Homeostatic derangement in the CBA rodent host during the growth of the CaNT tumor.

The purpose of this study was to evaluate some indicators of the pathogenesis of cancer cachexia in which the growth of the CaNT tumor markedly alters the metabolism and induces measurable biochemical changes of the host. An increase of hexokinase and lactate dehydrogenase activities with tumor volume, coupled with the decline of oxygen consumption are shown in this work. Furthermore changes in the mean spin lattice and spin-spin relaxation time values of the tumor provide additional information of the abnormal cellular spatial and metabolic relationships that exists within the tumor. In the liver of the host, the augmentation of the oxygen uptake and specific activities of lactate dehydrogenase and fructose-1,6-diphosphatase shown in this work, reflecting an increase in the glucose metabolism rate and thus, energy expenditure of the host. This may envisage some correlation with the onset of biochemical changes in the homeostatic derangement in the host during the fast growth of the tumor.

Cholinesterase response in the rhabdomyosarcoma tumor and small intestine of the BALB/c mice and the radioprotective actions of exogenous ATP after lethal dose of neutron radiation.

The rhabdomyosarcoma tumors were subjected to different doses of 2.0, 3.8 and 7.0 Gy from a neutron beam facility p(66 MeV)/Be. Elevated levels of cholinesterase activity are observed in which there is a correlation between the different doses of neutron radiation and the augmentation response of this enzyme. The increase of cholinesterase activity after 7 Gy neutron irradiation as a feature of involvement in the homeostatic mechanism maintaining the proper choline/acetylcholine ratio in the cell is also observed at 1 and 24 h in both tissues, rhabdomyosarcoma and small intestine. The activity of the enzyme after neutron irradiation with prior administration of ATP showed smaller increases when compared with increases observed after neutron irradiation alone. Moreover in the present work the protective mechanism of ATP in the response of cholinesterase activity is marked differential between both, normal and tumoral tissue and correlated inversely with the administered of the following concentrations of exogenous ATP (8, 25, 80, 250, and 700 mg/kg body weight) prior to exposure to 7 Gy neutron radiation. These results reflect the radioprotective ability of exogenous ATP to exert a number of metabolic adaptations as a defense mechanism in which the cell exposed to neutron radiation could remain viable because the injury is potentially repairable.

Radioprotective properties of ATP and modification of acid phosphatase response after a lethal dose of whole body p(66MeV)/Be neutron radiation to BALB/c mice.

The intraperitoneal administration of exogenous ATP prior to a lethal dose (7 Gy) of whole body neutron irradiation increased the radioresistance of BALB/c mice. This radiation used the beam from a neutron therapy facility produced by the reaction p(66 MeV)/Be. Survival of the mice, determined 7 days post-irradiation as the endpoint, was increased from 26% to 86% by the action of the exogenous ATP. Furthermore, the response of acid phosphatase activity as an indicator of the acute radiation effects showed a marked augmentation in both tissues studied, testes and small intestine. The activity of the enzyme after neutron irradiation with prior administration of ATP showed smaller increases when compared with the increases observed after neutron irradiation alone. This implies that exogenous ATP reduces the effect of the lytic enzyme and, hence, damage. Finally, changes were observed in the activity of acid phosphatase in the testes and intestine with different concentrations of exogenous ATP. In both tissues there was a monotonic decrease in the activity of the enzyme with increase of the concentration of exogenous ATP administrated before radiation. These results reflect the protective ability of exogenous ATP as an adaptive defence mechanism to reduce radiation damage in normal tissues after a lethal dose of neutron radiation.

Modification of the effects of hyperthermia and neutron radiation on the activity of acid phosphatase in CaNT tumors.

Acid phosphatase activity was measured in implanted murine CaNT tumors of varying volumes. There is a clear monotonically increasing relation between acid phosphatase activity and tumor volume. Also the tumors were subjected to either induced artificial hypoxia or hyperthermia (41.0 degrees C) alone, or combined with neutron irradiation (3.8 Gy). Changes in the activity of this enzyme following radiation damage could reflect tissue damage associated with metabolic disturbances. The effect on enzyme activity after sequential hyperthermia and neutron irradiation is not synergistic, as is shown in the quantitative experimental data. This implies that the mechanisms of heat damage differ from that of neutron beam damage, as reflected by acid phosphatase activity. The CaNT tumor was also shown to be thermosensitive after administration of mitoxantrone. Finally, the role of exogenous ATP was shown to provide heat protection by modification of those thermal effects resulting in the activity of acid phosphatase. The augmentation of this hydrolytic enzyme probably represents initial metabolic damage in the tumor after different modalities of radiation alone, or combined with mitoxantrone and exogenous ATP.

