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PubMed1988

Experimental cancer therapy in mice by adenine nucleotides.

Adenosine 5'-monophosphate (AMP), adenosine 5'-diphosphate (ADP) and adenosine 5'-triphosphate (ATP), injected intraperitoneally into tumor-bearing (s.c. implanted footpad tumors) mice, exhibited significant anticancer activity. Daily treatments (for 10 days) inhibited the growth of the fast-growing, aggressive CT 26 colon adenocarcinoma in CB6F1 mice. The growth-inhibitory activity of adenine nucleotides was also observed against a human pancreatic adenocarcinoma, CAPAN-1, xenografts in athymic nude mice. With low tumor burdens some 'cures' were obtained in both model systems. No inherent toxicity, as determined by changes in host weight, were observed during and after the period of treatment. Intraperitoneal injections of 1 ml of 50 mM AMP, ADP or ATP in saline, yielded elevated blood and plasma levels of ATP which lasted for several hours in both strains of mice. The growth-inhibitory activities of adenine nucleotides against tumor cells in vitro, have previously been demonstrated.

Adenine Nucleotides↗

PubMed1994

22-Oxa-1,25(OH)2vitamin D3, a synthetic analogue of vitamin D3, has no promoting activity in a rat liver medium-term bioassay.

Modifying effects of 22-oxa-1,25(OH)2vitamin D3(OCT), a synthetic analogue of vitamin D3, were evaluated in a liver medium-term bioassay using glutathione S-transferase placental form (GST-P)-positive foci and 5-bromo-2'-deoxyuridine (BrdU) labeling to give an index of DNA synthesis. F344 rats were given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg body wt.) and subjected to two-thirds partial hepatectomy at week 3. Commencing 2 weeks from the start, 500 p.p.m. phenobarbital sodium and/or basal diet were fed to the rats for 6 weeks, at the same time as OCT and/or propylene glycol as the vehicle injected intraperitoneally 5 times a week. OCT demonstrated no promoting activity for rat hepatocarcinogenesis, and, in fact, showed a tendency to decrease the area per unit area of (GST-P)-positive foci in the livers of rats fed 500 p.p.m. phenobarbital sodium. However, intergroup differences in areas and numbers per unit area as well as in BrdU labeling indices were not statistically significant.

Animals↗

PubMedDate not supplied

Congenital malformations and intrauterine growth retardation in streptozotocin induced diabetes during gestation in the rat.

Diabetes was induced in Wistar rats by single intraperitoneal injections of streptozotocin (STZ) (50 mg/kg, in citrate buffer pH 4.7) at both preimplantation and organogenetic stages. The controls were either buffer treated or, following STZ administration, injected intraperitoneally with 2 to 6 IU of insulin daily until term. Fetuses collected on day 20 were found to have several malformations. Major abnormalities included gastroschisis and evisceration, maxillary hypoplasia and interatrial, and interventricular septal defects. Intrauterine growth retardation was present in most of the diabetic groups. Heavier placentae and shorter umbilical cords were also observed. Malformations and intrauterine growth retardation were numerous and severe in the preimplantation treatment groups. Insulin administration significantly improved the fetal body weight but did not change the malformation rate in the group made diabetic during organogenesis. It appears that the duration of hyperglycemic state plays a crucial role in malformation and growth retardation, and meticulous control of blood sugar from early stages has significant beneficial effects on fetal development.

Animals↗

PubMed2007

Satellite glial cells in sensory ganglia: their possible contribution to inflammatory pain.

