Biomedical subjects

R Henriksson

Publications and source records attributed to R Henriksson.

At least 109 records · Page 6Linked to original sources

PubMed1994

Effects of irradiation on neuropeptide expression in rat salivary gland and spinal cord.

It is well-known that a large number of factors can influence the expression of neuropeptides in the nervous system. In the present study, the effects of unilateral and bilateral irradiation to the rat head and neck on the expression of neuropeptides in the innervation of the submandibular gland and in the ganglionic cells of the submandibular ganglion was examined ten days and six months after treatment. Antisera directed against enkephalin and bombesin and immunohistochemical methods were used. The effects of bilateral irradiation on the staining pattern of various neuropeptides in the cervical spinal cord were also studied. In the submandibular gland and in the submandibular ganglionic cells, there was a markedly increased neuropeptide expression ten days after bilateral treatment, as seen after staining with both antisera used, while no changes occurred after unilateral treatment. Six months after treatment, the pattern of neuropeptide expression in the submandibular gland/ganglion corresponded to that seen in controls. Irradiation did not lead to any changes in the staining pattern of neuropeptides in the spinal cord. The observations show that there is a great complexity in the susceptibility of nervous tissues to radiotherapy with respect to influences on the expression of neuropeptides.

Animals↗

PubMed1994

Expression of estramustine-binding protein in ependymomas and in human and developing rat ependymal cells.

The mainstays of primary treatment of ependymoma are aggressive surgery followed by radiotherapy. Although spreading occasionally occurs in the cerebrospinal pathways, chemotherapy is still not established and no ultimate drug has so far been found. Estramustine-phosphate (EMP), with a demonstrated effect on astrocytoma in vitro, has been shown to penetrate the blood-tumor barrier and to accumulate in human brain tumor tissue including ependymoma. It has been proposed that the cytotoxic effect of EMP depends on the presence of a binding protein, estramustine-binding protein (EMBP). In the present paper we have, for the first time, immunohistochemically demonstrated an EMBP-like protein in a series of ependymomas. Immunoreactivity was found within the cytoplasm of the tumor cells with a tendency to increase with increasing malignancy of the tumor. In addition, the occurrence of EMBP-like protein was demonstrated in human ependymal cells. In the rat brain, a weak immunoreactivity was detected in early fetal neuroepithelial cells while the staining intensity was increased in mature ependymal cells in late fetal, neonatal, and adult rat. Thus; immunoreactivity for an EMBP-like protein was demonstrated in ependymoma tissue, normal human ependyma and in the developing rat ependymal cells.

Adolescent↗

PubMed1994

Identification of potassium flux pathways and their role in the cytotoxicity of estramustine in human malignant glioma, prostatic carcinoma and pulmonary carcinoma cell lines.

Clinically-used drugs such as furosemide, bumetanide and cardiac glycosides, are modulators of transmembrane fluxes of cations. Recently, it has been suggested that the regulation of intracellular cation concentrations could be a primary target for anti-neoplastic drugs, and that the cytotoxic activity may be altered by inhibitors of cation fluxes at the level of the plasma membrane. Therefore, we investigated the mechanisms by which cations are translocated across the plasma membrane of malignant glioma (U251 MG), prostatic carcinoma (PC3) and pulmonary carcinoma (P31) cell lines. The interactions between cation flux inhibitors and the cytotoxicity of estramustine were also evaluated. Ouabain, the classical inhibitor of Na+, K+ATPase, markedly reduced 86Rb (K+) influx in all three lines, indicating that this ion transport system is present in the cells. Furosemide and especially bumetanide inhibited the 86Rb influx, indicating the presence of the Na+, K+, Cl- co-transport system. The potassium channel blocker, tetraethylammonium, but not apamin reduced the influx of 86Rb showing that high conductance K+ channels are present, but that channels of low conductance probably do not exist in these cell lines. The Na+, K+, Cl- co-transport inhibitors furosemide and bumetanide significantly reduced cytotoxicity of estramustine in P31 cells, whereas no interaction between other K+ flux inhibitors and the anti-neoplastic drugs were detected in any of the cell lines investigated. Thus, the data show that Na+, K+, ATPase and NA+, K+, Cl- co-transport systems and K+ channels of high conductance are present in malignant glioma (U251 MG), prostatic carcinoma (PC3) and pulmonary carcinoma (P31) cell lines, and that inhibition of the Na+, K+, Cl- co-transport system in P31 is associated with reduced cytotoxicity of estramustine. The results justify further studies evaluating the role of these cation flux pathways in terms of targets for anti-neoplastic therapy.

