the animals were maintained for 6 h after which time the brain was removed and sections submitted for electron microscopic and or light microscopic study. Gross anatomical analysis of the photoactivated brain revealed hemorrhagic dusky discoloration limited to the area of the tissue illuminated. Animals that failed to show a lesion were cats characterized by low Photofrin II dosage and low photoactivation intensity. The microscopic cortical features of cats with lesions included prominent capillary congestion and regions of marked vacuolization and rarefaction. Blood vessels were structurally altered and the lumen of many vessels was completely filled with tightly packed erythrocytes. Our study suggests that the acute neuropathological response of cerebral tissue to photoactivation resembles that of microvascular thrombosis. It is thus reasonable to explore PDT of normal tissue as a non invasive model of cerebrovascular thrombosis in the cat.

Animals↗
PubMed1986

Phototherapy of bladder cancer: dose/effect relationships.

Hematoporphyrin derivative photodynamic therapy has very important clinical applicability in the diagnosis and treatment of transitional cell carcinoma of the bladder, but many aspects of the photodynamic process are yet to be elucidated. This paper investigates the role of dihematoporphyrin ether (DHE) concentration, the duration of light exposure, and the initial size of the tumors in the treatment of a transplantable murine transitional cell tumor system. The best results were noted in tumors less than six mm. in diameter when treated with 15 mg./kg. DHE and exposed to 100 to 180 minutes of visible light. Animals with small initial tumor size combined with higher DHE concentration and longer light exposure time were most likely to show tumor response.

Animals↗
PubMed1985

Thermal distributions in a water bath heated mouse tumor.

In the past several years numerous investigators have employed various mouse tumor systems and a variety of heating methods to examine the effects of hyperthermia in vivo. These studies have led, in some cases, to different results in tumor response in what appear to be similar experiments. Our results indicate that these discrepancies may in part be attributable to variations in intratumor temperature and depend strongly upon the method and conditions of heating employed. In all cases, we have employed the C3H mammary carcinoma tumor system with the tumor implanted in the right hind limb of the mouse. All tumors were 7-9 mm in diameter at the time of the experiments. Water bath heating was employed with the animals under one of four possible conditions: the presence or absence of anesthesia, and the use or lack of core cooling. Thermometry was performed with an array of multiple microthermocouples, each less than 150 micron in diameter, implanted in the tumor in a grid-like pattern. Significant variations (1.0 degrees C for no anesthesia, p less than .01; 1.3 degrees C for Thorazine/Ketamine, p less than .001) in intratumor temperature were found across the tumor in the unperturbed state. These variations were essentially eliminated under all hyperthermic conditions. Control of core (rectal) temperature (with or without anesthesia) reduced the intratumor temperatures even though the water bath temperature was held constant resulting in variations between water bath and tumor temperatures of from 0.1-0.8 degrees C.

Animals↗