Neurons in dorsal root ganglia (DRG) are surrounded by an envelope of satellite glial cells (SGCs). Little is known about SGC physiology and their interactions with neurons. In this work, we investigated changes in mouse DRG neurons and SGC following the induction of inflammation in the hind paw by the injection of complete Freund's adjuvant (CFA). The electrophysiological properties of neurons were characterized by intracellular electrodes. Changes in coupling mediated by gap junctions between SGCs were monitored using intracellular injection of the fluorescent dye Lucifer yellow. Pain was assessed with von Frey hairs. We found that two weeks after CFA injection there was a 38% decrease in the threshold for firing an action potential in DRG neurons, consistent with neuronal hyperexcitability. Injection of Lucifer yellow into SGCs revealed that, compared with controls, coupling by gap junctions among SGCs surrounding adjacent neurons increased 2.7-, 3.2-, and 2.5-fold one week, two weeks, and one month, respectively, after CFA injection. In SGCs enveloping neurons that project into the inflamed paw this effect was more enhanced (5.4-fold). Interneuronal coupling was augmented by up to 7% after CFA injection. Pain threshold in the injected paw decreased by 13%, 16%, and 11% compared with controls at one week, two weeks, and one month, respectively, after CFA injection. Intraperitoneal injection of the gap junction blocker carbenoxolone prevented the inflammation-induced decrease in pain threshold. The results show that augmented glial coupling is one of the major events occurring in DRG following inflammation. The elevation in pain threshold after carbenoxolone administration provides indirect support for the idea that augmented intercellular coupling might contribute to chronic pain.

Action Potentials↗

PubMed2003

Antiendotoxin activity of protegrin analog IB-367 alone or in combination with piperacillin in different animal models of septic shock.

The therapeutic efficacy of protegrin peptide IB-367 was investigated in three rat models of septic shock: (i) rats injected intraperitoneally with 1mg Escherichia coli 0111:B4 lipopolysaccharide, (ii) rats given an intraperitoneal injection of 2 X 10(10) CFU of E. coli ATCC 25922, and (iii) rats in which intra-abdominal sepsis was induced via cecal ligation and puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1mg/kg of IB-367, 60mg/kg piperacillin and 1mg/kg of IB-367 plus 60mg/kg piperacillin. The peptide demonstrated lower level of antimicrobial activity than piperacillin, nevertheless it exhibited the dual properties of antimicrobial and antiendotoxin agent. Finally IB-367 and piperacillin association showed to be the most effective therapeutic approach.

Animals↗

PubMed2004

Oxidized low-density lipoproteins accumulate in rat lung after experimental lung edema induced by alpha- naphthylthiourea (ANTU).

Oxidation of the low-density lipoprotein (LDL) results in the production of modified LDLs. Oxidation of LDL cholesterol plays a role on the pathogenesis of endothelial dysfunction. This study was designed to investigate the possible participation of the oxidative modification of low density lipoprotein in the lung edema induced by alpha-naphthylthiourea (ANTU), which is a well-known noxious chemical agent on the lung endothelium. When ANTU injected intraperitoneally into rats (15 mg kg(-1)), it produced lung edema as indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion (PE) reaching a maximum within 4 h. A significant lung edema was observed 4 h after intraperitoneally injection of alpha-naphthylthiourea when compared with olive oil-injected control rats. On microscopic examination of alpha-naphthylthiourea-treated rats were shown to have severe lung injury, while no change was observed in olive oil-treated control rats. While there were no staining in control lungs, positive oxidized low-density lipoproteins immune-fluorescent staining were observed in lung edema group. Our study showed that oxidized low-density lipoprotein (oxLDL) accumulated in ANTU-induced lung damage. This is the first study in which accumulation of oxLDL molecules in the intact lung tissue were shown by fluorescent immune-staining method in experimental lung edema. The potential role of oxLDL in this pathology are still under investigation.

Animals↗

PubMed2006

Cellular immunity in salmonids infected with the microsporidial parasite Loma salmonae or exposed to non-viable spores.

Following a per os challenge of naive rainbow trout with live spores of Loma salmonae, head kidney mononuclear cells (MNC) in culture were able to proliferate in response to crude soluble parasite extract or intact dead spores. A significant response was seen by week 2 post-exposure and a maximum response developed by week 6 or 8, respectively. During this initial challenge, spore filled cysts developed on the gills of challenged fish, and the cysts ruptured by week 12 as is typical for microsporidial gill disease of salmonids (MGDS). Two weeks following this, fish were re-challenged with live spores, and in these fish an enhanced in vitro proliferative response of MNC was immediately apparent, and spore filled cysts did not develop. In contrast, when naive trout were given dead spores by intraperitoneal injection, the most pronounced proliferative responses of MNC developed earlier (week 2 PE) and the response was greater when cells were incubated in vitro with dead spores rather than with crude soluble extract. When these fish were re-challenged per os with live spores, a heightened proliferation in MNC was observed 4 weeks after this exposure and the fish likewise resisted development of xenomas. In fish infected orally or injected intraperitoneally with spores, a marked increase in the response to the mitogen concanavalin A was seen for 22 weeks post-exposure when compared to controls not receiving any spores.

