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Biomedical subjects

G M Hahn

Publications and source records attributed to G M Hahn.

At least 127 records · Page 7Linked to original sources
PubMed1980

Ultrasonic hyperthermia for animal tumor treatment: CT assessment.

The effect of cancer treatment by ultrasound-induced hyperthermia in domestic pets was evaluated by computed tomography (CT) regarding changes in tumor volume and x-ray attenuation after intravenous contrast material. CT scanning is more accurate in measuring tumor volume than estimates after surface measurements. A decrease inn tumor volume and x-ray attenuation after contrast medium seems to be a valuable index of tumor response to hyperthermia.

Animals↗
PubMed1980

Comparison of the malignant potential of 10T 1/2 cells and transformants with their survival responses to hyperthermia and to amphotericin B1.

Several responses of 10T 1/2 cells and of cells from strains transformed by X-irradiation or by methylcholanthrene exposure were examined. Malignant potential, as determined by the ability of the cells to initiate tumors in syngeneic hosts, either normal or rendered immunodeficient, varied by a factor of 10(6). The growth rate of tumors both in normal and in irradiated animals was closely correlated to malignant potential. The life spans of the animals were inversely correlated with malignant potential. Serum requirements were high for 10T 1/2 and for one of the X-ray transformants; neither of these cell strains gave rise to tumors when cells were injected into hosts. All malignant strains had uniformly lower serum requirements. While 10T 1/2 cells tended to be somewhat more heat resistant than were any of their transformed counterparts, this depended upon cell density (or state of growth) during heating. There was no correlation between malignant potential and heat sensitivity among the transformed strains. In fact, the most resistant transformant was also the most malignant; furthermore, its heat sensitivity was not modified by growth in vivo. No relationship between malignant potential and response to the polyene antibiotic amphotericin B could be observed.

Amphotericin B↗
PubMed1980

A proposed operational model of thermotolerance based on effects of nutrients and the initial treatment temperature.

The phenomenon of thermotolerance in mammalian cells has been extensively documented in the literature. Because of its potential clinical importance as well as the fundamental biological interest, we pursued additional studies investigating pH and nutritional effects. Split-dose experiments were performed using plateau phase Chinese hamster HA-1 cells. The effects of the nutritional environment during the initial 43 degrees incubation and the second 43 degree treatment on the induction of thermotolerance were studied by comparing survival in full medium at pH 7.4 or in Hanks' balanced salt solution at pH 6.7. In additional experiments, we examined the effect on thermotolerance of changing the temperature of the initial treatment to 41 degrees. Thermotolerance was induced independently of the nutrient conditions of the first treatment. However, survival at the time of maximum expression of thermotolerance depended primarily on the duration and temperature of the initial treatment. Temperatures of 43 degrees or higher inhibited the development of thermotolerance during the first heat exposure. In contrast, if the initial exposure was at 41 degrees, thermotolerance was almost fully expressed by the end of this initial treatment. Changing pH in Hanks' balanced salt solution from 6.7 to 7.4 did not affect survival. On the basis of these and other data, we suggest that thermotolerance can be divided into three complementary and sometimes competing processes: an initial event ("trigger"); the expression of resistance ("development"); and its disappearance ("decay"). Trigger is induced at all hyperthermic temperatures while development requires a permissive temperature, i.e., less than 43 degrees for HA-1 cells. This model can provide plausible interpretations of several currently puzzling aspects of the survival kinetics of heat-exposed mammalian cells.

Adaptation, Physiological↗
PubMed1979

Explorations of antimitotic agents in the treatment of a congenital disease, ichthyosis linearis circumflexa.

Successful therapy of a genetic disorder, Ichthyosis Linearis Circumflexa, was achieved using a low dose systemic cyclophosphamide. Prior to such therapy, 80 to 90% of the body surface was affected; the use of antimitotic agents reduced the extent of the lesions to less than 15% of the body surface. As a result, the clinical status was changed from severely disabling to being compatible with a normal way of life. It is believed that this phenomenon is related to selective effects of cyclophosphamide, such as those on lymphocyte subpopulations. To our knowledge, successful chemotherapy for diseases of genetic or congenital origin has not been previously reported.

Adult↗
PubMed1979

Tumor eradication and cell survival after localized hyperthermia induced by ultrasound.

