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Biomedical subjects

A S Michalowski

Publications and source records attributed to A S Michalowski.

At least 19 recordsLinked to original sources
PubMed1999

Low-doses of ionising radiation induce melanoma metastases and trigger the immune system--adrenal axis feedback loop.

Low-doses of ionising radiation are frequently implicated in triggering and/or accelerating the growth of skin and other malignancies. It seemed probable that the radiation at similar dose levels might initiate metastasis from already existing tumours. Highly pigmented human melanoma xenograft that had lost its ability for a spontaneous metastasising and grown subcutaneously in athymic mice was exposed to very low and well-defined doses of ionising radiation to determine whether low linear energy transfer radiation can restore metastatic potential of the tumour. To ensure that all effects derived from radiation-activated neoplastic cells only, I was delivered selectively to the cutaneous melanoma instead of using the external beam. The direct response of these tumours to radiation was monitored by determining the growth rate of the lesions. Histopathological methods were employed to detect metastases. The lowest radiation dose of approximately 6 cGy deposited in the tumours initiated metastatic spread in all animals. Gradual increase of the radiation doses diminished both the frequency of the appearance of metastases and their distance from the primary lesions. There were no metastases from non-irradiated melanomas. The highest dose used (60 cGy) did not affect significantly the growth of cutaneous (primary) tumours, but lower doses that enhanced inflammatory infiltration of the lesions reduced tumour growth. Such radiation-stimulated immune responses were accompanied by increased pigmentation in cutaneous lesions and activation of the adrenal cortex indicating that the immune system-adrenal axis feedback loop had been triggered. The results demonstrate that very low-doses of ionising radiation induce melanoma metastases. The phenomenon is accompanied by the stimulation of the immune system-adrenal axis feedback loop that regulates eicosanoid synthesis, thereby suggesting an involvement of these molecules in the process. Radiation doses approaching the therapeutic level do not initiate melanoma dissemination.

Adrenal Glands↗
PubMed1996

211At-methylene blue for targeted radiotherapy of disseminated melanoma: microscopic analysis of tumour versus normal tissue damage.

The present stage of our preclinical investigations of targeted radiotherapy for melanoma with 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)] labelled with astatine-211 (211At), an alpha-particle emitter, concerns toxicity of the treatment, as well as macro- and microscopic evaluation of its efficacy. Fragments of two human melanoma xenografts, pigmented HX118 and non-pigmented HX34 (used as a control), were implanted s.c. into nude mice subsequently treated with two doses of 211At-MTB injected i.v. Alterations in tumour growth rate were related to microscopic damage caused by 211At-MTB to the lesions, as determined by light microscopy using histopathological techniques. 211At-MTB-dependent growth inhibition of pigmented melanoma occurred either instantly or as a gradual reduction in the tumour growth rate. At a later stage, lesions that ceased to grow immediately consisted of quiescent, heavily pigmented tumour cells, as well as advanced fibrosis, and were extensively infiltrated by melanin-laden phagocytes. Large, unresorbed and often calcified necrotic deposits characterised the tumours responding gradually to the treatment. 211At-MTB remained non-toxic in normal organs. Only a relative number of small lymphocytes in the groin lymph nodes in a minority of animals was temporarily reduced, most often in conjunction with the treatment of pigmented tumours. The data demonstrated a high therapeutic effectiveness of 211At-MTB towards pigmented melanoma at the expense of negligible injury to normal tissues, and revealed that the macroscopic determination of tumour growth rate often underestimated an efficacy of the applied treatment.

Animals↗
PubMed1996

The role of blood flow in chronic duodenal ulcer.

BACKGROUND: Changes in gastroduodenal blood flow have been implicated in the pathogenesis of duodenal ulcer. We have studied duodenal blood flow during the development of an acute to chronic duodenal ulcer by using the abscopal model, in which ulcers are generated as an indirect effect of lower mediastinal irradiation. METHODS: Female CFLP mice (n = 108) weighing 25-40 g were randomly allocated to one of three groups. Controls were not irradiated. Irradiated 'controls' received 18 Gy 250 kV X-rays to the upper mediastinum (which does not cause duodenal ulceration). The lower mediastinum group received the same dose of irradiation, which has been shown to induce typical chronic duodenal ulcers in 45% of animals so treated. Animals were studied by means of radiolabelled microspheres 3 or 7 days later (that is, during and at the end of the lag period for ulcer induction). RESULTS: Proximal duodenal blood flow specifically was reduced by 32% in the lower mediastinum group compared with irradiated controls at 7 days (4.3 versus 6.3 ml/g tissue/min; P = 0.025 by ANOVA with contrast); there was no significant difference in blood flow to the stomach and to the distal duodenum. The decrease in proximal duodenal blood flow in the lower mediastinum group did not differ in the five animals that developed ulcer compared with the seven that did not. CONCLUSION: Although there is an overall decrease in duodenal blood flow associated with chronic duodenal ulcer, reduced blood flow may not explain individual susceptibility to ulceration.