Animals↗

PubMed1999

Lipoic acid prevention of neural tube defects in offspring of rats with streptozocin-induced diabetes.

OBJECTIVE: Increased oxidant stress has been suggested to play a role in the pathogenesis of disturbed embryogenesis in diabetic pregnancies. The present study was conducted to determine whether administration of lipoic acid, a naturally occurring antioxidant, would reduce the incidence of diabetic embryopathy in the streptozocin-induced diabetic rat model. STUDY DESIGN: After conception, rats were randomly distributed to 5 groups. From day 1, rats were daily injected intraperitoneally with either lipoic acid, 30 mg/kg, or vehicle. At day 6, rats from groups 3, 4, and 5 were made diabetic by a single intraperitoneal injection of streptozocin. Group 4 rats were injected with lipoic acid from day 1 to day 6, after vehicle treatment until day 17. At day 17 of gestation, rats were killed. The fetuses were released from the yolk sacs and surrounding decidua and were examined for size, resorption rate, and neural tube defects. RESULTS: Pregnant diabetic rats treated with vehicle lost weight during pregnancy (-3.2 +/- 1.9 g/d), as opposed to normal pregnancy-related weight gain (3.5 +/- 0.5 g/d). Treatment with lipoic acid protected against diabetes-induced weight loss, without a measurable effect on fed-state glucose concentrations. Daily treatment with lipoic acid (pregnancy days 1 to 17) was efficient in reducing the resorption rate from 24.0% +/- 9.5% in vehicle-treated diabetic rats to 10.2% +/- 4.8% in lipoic acid-treated diabetic rats (P <.05). The rate of neural tube defects in diabetic rats treated with lipoic acid throughout the pregnancy was reduced from 26.0% +/- 7.0% to 10.2% +/- 3.2% (P <.05). In rats treated only during pregnancy days 1 to 5 (before diabetes induction), lipoic acid failed to exert its protective effects against neural tube defects, which emphasizes the importance of the presence of lipoic acid during the organogenesis period. The atherosis of placental vasculature demonstrated in the vehicle-treated diabetic rats was absent from placentas obtained from lipoic acid-treated diabetic animals. CONCLUSIONS: Our data demonstrate a protective effect of lipoic acid against diabetic embryopathy, fetal losses, and ultrastructural alteration of diabetic placentas.

Animals↗

PubMed2004

Interferon-gamma-induced nitric oxide causes intrinsic intestinal denervation in Trypanosoma cruzi-infected mice.

In this study, the role of nitric oxide (NO) in neuronal destruction during acute-phase Trypanosoma cruzi infection was evaluated in male C57BL/6 (WT, wild-type) mice and knockout mice [inducible nitric oxide synthase (iNOS)(-/-) and interferon (IFN)(-/-)]. Selected animals were infected by intraperitoneal injection of 100 trypomastigote forms of the Y strain of T. cruzi. Others were injected intraperitoneally with an equal volume of saline solution and served as controls. Our findings support those of previous studies regarding myenteric denervation in acute-phase T. cruzi infection. In addition, we clearly demonstrate that, despite the fact that parasite nests and similar inflammatory infiltrate in the intestinal wall were more pronounced in infected iNOS(-/-) mice than in infected WT mice, the former presented no reduction in myenteric plexus neuron numbers. Neuronal nerve profile expression, as revealed by the general nerve marker PGP 9.5, was preserved in all knockout animals. Infected IFN(-/-) mice suffered no significant neuronal loss and there was no inflammatory infiltrate in the intestinal wall. On days 5 and 10 after infection, iNOS activity was greater in infected WT mice than in controls, whereas iNOS activity in infected knockout mice remained unchanged. These findings clearly demonstrate that neuronal damage does not occur in NO-impaired infected knockout mice, regardless of whether inflammatory infiltrate is present (iNOS(-/-)) or absent (IFN(-/-)). In conclusion, our observations strongly indicate that myenteric denervation in acute-phase T. cruzi infection is because of IFN-gamma-elicited NO production resulting from iNOS activation in the inflammatory foci along the intestinal wall.