Response of normal BALB/c mouse tissue to p(66 MeV)/Be fast neutron radiation: protection by exogenous ATP.

Exogenous ATP administered by intraperitoneal injection of 700 mg/kg has been used to provide radioprotection of BALB/c mice after a lethal dose of whole body irradiation (6 Gy). This comprised the beam from a neutron therapy facility produced by the reaction p(66 MeV)/Be. Survival of the mice, using 30 days post-irradiation as the endpoint, was increased from 40% to 85% by action of the exogenous ATP. Furthermore, ATP's glucoregulatory effects, which modify basal physiological regulatory processes were studied in the testes and caused significant augmentation in the activities of the glycolytic enzymes hexokinase and lactate dehydrogenase when compared with neutron radiation alone. Finally ATP reduced the activity of testicular acid phosphatase, an indicator of lytic processes in the tissues damaged. These radioprotection actions in BALB/c mice reflect an adaptive defence mechanism to maintain homeostasis in response to the radiation injury.

Acid phosphatase response in murine rhabdomyosarcoma for various tumour volumes and after different doses of neutron irradiation, alone or combined with exogenous ATP.

Acid phosphatase activity measured in a methylocholanthrene-induced murine rhabdomyosarcoma showed a monotonically increasing relation between enzyme activity and tumour volume. This could be related to the lytic activity of the enzyme in large tumours which become more hypoxic and necrotic, and hence enhance degradation and turnover of damaged tumour cells. The tumours were also subjected to irradiation using doses of 2.0, 3.8 and 6.0 Gy from a neutron therapy facility p(66MeV)/Be. The correlation between different doses and response of acid phosphatase activity could reflect the relation of magnitude of damage from metabolic disturbances, with dose. Furthermore exogenous ATP was shown to provide radioprotective action against neutron irradiation in two different experiments. The ATP reduced the activity of this lytic enzyme in irradiated tumours and also decreased tumour growth delay. This radioprotective role of exogenous ATP in a murine tumour could be related to physiological regulatory processes during defence mechanisms to maintain self-organisation in response to the radiation damage.

The multifactorial role of ATP in repair processes and radioprotection.

Endogenous ATP as a source of energy appears to play an important role associated with repair processes after ionising radiation damage in living organisms. Also exogenous ATP can play a central part in radioprotection. This paper considers interaction between the multifactorial roles of ATP in radioprotection and metabolic provision for repair processes, which can depend on its physiological regulatory function as a neuromodulator via cell membrane receptors. It is hypothesised that all these complex functions reflect an adaptive defence mechanism, against radiation insults, in which ATP plays a pivotal role to maintain homeostasis.

Theoretical and experimental considerations linking an environmental stress to expression of endogenous retroviruses in a mammalian tumour.

CBA mice, containing the transplantable CaNT adenocarcinoma were exposed to magnetic fields of 0.5T. Doubling times of the tumours were found to increase significantly from 71 to 123 hours. Electron microscopy of these tumours revealed that the numbers of intracisternal A-type viral-like particles increased from a total of 127 in control mice (counted in 97 fields from 4 different tumours), to 459 in mice exposed to magnetic fields (counted in 95 fields from 5 different tumours). Similarly, intra-cytoplasmic A-type particle numbers increased from 98 to 184. In contrast the number of budding and extracellular C-type virus particles did not differ significantly in mice exposed to the magnetic field. To our knowledge this is the first report linking an environmental stress (magnetic field) to the visible expression of endogenous retro-viral-like type-A particles. We therefore propose the hypothesis that environmental stress may be relevant to the expression of endogenous retroviruses in mammalian cells. Such a mechanism could be relevant in the mechanisms of carcinogenesis and in the rapid evolution of species.

Glucose-6-phosphate dehydrogenase activity in CaNT tumours of different volume and response to tumour clamping and X-irradiation.