This study was designed to test the effect of localized ultrasound-induced hyperthermia on experimental mouse tumors. Transducers operating at 5.17 MHz with relatively uniform output over an area 1 cm in diameter were used to heat EMT6 and KHJJ tumors in 407 BALB/cKa mice. Treatments were at 43, 43.5, 44, and 44.5 degrees. At each temperature level, treatments were applied for 15, 30, or 45 min. Temperature profiles measured in tumors treated by ultrasound hyperthermia indicated that heating was not completely uniform. In general, both rate of tumor eradication and growth delay increased as temperature and/or time of exposure increased. The EMT6 and KHJJ tumors had comparable rates of eradication for the same temperatures and times of exposure. Cell survival studies indicated that there was considerable variation in cell killing between individual EMT6 tumors exposed to the same hyperthermic dose. In addition, cell death appeared to be progressive over a period 2 to 48 hr after hyperthermic exposure. The mechanism of this delayed cell death is not known but may be important in eradicating the tumors. Ultrasound was a relatively safe and effective method of heating tumor volumes up to 44 degrees, and hyperthermia alone resulted in high rates of tumor eradication in the EMT6 and KHJJ systems.

Animals↗
PubMed1979

Thermosensitization by sulfhydryl compounds of exponentially growing Chinese hamster cells.

The effect of various sulfhydryl compounds on the survival of exponentially growing monolayer cultures of Chinese hamster cells (HA1) heated to temperatures of 37-43 degrees was examined. Concentrations of cysteamine which were nontoxic or minimally toxic at room temperature or 37 degrees became increasingly toxic at elevated temperatures, greatly potentiating the killing produced by heat alone in the absence of cysteamine. This enhancement of hyperthermia-induced cell killing increased with increasing cysteamine concentration, increasing duration of cysteamine exposure, and increasing temperature. Studies with synchronized Chinese hamster cells heated at 43 degrees for 1 hr in the presence of 16 mM cysteamine demonstrated that the potentiation of heat killing occurred in all phases of the cell cycle. Similarly, enhancement of hyperthermia-induced cell killing was seen for asynchronous cells exposed to 2-amino-ethylisothiourium bromides and cysteine, but the magnitude of the effect differed for the various sulfhydryl compounds.

Animals↗
PubMed1979

Potential for therapy of drugs and hyperthermia.

The interaction of hyperthermia (41--45 degrees C) and chemotherapeutic agents frequently results in increased cytotoxicity over that predicted for an additive effect, although to date only a very limited number of drugs have been examined for such a possible interaction. At 42 degrees C, the upper limit of temperature useful for whole-body hyperthermia, the most promising agents of those examined to date appear to be the nitrosoureas and cis-platinum. Insufficient data exist for cyclophosphamide, whose long plasma half-life makes it an attractive candidate. Localized heating seems optimum at higher temperatures (43--45 degrees C). At these temperatures, not only those drugs effective at 42 degrees C but particularly bleomycin and possibly amphotericin B become candidates. No data exist in the literature on possible "thermic sensitizers," i.e., drugs which are noncytotoxic at 37 degrees C but which become effective at elevated temperatures. Two special cases are Adriamycin and actinomycin D. These drugs may be contraindicated for clinical use, since not only synergism but also protection by hyperthermia have been demonstrated, depending upon the time-sequence relationships of the heat and drug treatments.

Alkylating Agents↗
PubMed1979

Effects of systemically administered bleomycin or adriamycin with local hyperthermia on primary tumor and lung metastases.