Animals↗

PubMed2003

L-NAME protects against acute light damage in albino rats, but not against retinal degeneration in P23H and S334ter transgenic rats.

Two previous studies have shown that N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of neuronal nitric oxide synthase, protects retinas of albino rats and mice from damaging levels of light. The aims of the present study were two-fold: (1) to confirm the protective effect of L-NAME on wild type albino rats and (2) to determine if L-NAME protects the retinas of transgenic rats with P23H and S334ter rhodopsin mutations. In the first study, albino rats born and raised in 5-10 lux cyclic light were injected intraperitoneally with either L-NAME or its inactive isomer D-NAME 30 min before being placed in bright light (2700 lux) for 24hr. Electroretinograms (ERGs) were recorded before light treatment and 2 days after cessation of exposure, and eyes were enucleated for morphologic evaluation. L-NAME, but not D-NAME provided structural protection of photoreceptor cells from light damage. The functional rescue was not statistically significant between the drug treated groups. In the second study, albino WT, P23H transgenic, and S334ter transgenic rats were born and raised in 400 lux cyclic light. Three week old animals received daily intraperitoneal injections of L-NAME or D-NAME for 4 weeks, and the same drugs were added to their drinking water. At 7 weeks of age, the ERG sensitivity curves and the outer nuclear layer thickness of both transgenic groups were significantly reduced compared to WT controls. However, administration of L-NAME did not protect against retinal degeneration caused by the rhodopsin mutation in either strain of transgenic (P23H and S334ter) rats. Thus, although photoreceptor cell death in light damage and inherited retinal degenerations share a common apoptotic mechanism, there must be significant 'up-stream' differences that allow selective neuroprotection by L-NAME.

Albinism, Ocular↗

PubMed1991

Decrease in neutrophil migration induced by endotoxin and suppression of interleukin-1 production by macrophages in lactic dehydrogenase virus-infected mice.

Neutrophil (PMN) migration into the peritoneal cavity after intraperitoneal injection of lipopolysaccharide (LPS), chemotactic activity of PMN, interleukin-1 (IL-1) production by macrophages (M phi) and its ability to attract PMN in mice chronically infected with lactic dehydrogenase virus (LDV) were compared with those in uninfected control mice. PMN migration into the peritoneal cavity decreased in infected mice when LPS was injected intraperitoneally. PMN chemotactic activity did not show any difference following infection. To assess the mechanism of this decreased PMN migration, IL-1 production, which is responsible for PMN attraction, was studied in LDV-infected mice. IL-1 production by M phi derived from infected mice decreased and its ability to attract PMN was weak. IL-1 production by M phi from control and infected mice increased after treatment by indomethacin and LPS. PMN migration into the peritoneal cavity increased after treatment with indomethacin and LPS in both control and infected mice. However, the rate of increase of IL-1 production and PMN migration was greater in infected mice. These results suggest that the excess activation of cyclo-oxygenase-derived products (prostaglandins) in infected mice might be responsible for the suppression of IL-1 production by M phi, resulting in decreased PMN migration induced by endotoxin.

Animals↗

PubMed2000

Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotein knockout and in wildtype mice in the hotplate test.