Bumetanide↗

PubMed1994

Parotid saliva composition during and after irradiation of head and neck cancer.

Parotid saliva composition was studied before, during and up to 18 months after the irradiation period in 16 cancer patients treated for malignancies in the head and neck region. Stimulated parotid saliva was collected prior to radiotherapy and, when possible, weekly during treatment. New samples were taken 2, 4, 6, 12 and 18 months after the end of radiotherapy. Nine of the 16 patients were treated with bilateral irradiation fields and 7 patients with unilateral irradiation fields, with a total dose not exceeding 52 Gy. During the entire irradiation period the fraction of glands producing measurable volumes of saliva decreased to 40%. In the postirradiation period the number of active glands gradually increased and saliva secretion rate returned to an average of 72% of the initial value 18 months after the end of irradiation. The concentrations of the measured variables increased already during the first week of radiotherapy and at the end of the treatment period the concentrations for total protein, salivary peroxidase, hexosamine and salivary IgA were significantly increased. The concentrations for total protein, salivary peroxidase and salivary IgA were still increased 6 months after the end of irradiation. At the 18-months observation all concentrations had returned to normal, as evaluated in a paired t-test. The majority of glands irradiated with 40-52 Gy recovered not only in secretion rates but also with respect to the components studied in this investigation.

Adult↗

PubMed1994

Increase in mast cells and hyaluronic acid correlates to radiation-induced damage and loss of serous acinar cells in salivary glands: the parotid and submandibular glands differ in radiation sensitivity.

The detailed mechanisms which can explain the inherent radiosensitivity of salivary glands remain to be elucidated. Although DNA is the most plausible critical target for the lethal effects of irradiation, interactions with other constituents, such as cell membrane and neuropeptides, have been suggested to cause important physiological changes. Moreover, mast cells seem to be closely linked to radiation-induced pneumonitis. Therefore, in the present study the effects of fractionated irradiation on salivary glands have been assessed with special regard to the appearance of mast cells and its correlation with damage to gland parenchyma. Sprague-Dawley strain rats were unilaterally irradiated to the head and neck with the salivary glands within the radiation field. The irradiation was delivered once daily for 5 days to a total dose of 20, 35 and 45 Gy. The contralateral parotid and submandibular glands served as intra-animal controls and parallel analysis of glands was performed 2, 4, 10 or 180 days following the last radiation treatment. Morphological analysis revealed no obvious changes up to 10 days after the irradiation. At 180 days a radiation dose-dependent loss of gland parenchyma was seen, especially with regard to serious acinar cells in parotid gland and acinar cells and serous CGT (convoluted granular tubule) cells in the submandibular gland. These changes displayed a close correlation with a concomitant dose-dependent enhanced density of mast cells and staining for hyaluronic acid. This cell population seems to conform with the features of the connective tissue mast cell type. The parotid seems to be more sensitive to irradiation than the submandibular gland. Thus, the present results further strengthen the role of and the potential interaction of mast cells with radiation-induced tissue injury and alterations in normal tissue integrity.

Animals↗

PubMed1994

Estramustine binding protein in primary tumours and metastases of malignant melanoma.

