Biomedical subjects

J Overgaard

Publications and source records attributed to J Overgaard.

At least 343 records · Page 19Linked to original sources

PubMedDate not supplied

A paradoxical cerebral hemodynamic effect of hydralazine.

Hydralazine is shown to have a very complex cerebral hemodynamic effect. It raises the intracranial pressure which, together with its effect upon systemic blood pressure, reduces the cerebral perfusion pressure. In spite of this and a concomitantly induced hyperventilation by hydralazine, CBF increases with some delay. The conclusion is that hydralazine is a cerebral vasodilator acting immediately upon cerebral capacitance vessels but later upon the resistance vessels as well.

Adolescent↗

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Studies on fractionated hyperthermia in L1A2 tumour cells in vitro: response to multiple equal heat fractions.

The development of thermotolerance in L1A2 cells in vitro was investigated after fractionated hyperthermia at 42 degrees C. A single pretreatment of 90 min at 42 degrees C resulted in maximal thermotolerance at a 10 h fractionation interval with a thermotolerance ratio (TTR) of approximately 4.5. Thermotolerance was maintained at this level if the cells were exposed to 1-3 additional 90 min pretreatments separated by 10 h intervals. At a 6 h fractionation interval, where thermotolerance was still developing, additional 90 min pretreatments raised the level of thermotolerance to the level induced by the 10 h interval; the TTR increased from 2.1 to 4.5. Intervals of 20 and 24 h, at which there was decay but not complete disappearance of thermotolerance, did not induce such a build-up, and the TTR remained constant at 2.5 and 1.6, respectively. With 2 h fractionation intervals, where a single pretreatment did not induce thermotolerance, no thermotolerance was induced by additional pretreatments. With a shorter preheating time (e.g. 45 min at 42 degrees C) administration of a single pretreatment induced maximal thermotolerance after 6 h with a TTR of 3.0; additional 45 min pretreatments separated by 6 h intervals maintained this level. The thermotolerance induced by multifractioned hyperthermia as described above decayed in a similar way to that of cells exposed to a single pretreatment.

Animals↗

PubMedDate not supplied

Factors of importance for the development of the step-down heating effect in a C3H mammary carcinoma in vivo.

The effect of step-down heating (SDH) was investigated in a C3H mammary carcinoma inoculated into the feet of CDF1 mice. The SDH effect was evaluated by comparing slopes of time versus growth delay curves of SDH-heated with the curve for single-heated controls. The effect was quantified by a ratio: 'step-down ratio' (SDR), defined as slope (SDH-heated)/slope (single-heated). Step-down heating resulted in thermosensitization in contrast to step-up heating which did not affect the heat sensitivity. The kinetics of the step-down heating effect was investigated by inserting an interval between a 44.5 degrees C/10 min sensitizing treatment (ST) and a 42.0 degrees C test treatment (TT). The effect of SDH was maximal with no interval between ST and TT (SDR = 2.3), decayed within 2 h and turned into thermotolerance. This thermotolerance was maximal after 12 h and decayed within 120 h. The effect of varying the TT temperature was investigated in the range 39.0-44.5 degrees C (ST = 44.5 degrees C/10 min). Below 42.5 degrees C the SDR value increased exponentially, and even a 39 degrees C TT produced a significant heat damage. An Arrhenius analysis was made showing a straight line in the whole temperature range with an activation energy of 526 kJ/mol and an increased activation entropy. These data show that thermosensitization can be induced by SDH in C3H mammary carcinomas in vivo. The effect seems to decay within 2 h, and by decreasing the heat activation energies the effect of low temperature heating is increased.

Animals↗

PubMedDate not supplied

Some problems related to the clinical use of thermal isoeffect doses.

The well-known biological isoeffect relationship between treatment time and temperature has been suggested as a basis for a general biological heat dose unit which could be used to compare the effect of different heat treatment schedules. This is frequently expressed as 'equivalent heating time at 43 degrees C'. Such a conversion has in experimental studies been shown to be effective in comparing single heating schedules. However, clinical treatment has some features which may strongly influence the usefulness of an isoeffect heat dose. Firstly, the heat distribution is generally heterogeneous and fluctuates with time, which in some situations results in increased damage due to step-down heating. Secondly, in the situation where hyperthermia and radiation are given simultaneously, the time-temperature relationship may be different from that in the case of heat alone, and from the effect of heat given as an adjuvant to radiotherapy. Thirdly, most clinical treatments are given as fractionated treatments, and it is almost certain that thermotolerance may influence the biological heat effect to some extent. However, with the unknown kinetics of thermotolerance the magnitude of this phenomenon cannot be predicted. A series of experiments in a C3H mammary carcinoma were performed in order to analyse some of these problems.