Changes in the levels of glucose-6-phosphate dehydrogenase (G6P-DH) activity, versus tumour volume were measured in vivo under normoxic conditions in the CaNT tumours grown in CBA mice. A monotonically increasing relation was found. Artificially induced tumour hypoxia resulting from 15 min of clamping was accompanied by enhanced G6P-DH activity, but one hour after release of the clamps (reflow), the specific activity of the enzyme decreased to about the same level as that of the normoxic controls. Also the levels of G6P-DH activity in normoxia were measured one hour after 5, 10 and 15 Gy of X-rays (100 kVp). A significantly higher G6P-DH activity which increased with dose, was found in the tumours. This paper gives evidence of increased G6P-DH activity linked with tumour progression, under gradual amplification of the metabolic unbalance. The augmentation of G6P-DH following X-irradiation probably represents a cellular adaptive defence mechanism during the demand for increased metabolism.

The relation of ATP response in CaNT tumours after X-irradiation to varying tumour volumes.

The response of adenosine-5'-triphosphate (ATP) levels in implanted murine CaNT tumours, 2.5 h after 10 Gy X-rays (100 kVp) was measured in vivo using various tumour volumes. It is probable that the concentration of ATP, which increased after X-irradiation, plays a major role in energy supply associated with cellular repair processes. Nevertheless, when ATP levels in irradiated tumours were plotted against tumour volume in the range 150-550 mm3, a monotonically decreasing relation was found. This is interpreted as reflecting the degree of hypoxia and changes in the tumour metabolic status. In addition effects of vascular occlusion and artificial hypoxia have been studied after clamping the tumour for 15 min, followed by a radiation dose of 10 Gy and maintaining the clamp for a further 2.5 h. This showed a drastic decrease in the ATP levels 2.5 h after the irradiation, compared with controls in normoxia. It is thought this is due to induction of hypoxia which is produced throughout the tumour volume, resulting in the depletion of cellular ATP. This implies that the clamped tumour cells are less capable of generating a metabolic response following radiation damage.

Microbiological analyses of Merluccius merluccius hubbsi (Marini, 1933) fillets treated with Co-60 ionizing radiation.

Fillets of a hake, Merluccius merluccius hubbsi, were exposed to 2 kGy, 6 kGy, and 10 kGy of ionizing radIation from a Cobalt 60 source and were subsequently stored frozen at 0 degree C. Both these irradiated samples and control samples were examined to determine their bacterial counts and organoleptic qualities (texture, elasticity odor, color, and drip loss) for a period of seven weeks following the irradiation. The irradiated fillets showed an initial marked decrease in the total number of bacteria--amounting to roughly one order of magnitude for those exposed to 2 kGy and roughly three orders of magnitude for those exposed to 6 kGy and 10 kGy as compared to the controls. The samples irradiated with 6 and 10 kGy had bacterial counts well below the minimum acceptable level of 0.8 x 10(6) bacteria per gram for the entire seven-week study period. Regarding organoleptic quality, the fillets exposed to 2 kGy and 6 kGy were found to retain acceptable qualities for an average of about six weeks, somewhat longer than the controls and other irradiated samples. Considering both bacterial counts and organoleptic qualities, the most effective of the three radiation doses employed was 6 kGy.

Adenosine-5'-triphosphate levels in experimental CaNT and Fib/t tumours of varying volume and degree of hypoxia.

The variation of adenosine-5'-triphosphate (ATP) content per unit mass of tumour, versus tumour volume was measured in vivo under normoxic conditions, using CaNT and Fib/t murine tumours grown in CBA and WHT mice respectively. A monotonically decreasing relation was found. Artificially induced tumour hypoxia resulting from 15 min of clamping was accompanied by reduced ATP levels.

Effect of X irradiation on adenosine triphosphate and glucose-6-phosphate dehydrogenase in the CaNT mouse tumor.

The levels of adenosine triphosphate (ATP) in the transplantable CaNT murine tumor grown in CBA mice at various times following 5, 10, and 15 Gy X rays (100 kVp) were increased within 45 min. Maximal ATP levels occurred at 2.5 h following the 10 Gy dose (3.8 times that of unirradiated controls), returning almost to control levels by 13 h after irradiation. The specific activity of glucose-6-phosphate dehydrogenase (G-6-PDH) after 10 Gy increased about 1.5-fold 1 h after irradiation, returning to control levels by 48 h. It is suggested that the increased ATP following irradiation might play a major role in energy provision when cellular repair processes are able to operate. The increased G-6-PDH activity after irradiation may reflect enhanced metabolism associated with cellular repair mechanisms.