The presence of estramustine binding protein (EMBP), a 54 kD cytosolic glycoprotein, which is distinct from the estrogen receptor, was investigated in a pilot study of primary malignant melanomas and their metastases. In 11 primary melanomas EMBP was demonstrated by immunohistochemistry. The percentage of positive melanoma cells ranged between 11-91% with a mean of 57%. Radioimmunoassay on metastatic tissue revealed significant amounts of EMBP, with values ranging between 0.6-4.2 with a mean of 1.6 ng/mg protein. A high number of cells with a positive stain for EMBP in the primary tumours was significantly correlated to a short interval between diagnosis and the occurrence of metastases. Presence of EMBP in malignant melanoma may have prognostic significance and the role of hormone-linked cytostatic drugs in the treatment of this disease needs further investigation.

Adult↗

PubMed1994

Acute effects of accelerated radiotherapy in combination with carbogen breathing and nicotinamide (ARCON).

Combining accelerated radiotherapy with carbogen and nicotinamide (NAM) has been proposed as a strategy to overcome the sparing effect of tumour clonogen repopulation and hypoxia. Six patients with squamous cell carcinomas of the head and neck were given accelerated radiotherapy, carbogen breathing and high dose nicotinamide in order to evaluate the feasibility of this treatment regimen. The patients received radiotherapy in two daily fractions of 1.8-1.9 Gy, five days/week, total dose 54-57.6 Gy, in an overall treatment time of 19-22 days. The interfraction intervals were 7-8 hours between the two fractions on the same day. Carbogen breathing was started 5 minutes before and went on during each radiation fraction. a variety of NAM doses were administered orally in conjunction with radiation therapy and analyses of plasma concentrations of NAM and its metabolites were performed. The most common side-effect from NAM was nausea and vomiting, which in one case hampered further NAM administration. The side effects were not related to plasma levels of NAM or its main metabolites. Additionally, one patient with preexisting heart disease developed a severe hypotension and renal dysfunction. All acute reactions healed without further complications. The mucosal reactions were generally brisk. Thus, the combination of accelerated radiotherapy with carbogen and NAM seems to be tolerable.

Administration, Inhalation↗

PubMed1994

Tolerance to accelerated fractionation in the head and neck region.

To improve efficacy of radiotherapy in head and neck carcinomas, shortening the treatment time by accelerated fractionation is one possible method. However, there is a risk of enhancing side-effects. To study the tolerance to accelerated fractionation a study was thus performed where 2.0 Gy/fraction was given twice daily with 7-8 h interval between fractions. The total dose was 60 Gy and the overall treatment time 19-22 days. Thirteen patients with tumours in the head and neck region were consecutively included in the study. The treatment volumes ranged from encompassing the primary tumour with a margin to including the oral cavity and neck nodes bilaterally. Evaluation has been done by means of scoring the mucosal reactions, subjective estimation of pain, and functional impairment. Furthermore, the late radiation effects have been assessed by scoring of telangectasia, fibrosis of subcutaneous tissues and necrosis. The median follow-up time was 37 months. The treatment was generally well tolerated and could be completed without interruptions. However, in most cases the acute mucosal reactions appeared to be severe for a longer time than after standard fractionation. Restitution of normal mucosa without persistent complications has been achieved in all cases. The toxicity of this treatment schedule seems to be acceptable. No severe late complications have occurred during the follow-up period. A comparison with other treatment schedules has been made, using the linear-quadratic (LQ) model to calculate biologically effective dose (BED). In the present schedule it is shown that the early reacting normal tissue and tumour effects are predicted to be similar to the EORTC schedule whereas the late effects would be less pronounced. The CHART protocol gives less effects on early responding tissues due to the low total dose.

Acute Disease↗

PubMed1993

[Hypofractionation. A method for stereotaxic radiation of major brain lesions with linear accelerator].

Fifteen patients with brain tumours or arteriovenous malformations (AVMs) underwent hypofractionated stereotactic irradiation, 2-5 fractions being delivered using a linear accelerator and a non-invasive stereotactic frame. Results of the treatment of brain metastases were comparable with those reported for single fraction radiosurgery. With the AVMs, the rate of obliteration would seem to be slower than that after radiosurgery, perhaps because the irradiated volumes in our study were significantly larger than those treated with radiosurgery. An advantage of hypofractionated stereotactic irradiation is that larger brain lesions can be treated than is appropriate with radiosurgery.