Hot Temperature↗

PubMedDate not supplied

Hyperthermia as an adjuvant to radiotherapy in the treatment of malignant melanoma.

One hundred and fifteen cutaneous or lymph node metastases from malignant melanoma were treated with three fractions of irradiation alone in 8 days (62 tumours) or followed by heat either immediately (simultaneous treatment, 26 tumours) or after an interval of 3-4 h (sequential therapy, 27 tumours). In addition, three tumours were treated unsuccessfully with heat alone. The total doses of radiation varied between 15 and 30 Gy, allowing a dose-response analysis. For irradiation alone the isoeffective dose to obtain 50 per cent complete response (TCD50) was 26.3 Gy. Addition of heat reduced the TCD50 significantly (p less than 0.05) with a thermal enhancement ratio (TER) of 1.43 for simultaneous treatment and 1.24 for sequential therapy. Also the persistent local control at 18 months was improved by hyperthermia (56 per cent versus 86 per cent, p less than 0.05). However, simultaneous treatment also enhanced the acute skin response to the same extent as the tumour (TER 1.42 for severe erythema). This schedule thus gave no therapeutic gain. In contrast, no normal tissue enhancement was found after sequential treatment (TER 1.02). Such a treatment schedule resulted in a significantly improved therapeutic ratio of 1.22. This effect was especially prominent in larger tumours (if sufficiently heated) and an analysis corrected for volume showed a TER of 1.51. A special analysis was performed in patients with multiple lesions. 15 pairs of tumours were given the same radiation dose, with or without hyperthermia. Out of these, 11 showed a better response, three showed the same response, and only in one pair was the best response in the tumour obtained by radiation alone.

Combined Modality Therapy↗

PubMedDate not supplied

Hydralazine-induced enhancement of hyperthermic damage in a C3H mammary carcinoma in vivo.

Prolonged oxygen deprivation of cells in vitro or in vivo increases the sensitivity of those cells to heat. Hydralazine is a peripheral vasodilator, currently used clinically as an antihypertensive agent, which has been reported to be able to reduce tumour blood flow and increase the degree of tumour hypoxia. We have investigated the potential of hydralazine to enhance the response of a C3H mammary carcinoma to local hyperthermia. The tumour was grown in the foot of mice and its response to treatment assayed by regrowth delay. Our results show that a single intravenous injection of hydralazine (5 mg/kg) significantly enhances the heat damage produced by heating for various times at either 41.5, 42.5, or 43.5 degrees C. This effect was dependent on the time of starting to heat after hydralazine injection, with the greatest enhancement occurring when heat was given within 1 h following drug administration. However, the effect was independent of the hydralazine concentration, at doses above 2.5 mg/kg. Hydralazine also significantly decreased mean arterial blood pressure and the uptake of 86RbCl into tumours. Our results suggest that the observed heat sensitization was primarily a consequence of an increase in tumour hypoxia, probably resulting from a decrease in tumour blood perfusion.

Animals↗

PubMedDate not supplied

Step-down heating in a C3H mammary carcinoma in vivo: effects of varying the time and temperature of the sensitizing treatment.

The effect of step-down heating (SDH), consisting of an initial sensitizing treatment (ST) performed at either 44.5 degrees C or 43.5 degrees C followed by a lower temperature test treatment (TT), was investigated in a C3H mammary carcinoma in vivo. A linear relationship between heating time and tumour growth delay was observed for all temperature combinations applied. At a given TT temperature, SDH increased the slope of the dose-response curve compared to the curve for tumours, single-heated without an initial ST. The slope of the SDH curves increased asymptotically towards a plateau value as the ST time at 44.5 degrees C was increased. The time-temperature relationship for single heating was described by a biphasic Arrhenius curve with activation energies of 1361 +/- 34 and 666 +/- 54 kJ/mol below and above an inflection point at 42.5 degrees C, respectively. For SDH, the Arrhenius curve gradually became straight with increasing ST time, and the activation energy saturated at a value of 425 +/- 25 kJ/mol. The reduction of the activation energy at an ST temperature of 43.5 degrees C was due rather to the extent of ST heat damage than to the ST time or temperature used. These results may be relevant for calculations of thermal doses, since even a short temperature peak (e.g. 44.5 degrees C/5 min) significantly changed the time-temperature relationship.

Animals↗

PubMedDate not supplied

A comparison between the effect of step-down heating in a tumour and a normal tissue in vivo.