Acute Disease↗
PubMed1994

211At-methylene blue in targeted radiotherapy of disseminated melanoma.

Targeted radiotherapy with 211At-methylene blue (211At-MTB) is a systemic treatment selectively directed at melanoma due to a high affinity of MTB to melanin synthesized in the tumor cells. Since MTB forms a strong complex with melanin, it is an effective carrier for a number of radioisotopes to be addressed to the tumor deposits of any size including individually dispersed melanoma cells. Thus, appropriately radiolabeled MTB can be used for either diagnosis or therapy of the neoplasm. As predicted and found in animal experiments, 211At-MTB is most effective therapeutically. Histopathological investigations showed that the highly pigmented 211At-MTB-treated tumors were characterized initially by perivascular oedema and hydropic degeneration of tumor cells followed by gradual development of extensive areas of coagulative necrosis. The necrotic tumor areas contained microvessels occluded by thrombi and tended to undergo microfocal calcification. Although melanoma-bearing animals successfully treated with 211At-MTB did not reveal any adverse effects of the therapy, detailed toxicological studies were undertaken. No serious macro- or microscopic lesions were observed in normal organs of 211At-MTB treated mice. Only the relative number of small lymphocytes in the groin lymph nodes in a minority of animals was variably reduced, most often in conjunction with the treatment of highly, but not poorly, pigmented tumors.

Animals↗
PubMed1994

On radiation damage to normal tissues and its treatment. II. Anti-inflammatory drugs.

In addition to transiently inhibiting cell cycle progression and sterilizing those cells capable of proliferation, irradiation disturbs the homeostasis effected by endogenous mediators of intercellular communication (humoral component of tissue response to radiation). Changes in the mediator levels may modulate radiation effects either by assisting a return to normality (e.g., through a rise in H-type cell lineage-specific growth factors) or by aggravating the damage. The latter mode is illustrated with reports on changes in eicosanoid levels after irradiation and on results of empirical treatment of radiation injuries with anti-inflammatory drugs. Prodromal, acute and chronic effects of radiation are accompanied by excessive production of eicosanoids (prostaglandins, prostacyclin, thromboxanes and leukotrienes). These endogenous mediators of inflammatory reactions may be responsible for the vasodilatation, vasoconstriction, increased microvascular permeability, thrombosis and chemotaxis observed after radiation exposure. Glucocorticoids inhibit eicosanoid synthesis primarily by interfering with phospholipase A2 whilst non-steroidal anti-inflammatory drugs prevent prostaglandin/thromboxane synthesis by inhibiting cyclooxygenase. When administered after irradiation on empirical grounds, drugs belonging to both groups tend to attenuate a range of prodromal, acute and chronic effects of radiation in man and animals. Taken together, these two sets of observations are highly suggestive of a contribution of humoral factors to the adverse responses of normal tissues and organs to radiation. A full account of radiation damage should therefore consist of complementary descriptions of cellular and humoral events. Further studies on anti-inflammatory drug treatment of radiation damage to normal organs are justified and desirable.

Animals↗
PubMed1992

Duodenal ulcer: a model of impaired mucosal defence.

There is a new model of chronic duodenal ulcer in which the ulcer is generated by irradiating the lower mediastinum of mice with a single dose of 18 Gy 250 kV x rays. Single ulcers develop in the proximal duodenum of about half the animals. Previous studies have shown a remarkable morphological and behavioural similarity to duodenal ulcer in man. Ulceration occurs because of an imbalance between aggressive and defensive forces within the duodenum and an attempt has been made to elucidate the pathomechanism of this ulcer by determining acid and pepsin secretion. The basal and pentagastrin stimulated secretion of acid, pepsin, and histamine were measured and no changes in acid or pepsin secretion were shown to occur (risk of type II error < 1%). It is therefore concluded that this chronic ulcer is a model of impaired duodenal defence.

Animals↗
PubMed1991

Acid blockade by omeprazole or ICI 162846 in a chronic duodenal ulcer model.