Adult↗

PubMed1993

Structural changes in the middle ear tissues of the rat after fractionated irradiation.

Chronic suppurative otitis media often ensues in patients treated with irradiation against a head and neck tumor. In an experimental study, rats were exposed to irradiation to evaluate the sensitivity of the middle ear to an accumulated irradiation dose of 20-45 Gy. Observed otomicroscopically, all animals appeared to have normal tympanic membranes and no fluid developed in the middle ear space. Ten days after the irradiation, minor structural changes had occurred in the pars flaccida. The keratinizing epithelium had thickened and mitoses were seen histologically. The lamina propria was edematous and contained polymorphonuclear cells and macrophages. The middle ear mucosa from all other tissue sites appeared normal. Six months after irradiation only minor changes in the pars flaccida were evident: the lamina propria was thin and inelastic and macrophages were present in the stroma. It is inferred from this study that the middle ear of the rat is relatively resistant to irradiation.

Animals↗

PubMed1993

Interleukin-2-administration intravenously and intrapleurally in a patient with primary pulmonary adenocarcinoma. Cellular responses in peripheral blood, intrapleural fluid and bronchoalveolar lavage.

A case report of a patient who suffered from a rapidly progressive lung adenocarcinoma with malignant pleural effusions, is given. The patient failed to respond on two series of conventional cytotoxic drug therapy (Carboplatin, Etoposide). Interleukin-2 (IL-2) treatment was first started as intrapleural instillations (3.0 million IU per day in 6 days). A clear clinical response was achieved with ceasing of the pleural effusion, and the overall disease became stable. In the peripheral blood, there was an increase of CD4 positive lymphocytes that remained elevated after finishing the installation period. Both in bronchoalveolar lavage (BAL), and in the pleural fluid, there was a marked decrease of cells recovered, possibly due to an enhanced tissue attachment of activated cells. A second analysis with subtyping of lymphocytes in BAL was impossible due to the low cell number. In the pleural fluid, the fractions of CD3 positive cells increased from 20 to 71% while the ratio between CD4 and CD8 remained persistently elevated at 6.1:1. Because of the disappearance of the pleural effusion, the patient was thereafter treated with IL-2 given as a continuous infusion (18 million IU per square-metre during 24 hours for 5 days). Hereby a more pronounced cell response was achieved in the peripheral blood. In contrast to the intrapleural treatment route, not only CD4 positive cells, but also the numbers of natural killer cells (NK) increased. However this treatment was also associated with a much higher degree of side effects. It can be concluded from both intrapleural and intravenous IL-2 therapy, that a clinical and immunological response was achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMed1993

Irradiation-induced effects on the innervation of rat salivary glands: changes in enkephalin- and bombesin-like immunoreactivity in ganglionic cells and intraglandular nerve fibers.

When treating head and neck for cancer with the use of radiotherapy the salivary glands are usually within the treatment volume with ensuing dryness and discomfort. Since the autonomic nervous system is of pivotal importance for the salivary gland function and integrity, the irradiation-induced effects may involve an influence on the innervation of salivary glands. Therefore, the rat submandibular gland, including the submandibular ganglionic cells, has been subjected to immunohistochemical examination with respect to expression of neuropeptides following fractionated irradiation with high energy photons. A markedly enhanced expression of bombesin- and leu-enkephalin-(ENK)-like immunoreactivities (LI) in the ganglionic cells and a pronounced increase in the number of nerve fibers showing these immunoreactivities in the submandibular gland tissue following irradiation were observed 10 days after treatment. On the other hand, no changes in the patterns of VIP (vasoactive intestinal polypeptide)- and NPY (neuropeptide Y)-immunoreactivities occurred. Thus, the present study shows that alterations in the expression of certain neuropeptides take place in the submandibular gland and its associated ganglionic cells in response to irradiation of the head and neck region. These changes may add further explanation to the inherent radiosensitivity of salivary glands.