A comparison between the effect of step-down heating (SDH) obtained in a C3H mammary carcinoma grown in the feet of CDF1 mice and the skin of normal CDF1 feet is presented. Water-bath heating was used, and SDH was obtained by giving a 44.7 degrees C/10 min treatment followed by heating at 42.2 degrees C for variable times. Single heating at 42.2 degrees C and step-up heating (SUH), i.e. 42.2 degrees C followed by 44.7 degrees C/10 min, were used as controls. The endpoint was the heating time at 42.2 degrees C to obtain either a definite tumour growth time (TGT50) or a specific skin score level (RD50) in 50% of the animals. The effect of SDH and SUH was quantified by the step-down ratio (SDR), calculated as the ratio of the heating times at 42.2 degrees C to obtain the specific endpoint. In both assays the effect of SDH was seen as a significant left shift of the SDH dose-response curve compared to the curve for single heating and SUH. For the comparison of the tumour and the normal tissue response, damage levels with comparable heating times for single heating were used. The therapeutic effect was then investigated by calculating the therapeutic gain factor (TGF), where TGF = SDR(tumour)/SDR(normal tissue). Neither SUH nor SDH gave a TGF significantly different from 1. The results suggest that SDH may be used clinically to shorten the heating time without decreasing the therapeutic effect.

Animals↗

PubMedDate not supplied

Use of tetrahydraindazolone dicarboxylic acid (HIDA) to improve the therapeutic effect in vivo of combined cisplatin, heat and radiation treatment.

The effect of tetrahydraindazolone dicarboxylic acid (HIDA) on tumour response and mouse lethality after treatment with cisplatin given either alone or combined with hyperthermia (43.5 degrees C/60 min) with or without radiation, was studied in the CDF1 mouse bearing a foot transplanted C3H mouse mammary carcinoma. The tumour response to a combined heat, cisplatin and HIDA treatment was assessed by tumour growth time, while local tumour control was used when irradiation was added to that treatment scheme. Toxicity was estimated as lethality within 14 days. Cisplatin and heat exerted the highest antitumour effect when given simultaneously, but at the same time there was a substantial increase in lethality. No sensitization of the tumour response or enhanced toxicity to cisplatin was observed if heat was given sequentially (i.e. 4 h) after cisplatin. The effect of this sequential schedule being only additive. When HIDA (100 mg/kg) was given 150 min before cisplatin and tumours heated 15 min later, the lethal toxicity was significantly reduced. HIDA did not, however, influence tumour growth time results. In tumour control studies combining radiation, drug and heat, cisplatin (6 mg/kg) and heat (43.5 degrees C/60 min) were given simultaneously 4 h after local irradiating the leg of tumour-bearing mice. The lethality of this regime was more than 55%, but when HIDA was added to the protocol, the toxicity fell to 5% without affecting local tumour control. In conclusion, HIDA administered before cisplatin protects against drug-induced toxicity without reducing the drug's antitumour activity when used alone or in combination with hyperthermia and/or radiation, and thus results in a significantly improved therapeutic benefit.

Animals↗

PubMedDate not supplied

Effects of step-down and step-up heating on the development of thermotolerance in a C3H mammary carcinoma in vivo.

The effects of step-down (SDH) and step-up heating (SUH) on the development of thermotolerance were investigated in a C3H mammary carcinoma in vivo. The endpoint was tumour growth time, i.e. the time for a tumour to reach a volume five times that of the first treatment day. SDH consisted of 44.5 degrees C/5 min followed immediately by 41.0 degrees C/120 min. SUH consisted of the same heat treatments but in reverse sequence. Thermotolerance was detected by subsequent heating at 43.5 degrees C at variable intervals following the primary SDH or SUH. The degree of thermotolerance was quantified by the thermotolerance ratio (TTR) calculated as a ratio between the slope of the dose-response curve for tumours heated at 43.5 degrees C and tumours preheated with either SDH or SUH followed by 43.5 degrees C. Both SDH and SUH induced thermotolerance. However, the maximal degree of thermotolerance and the time interval to reach maximum thermotolerance were different. For SUH maximal thermotolerance was observed at 8 h with a TTR of 3.6. For SUH, thermotolerance peaked at 24-28 h with a TTR of 7.3. In both cases thermotolerance had decayed with a 120 h interval. The SDH priming induced about 2.5 times more heat damage than SUH. The results are therefore in agreement with previous data obtained in the same tumour model by single heating showing that both the degree and the time to reach maximal thermotolerance increases with pretreatment heat damage. In addition, the results indicate that thermotolerance and thermosensitization are independent phenomena.

Animals↗

PubMedDate not supplied

Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology.