Exposure of cells in tissue culture to bleomycin or Adriamycin during 43 degrees C hyperthermia increased cytotoxicity dramatically compared to exposure at 37 degrees C. This study was designed to test whether this interaction was useful in tumor-bearing animals. C3H mice bearing the KHT tumor were treated with bleomycin (7 or 15 mg/kg) or with Adriamycin (2.5 or 5 mg/kg) with or without local heating of the tumor to 43 degrees C for 30 minutes by 13.56 MHz radiofrequency fields. The effects were assessed by growth delay (mean tumor diameter doubling time) and cure rate. In separate experiments, BALB/c mice bearing EMT6 tumors were treated identically, but tumors were excised 2 hours after treatment and tumor cell survival was assayed by colony formation. Antitumor effects of systemic bleomycin were potentiated by local hyperthermia. The two modalities had to be administered close together in time to observe the potentiation, suggesting a true interaction. There was a "threshold" for bleomycin potentiation in vivo between 42 degrees C and 43 degrees C, just as observed in tissue culture experiments. The antitumor activity of Adriamycin was not potentiated in vivo in these tumor systems except in cell survival experiments at doses higher than those compatible with survival of the host. The toxicity of drug combined with heat was greater than that of either modality alone. Hyperthermia did not adversely affect the incidence or severity of spontaneous lung metastases from KHT tumors. In fact, groups treated with heat and bleomycin had less severe lung metastases than groups treated with bleomycin alone. We conclude that local heating of tumors may be a useful adjunct to systemic bleomycin therapy. In vivo potentiation of Adriamycin by heat, however, could not be demonstrated in these tumor systems.

Animals↗
PubMed1978

Protective effect of hyperthermia against the cytotoxicity of actinomycin D on Chinese hamster cells.

Hyperthermia is being tested as an adjuvant to chemotherapy for clinical use. We elected to study the interaction of heat at 43 degrees C with actinomycin D (AMD) (0.5 microgram/ml) in tissue culture using plateau phase Chinese hamster cells. The simultaneous administration of 43 degrees C and AMD produces more than additive cytotoxicity if the duration of exposure is less than 30 minutes; however, this is quickly reversed with longer exposures with the cells developing resistance to further cytotoxicity of AMD. If heat (43 degrees C) is applied before AMD exposure, the cells also are rendered insensitive, with a greater protection observed for longer periods of heating. For example, for cells heated for 2 hours at 43 degrees C and then exposed to AMD (0.5 microgram/ml for 2 hours), cytotoxicity to AMD is decreased by a factor of 10. Heat-induced resistance to AMD persists for at least 18 hours before full recovery of AMD effect returns. The application of heat following AMD exposure also protects against the cytotoxicity of AMD. Studies using 3H-AMD demonstrate that the resistance does not correlate with reduced membrane permeability to AMD of heated cells. Attention must be given to the timing of hyperthermia when used clinically as adjuvant therapy in patients receiving AMD.

Animals↗
PubMed1977

Cellular inactivation by ultrasound.

The lethal effect of ultrasound (US) on mammalian cells has received relatively little attention. Understandably, potential genetic aspects of US have been of prime concern to physicians who use US as a diagnostic tool; at the average power densities involved (<<1 W cm(-2)) little, if any cell killing is to be expected. There have been sporadic attempts to use higher intensities ( approximately 1 W cm(-2)) as a treatment modality in cancer therapy, but those experiments seem to have been based on inadequate cellular studies. The effects of US usually were evaluated in terms of morphological criteria rather than on quantitative determination of the loss of viability as measured by colony formation. There are few reports of the effects of US on survival of mammalian cells, and none specifically examine hyperthermic interaction. With the increased interest in hyperthermia for tumour therapy, attention has been directed towards the use of ultrasound to achieve tumour heating. In preliminary experiments in which US was used to heat the EMT6 sarcoma and KHJJ carcinoma in mice, we found a high percentage of tumour cures with short (approximately 30 min) treatments at temperatures (43-44 degrees C) where in vitro results of hyperthermia-induced cell killing would not have led to a prediction of any cures. We therefore initiated an investigation of the effects of US on survival of Chinese hamster cells to see if direct cell killing by US could explain our in vivo results, or, as in the case of radiofrequency (RF) electromagnetic heating, we would be forced to invoke host response(8). In particular, we examined the thermal and non-thermal components of cellular inactivation by US. We report here that there is a definite non-thermal cytotoxic effect of US. Its relative contribution to cell killing is a highly nonlinear function of the temperature of the cellular milieu. The survival curves show clearly that, beyond an initial threshold, small changes in temperature and/or US intensity can give rise to impressive changes in survival values. The threshold nature of the data strongly suggests that by means of overlapping beams, ultrasound energy could be delivered to tumour tissue to achieve massive cell killings while sparing normal tissue outside the tumour volume to a degree far exceeding that of conventional techniques.

Animals↗