Animals↗

PubMed1993

Uptake and retention of estramustine and the presence of estramustine binding protein in malignant brain tumours in humans.

Estraumustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, has been shown to exert cytotoxic effects on glioma cells in vitro. The drug uptake is assumed to depend on a specific estramustine binding protein (EMBP). One of the main difficulties in achieving cytotoxic effect in malignant brain tumours is believed to be due to the poor penetration of cytotoxic drugs into tumour tissue. In patients with malignant supratentorial brain tumours we have analysed the uptake of EMP metabolites in tumour tissue after oral administration and demonstrated EMBP in the same tissue specimens. Sixteen patients were given 280 mg EMP orally 14 h prior to surgery. Specimens from brain tumour tissue, cystic fluid, and serum were collected during surgery. Using gas chromatography the metabolites of EMP, estramustine (EaM) and estromustine (EoM), were quantified, EMBP was demonstrated by immunohistochemistry. The mean concentrations of EaM and EoM, expressed in ng g-1, were 60.3 and 38.4 in tumour tissue and 3.5 and 56.3 in serum, respectively. An accumulation of EaM in tumour tissue was found with a mean concentration gradient of 16.1 versus serum, while the gradient for EoM was 0.76. EMBP was demonstrated with a high degree of staining in all but one tumour. The high concentrations of EaM and EoM found in malignant brain tumour tissue correspond to potentially cytotoxic levels. The present results as well as the earlier in vitro demonstrated cytotoxic effects on glioma cells strengthen the possibility of a therapeutic effect of EMP in the treatment of malignant brain tumours.

Adult↗

PubMed1993

Fractionated irradiation and late changes in rat parotid gland: effects on the number of acinar cells, potassium efflux, and amylase secretion.

Irradiation of head- and neck cancer commonly results in oral dryness and discomfort for the patients due to salivary gland damage. The exact mechanisms behind the inherent radiosensitivity of salivary glands remain to be elucidated. In the present study, we used different in vitro secretory models and quantitative morphological characterization of rat parotid gland following fractionated unilateral irradiation to one gland on a 5-day fraction schedule (Monday-Friday) with 6 MV photons (total dose 30, 35, 40 and 45 Gy) or a two-fractions regimens in 5 days (Monday and Friday) with total dose of 24 and 32 Gy. The contralateral shielded gland served as control, and parallel analyses of irradiated and control glands were performed 180 days following the last irradiation treatment. The relative noradrenaline stimulated electrolyte secretion (86rubidium tracer for potassium) was decreased in the irradiated compared with control glands. The noradrenaline-stimulated exocytotic amylase release was not significantly affected by irradiation, but the gland content of amylase was decreased dose-dependently. The quantitative morphological analysis revealed a dose-dependent decline in the number of acinar cells, whereas the other parenchymal cells (intercalated, striated- and excretory duct cells) were unaffected by the irradiation compared with control glands.

Amylases↗

PubMed1993

Tobacco smoke exposure suppresses radiation-induced inflammation in the lung: a study of bronchoalveolar lavage and ultrastructural morphology in the rat.