Oral treatment with the H2-antagonist ICI 162,846 or omeprazole for five days inhibited both basal and pentagastrin stimulated acid secretion by 50% or more in mice. Either treatment increased the luminal secretion of histamine in the basal (12-fold) and stimulated (9-fold) states. Mice treated with the H2-antagonist had a 27% reduction (p less than 0.05) in mural histamine in the acid-producing area of the stomach. Mice were treated so as to induce duodenal ulcers (abscopal model) and were then treated with the H2-antagonist ICI 162,846, omeprazole or vehicle, orally for one week. Fewer duodenal ulcers were found in animals receiving drug treatments than in the oral vehicle group. Both the H2-receptor antagonist and the proton pump blocker inhibit acid production; acid blockade by either drug is accompanied by a massive increase in secretion of histamine. This rise was associated with depletion of the gastric histamine store only with H2-receptor blocker. Both means of acid inhibition reduce the formation of ulcers in this model.

Adenosine Triphosphatases↗
PubMed1991

The curability of tumours of differing size by targeted radiotherapy using 131I or 90Y.

A mathematical model has been used to investigate the relationship of curability to tumour size and cell number for spherical tumours treated with targeted 131I or 90Y, assuming uniform uptake of radionuclide throughout the tumour. The analysis shows that, for any given cumulated activity per unit mass of tumour, cure probability is greatest for tumours whose diameter is close to an optimum value which depends on the path length of the emitted beta-particle. Smaller tumours are less curable because of inefficient absorption of radiation energy, and larger tumours are less curable because of greater clonogenic cell number. The lesser curability of very small tumours is a feature of targeted radiotherapy using long-range beta-emitters which does not occur with external beam irradiation. The predicted inefficiency of sterilisation of microscopic tumours poses a problem for targeted radiotherapy which is analogous to "geographic miss" in conventional radiotherapy. The implication is that small micro-metastases could escape sterilisation by radionuclides administered at activity levels sufficient to eradicate larger tumours. It is suggested that single agent targeted radiotherapy should not be used for treatment of disseminated malignancy when multiple tumours of differing size, including micrometastases, may be present. The analysis implies that an advantage might result from the use of a panel of several radionuclides (including short-range emitters) or from combining targeted radiotherapy using long-range beta-emitters with external beam irradiation or some other modality to which microscopic tumours are preferentially vulnerable.

Beta Particles↗
PubMed1990

Effect of acid blockade on gastric histamine in mice.

Vagotomy and omeprazole effectively inhibited 2-deoxy-D-glucose (-91%) and pentagastrin (-72%) stimulated acid production in mice, respectively. Both vagotomy and omeprazole treatment were accompanied by massive increases in histamine secretion (8-fold or more, during both basal and stimulated states). Mucosal stores of histamine, however, were not depleted. Similar rises in luminal histamine have been observed in patients treated in these ways. The mouse model may thus be suitable to elucidate the kinetics of histamine release in patients.

Animals↗
PubMed1990

Gastrointestinal histamine and histamine formation capacity after gastric irradiation in mice.

Mice were exposed to a single dose of 9 or 15 Gy of X rays directed to the stomach. Histamine and histamine formation capacity (HFC) in the oxyntic region of the stomach were assayed at regular intervals for 7 weeks. After 9 Gy, mean gastric mural histamine fell to 61% of the control value (p less than 0.01) 7 days after irradiation while HFC rose to 172% (p less than 0.05). Both histamine and HFC returned to control values within 2 weeks after irradiation. With 15 Gy, on Day 7, histamine fell to 46% (p less than 0.01) and HFC rose to 260% (p less than 0.05). Histamine concentration remained low (less than half of the control value) while HFC returned to normal. These dose-dependent changes in histamine were observed neither elsewhere in the gut nor in the circulating blood. Further groups of mice were exposed to 3, 6, 9 or 15 Gy to the stomach, with gastric histamine and HFC assayed on Day 7. Histamine concentration was inversely related to dose (r = -0.59, p less than 0.001) and HFC was directly dose dependent (r = 0.52, p less than 0.001). These results suggest that irradiation of the stomach may reduce gastric histamine without inducing a general histamine release. The depletion of the gastric histamine store may explain the inhibitory effect of irradiation of the stomach on gastric acid secretion.

Animals↗
PubMed1989

Gastric histamine in a chronic duodenal ulcer model induced by partial thoracic irradiation.

In a new model, chronic duodenal ulcers are generated by irradiating the lower mediastinum of mice with single doses of X-rays. Histamine, a potent secretagogue, may have a role in the aetiology. Seven days after irradiation, the lag period for ulcerogenesis, mice were given a gastric perfusion test. In mice given irradiation to the lower mediastinum tissue histamine in the oxyntic region of the stomach assayed after perfusion was significantly lower than that of controls. Acid and peptic activity were not different from controls. Histamine release may mediate the abscopal ulcer without increasing acid and peptic activity.

Animals↗