The ESHO protocol 3-85 is a multicentre randomized trial investigating the value of hyperthermia as an adjuvant to radiotherapy in treatment of malignant melanoma. A total of 134 metastatic of recurrent malignant melanoma lesions in 70 patients were randomized to receive radiotherapy alone (3 fractions in 8 days) or each fraction followed by hyperthermia (aimed for 43 degrees C for 60 min). Radiation was given with high voltage photons or electrons. Tumours were stratified according to institution and size (above or below 4 cm) and randomly assigned to a total radiation dose of either 24 or 27 Gy to be given with or without hyperthermia. The endpoint was persistent complete response in the treated area. A number of 128 tumours in 68 patients were evaluable, with an observation time between 3 and 72 months. Sixty-five tumours were randomized to radiation alone and 63 to radiation + heat. Sixty received 24 Gy and 68 tumours received 27 Gy, respectively. Size was < or = 4 cm in 81 and > 4 cm in 47 tumours. Overall the 2-year actuarial local tumour control was 37%. Univariate analysis showed prognostic influence of hyperthermia (rad alone 28% versus rad + heat 46%, p = 0.008) and radiation dose (24 Gy 25% versus 27 Gy 56%, p = 0.02), but not of tumour size (small 42% versus large 29%, p = 0.21). A Cox multivariate regression analysis showed the most important prognostic parameters to be: hyperthermia (odds ratio: 1.73 (1.07-2.78), p = 0.02), tumour size (odds ratio: 0.91 (0.85-0.99), p = 0.05) and radiation dose (odds ratio: 1.17 (1.01-1.36), p = 0.05). Analysis of the heating quality showed a significant relationship between the extent of heating and local tumour response. Addition of heat did not significantly increase the acute or late radiation reactions. The overall 5-year survival rate of the patients was 19%, but 38% in patients if all known disease was controlled, compared to 8% in the patients with persistent active disease.

Adult↗

PubMedDate not supplied

The in vivo interaction between flavone acetic acid and hyperthermia.

The in vivo interaction between flavone acetic acid (FAA) and hyperthermia was studied in a C3H mammary carcinoma grown in the feet of female CDF1 mice and in normal foot skin. FAA was intraperitoneally injected prior to local tissue heating in restrained non-anaesthetized animals. Alone, FAA at doses of 100 mg/kg and above, inhibited tumour growth in a dose-dependent fashion. FAA also enhanced the tumour response to heat, the effect being dependent on both the time interval between the two modalities and the FAA dose, the greatest effect occurring when FAA doses of > or = 150 mg/kg preceeded heat by 3-48 h. These effects of FAA correlated with the drug's ability to decrease tumour blood perfusion measured using the RbCl extraction procedure. Injecting 150 mg/kg FAA 3 h before heating (42.7 degrees C) resulted in a 2.2-fold increase in tumour heat damage, but had little effect on the response of normal foot skin in non-tumour-bearing mice. However, this treatment gave a 2.0-fold increase in normal tissue damage when the skin experiments were repeated in tumour-bearing animals. These effects in skin occurred in the absence of any blood perfusion changes, but appeared to be associated with FAA-induced TNF-alpha production.

Animals↗

PubMedDate not supplied

Can mild hyperthermia improve tumour oxygenation?

The oxygenation status of C3H mammary carcinomas, grown in the feet of CDF1 mice, was measured with an Eppendorf oxygen electrode. Tumours were locally heated in a water bath at temperatures of 38.5-41.5 degrees C for 1 h. Measurements made during heating showed temperature-dependent increases in tumour oxygenation. However, measurements performed after heating showed a rapid return to normal oxygenation status. Mild hyperthermia thus improves tumour oxygenation and this can explain the radiosensitization seen with low heat treatments, but only when the heat and radiation are administered concurrently, which is typically not the way that are given clinically.

Animals↗

PubMedDate not supplied

Interactions of radiation and cancer chemotherapeutic drugs in a C3H mouse mammary carcinoma.

The interactions of radiation and adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C), or cis-diamminedichloroplatinum II (cis-DDP) were studied in a spontaneously arisen C3H mouse mammary carcinoma. The tumour response to drugs alone was evaluated by measuring the tumour to reach a volume 5 times that of the treatment day. CTX resulted in a marked tumour growth delay whereas the other drugs had a modest or uncertain effect. In the combined treatment experiments, drugs were administered as single doses either 15 min before or 4 hours after graded single doses of irradiation. The end point for each treatment was the radiation dose which on an average was required to achieve local tumour control in 50 per cent of the mice (TCD50). The dose effect factor (DEF) was 1.16 for ADM and 1.17 for CTX, the enhanced radiation response being independent of administration before or after irradiation. MM-C also decreased the TCD50 for radiation alone, but its effect was more marked 15 min before (DEF 1.32) than 4 hours after irradiation (DEF 1.18). BLM, 5-FU, MTX, and cis-DDP had no effect on the radiation response neither when administered 15 min before nor 4 hours after irradiation.