Previous studies on patients with breast cancer, who received postsurgical irradiation, displayed a markedly suppressed inflammatory response in the lung of smoking patients compared to nonsmokers. The aim of the present study was to investigate further the effect of exposure to tobacco smoke on the development of irradiation-induced pneumonitis in the rat. Four groups of animals were used: controls (C); those exposed to tobacco smoke (S); those irradiated but not exposed to smoke (RNS); and those irradiated and exposed to tobacco smoke (RS). The rats were exposed to a diluted main stream of cigarette smoke, at a concentration of about 0.4 mg.l-1, in a nose-only exposure system for 1 h.day-1, 5 days.week-1 for 10 weeks. Exposure to tobacco smoke started 3 weeks before irradiation. The basal one third of both lungs was exposed to a single radiation dose of 28 Gy (6 MeV photons). All animals were killed 7 weeks after irradiation. We compared findings in bronchoalveolar lavage (BAL) and tissue morphology. The alveolar tissue showed less inflammation in the RS-group than in the RNS-group. Most strikingly, mast cells were increased one hundredfold in the lung interstitium and thirty fold in the peribronchial area in the RNS-group, whereas no increase was found in the RS-group or in the controls. The alveolar septa of the RNS-group were thickened, with occurrence of inflammatory cells and mast cells, whereas the RS-group displayed no difference as compared to the non-irradiated, nonsmoking group (C).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Amiloride but not bumetanide protects against the cytotoxic effects of estramustine and bleomycin in cultured fibroblasts.

The effects of the clinically used diuretics amiloride (an inhibitor of Na+/H+ exchange) and bumetanide (an inhibitor of Na+, K+, Cl- co-transport) were tested on the cytotoxicity of estramustine and bleomycin in cultured fibroblasts. Both estramustine (50 micrograms/ml) and bleomycin (10 micrograms/ml) reduced the number of surviving clones. Amiloride (100 microM) but not bumetanide (100 microM) partly protected against the cytotoxic effect of both estramustine and bleomycin. The protective effect of the combination of amiloride and bumetanide was not stronger than the effect of amiloride alone. Amiloride or bumetanide alone did not affect the clonal survival. It is suggested that the protective effect of amiloride is not mediated by an effect of the molecular mechanism of cytotoxicity but may rather be due to changes in cellular metabolism and/or drug handling.

Amiloride↗

PubMed1992

Effects of clonidine-induced hypotension and dopamine-induced hypertension on blood flows in prostatic adenocarcinoma (Dunning R3327) and normal tissues.

In the present study it was investigated whether hypertension induced by dopamine or hypotension induced by clonidine could influence the relative blood distribution in a s.c. transplanted prostatic adenocarcinoma in relation to blood flow in normal tissues in rats. The blood flow was measured by using a radioactive microspheres technique. A bolus injection of 5 micrograms clonidine caused a decrease in the systemic blood pressure with 15-45 mm Hg, and blood flow to the central parts of the tumor, decreased with more than 50%. In the prostate, testes and ileo-psoas muscle a similar reaction was seen. During an infusion of 95-120 micrograms/kg/min dopamine, the blood pressure increased with 15-30 mm Hg, but the blood flow to the tumor was unchanged. However, in the testes and kidneys a decreased blood flow was observed. Moreover, mean blood flow to the central parts of the tumor decreased with increase in tumor size. The results further indicated that hyper- or hypotension or concomitantly given vasoactive drugs with the specific cancer treatment can have unwarranted effects on the distribution of cytotoxic drugs and oxygenation of the tumor.

Adenocarcinoma↗

PubMed1992

Interleukin-2-induced growth inhibition of prostatic adenocarcinoma (Dunning R3327) in rats.

The present study was designed to evaluate the effect of a biological response modifier, interleukin-2 (IL-2), on the growth in rats of Dunning (R3327, androgen sensitive) prostatic adenocarcinoma. IL-2 was given to one group of tumour-bearing rats by subcutaneous infusion (Alzet micro-osmotic pump 2002, 14 days) of 424,286 IU/kg per day during 4 weeks. Another group was sham-operated and served as control. Tumour growth was calculated by weekly measurement of tumour volume. IL-2 treatment caused a significant growth delay without any significant toxicity. Plasma testosterone concentrations were similar in both groups and ventral prostatic weights did not differ. Morphometric analyses of epithelial cells, stroma, luminal compartment in tumour tissue and calculation of the number of intratumoral lymphocytes did not show any differences between the two groups. It is suggested that IL-2 treatment can decrease prostatic tumour growth without apparently affecting the testosterone metabolism. Further studies with special interest on the mechanism of action are justified.

Adenocarcinoma↗