Animals↗

PubMedDate not supplied

Bleomycin, methotrexate and vincristine before irradiation of stage III and IV laryngeal and pharyngeal squamous cell carcinoma. A study initiated by the Danish Society of Head and Neck Cancer.

Primary treatment with bleomycin, methotrexate and vincristine for two weeks followed by curatively intended 60Co irradiation was administered to 153 patients consecutively referred to the three main treatment centres in Denmark over more than a two-year period. Seventy-one laryngeal and 82 pharyngeal squamous cell carcinomas were evaluated. According to the TNM classification (UICC) 76 patients had stage III and 77 patients stage IV disease. The immediate response (complete + partial) to chemotherapy was 20 per cent. Judging from frequency of local recurrence, metastases as well as survival the treatment results were not obviously improved. A high frequency of complications was observed after this combination of chemotherapy and irradiation, and it was often impossible to fulfil the irradiation to the planned dose in appropriate time.

Adolescent↗

PubMedDate not supplied

Importance of overall treatment time for the response to radiotherapy in patients with squamous cell carcinoma of the head and neck.

In the nineties, several national protocols by the Danish Head and Neck Cancer Study group DAHANCA and other randomized trials, which have included several thousand patients, were performed on squamous cell carcinoma of the head and neck, now the most common malignant disease worldwide. It is a locoregional disease and distant metastases are rarely seen at diagnosis. Radiotherapy and surgery are thus the treatment of choice, with radiotherapy being the treatment modality if organ conservation is required. Since the late eighties there has been a strong focus on the importance of overall treatment time for the outcome of curative radiotherapy for these carcinomas. Based on the results of the Danish protocols it was concluded that the schedule of radiotherapy should be given with the shortest possible overall treatment time. In fact, as a consequence of the loco-regional control rate, the disease-specific and overall survival have shown a significant dependency on the overall treatment time: when this is short, the most beneficial results are achieved. Furthermore, treatment with 6 fractions per week is now the standard radiotherapy in Denmark in most head and neck carcinomas, associated with hypoxic modification using nimorazole. The response to accelerated fractionation is however heterogeneous and until proper predictive factors can be identified and further clarified which are the patients who truly benefit from accelerated fractionation, the radiotherapy schedules should secure a sufficient dose to all patients.

Carcinoma, Squamous Cell↗

PubMedDate not supplied

Invasive blood pressure measurements in restrained but non-anaesthetized mice.

We have developed a procedure for directly measuring mean arterial blood pressure in fully awake, non-anaesthetized mice. The technique involves surgical implantation of a small tube into the carotid artery. This tube is then passed under the skin, out through the nape of the neck, and secured in a position which exposes it to the surface. Mice are allowed to recover overnight and are then transferred to jigs which lightly restrain them while allowing access to the tube still inserted in the carotid. By attaching the tube to a pressure transducer, repeated or continuous measurement of blood pressure is possible.

Animals↗

PubMedDate not supplied

Experimental studies on the radiation-modifying effect of bleomycin in malignant and normal mouse tissue in vivo.

The interaction between bleomycin (BLM) and radiation was studied in a C3H mammary carcinoma and its surrounding normal skin. In the skin, single and fractionated doses of sequential treatment with BLM (25 mg/kg) 24 hours prior to radiation therapy did not influence the response to irradiation, whereas simultaneous treatment with BLM given 15 minutes before radiation therapy enhanced the reaction to irradiation by a factor of 1.2 or 1.4 following treatment with one fraction or five fractions, respectively. The tumor response to irradiation was not influenced by a single sequential treatment, but five daily fractions of radiation therapy following five daily dose fractions of BLM increased the radiation dose needed to control 50% of the tumors, probably because the tumors continued to grow during the BLM treatment. Simultaneous treatment enhanced the response to irradiation by a factor of 1.2 after both single-dose and fractionated therapy. Based on these data it was concluded that none of the combined treatment schedules were able to produce a better therapeutic effect than radiation therapy alone. Furthermore, mortality due to lung fibrosis in mice treated with BLM indicated the marked toxicity of the drug. This toxicity was most pronounced after fractionated treatment and when radiation therapy and BLM were given simultaneously.

Animals↗