Morphine-6-glucuronide (M6G), a major metabolite of morphine with agonist opioid-receptor activity, was reported to be a substrate of P-glycoprotein (P-gp). Inhibition of P-gp may thus result in higher brain uptake of M6G. The goal of this observer-blinded, placebo controlled study, was to compare the antinociceptive effects of M6G in homozygous P-gp knockout (mdr1a(-/-)) and wildtype (mdr1a(+/+)) mice. M6G was injected intraperitoneally as a single dose of 0, 0.5, 1, 2.5, 5, and 10 mg/kg. Eight P-gp knockout and eight wildtype mice were studied per dose. A hot plate test was performed before and 5, 15, 30, 60, 90, 120, and 150 min after M6G administration. Plasma-concentrations of M6G, morphine, and morphine-3-glucuronide (M3G) were measured after intraperitoneal injection of 5 mg/kg M6G in another 14 P-gp knockout and 14 wildtype mice. No difference neither in the dose response relationship, nor in the time course of response latency times were observed between P-gp knockout and wildtype mice. However, latency times increased with higher doses of M6G, with antinociception significantly different from placebo at a M6G dose of 5 and 10 mg/kg. P-gp knockout mice tended to have higher plasma concentrations than the wildtype. However, plasma concentrations widely overlapped between groups and therefore no statistical significant group difference could be detected. We conclude that despite reported doubling of M6G brain uptake, absence of mdr1a coded P-gp does not enhance antinociceptive effects of M6G in the hotplate test after acute single-dose administration in mdr1a(-/-) knockout mice.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2001

Brain catalase activity is highly correlated with ethanol-induced locomotor activity in mice.

It has been demonstrated that acute administration of lead to mice enhances brain catalase activity and ethanol-induced locomotion. These effects of lead seem to be related, since they show similar time courses and occur at similar doses. In the present study, in an attempt to further evaluate the relation between brain catalase activity and lead-induced changes in ethanol-stimulated locomotion, the interaction between lead acetate and 3-amino-1H,2,4-triazole (AT), a well-known catalase inhibitor, was assessed. In this study, lead acetate or saline was acutely injected intraperitoneally to Swiss mice at doses of 50 or 100 mg/kg 7 days before testing. On the test day, animals received an intraperitoneal injection of AT (0, 10, or 500 mg/kg). Five hours following AT treatment, ethanol (0.0 or 2.5 g/kg, ip) was injected and the animals were placed in open-field chambers, in which locomotion was measured for 10 min. Neither lead exposure nor AT administration, either alone or in combination, had any effect on spontaneous locomotor activity. AT treatment reduced ethanol-induced locomotion as well as brain catalase activity. On the other hand, ambulation and brain catalase activity were significantly increased by both doses of lead. Furthermore, AT significantly reduced the potentiation produced by lead acetate on brain catalase and on ethanol-induced locomotor activity in a dose-dependent manner. A significant correlation was found between locomotion and catalase activity across all test conditions. The results show that brain catalase activity is involved in the effects of lead acetate on ethanol-induced locomotion in mice. Thus, this study confirms the notion that brain catalase provides the molecular basis for understanding some of the mechanisms of the action of ethanol in the central nervous system.

Animals↗

PubMed2001

Cannabinoids of diverse structure inhibit two DOI-induced 5-HT(2A) receptor-mediated behaviors in mice.

We have recently shown that the selective cannabinoid CB(1) receptor antagonist SR 141716A produces robust frequencies of head-twitch response (HTR) and ear-scratch response (ESR) in drug-naive mice. Both behaviors were potently blocked by the selective 5-HT(2A/C) receptor antagonist SR 46349B. Selective 5-HT(2A/C) agonists such as DOI also produce these behaviors in mice. The purpose of the present study was to: (1) investigate whether Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and its analogs [Delta(8)-tetrahydrocannabinol (Delta(8)-THC), HU-210, CP 55,940, and WIN 55,212-2] can prevent the DOI-induced behaviors and (2) to see whether any correlation exists in the ID(50) potency order of these cannabinoids in inhibiting the DOI-induced HTR and ESR relative to their published ED(50) potency profiles in producing the tetrad of behaviors in mice. Thus, at 0 min, different groups of mice were injected intraperitoneally with either vehicle or varying doses of the following cannabinoids: Delta(9)-THC (0.25-20 mg/kg), Delta(8)-THC (2.5-20 mg/kg), HU-210 (0.02-0.5 mg/kg), CP 55,940 (0.004-0.5 mg/kg), and WIN 55,212-2 (0.5-10 mg/kg). Twenty minutes later, each mouse received an intraperitoneal injection of DOI (1 mg/kg) and the frequencies of DOI-induced behaviors (mean +/- S.E.M.) were recorded for the next 20 min. The tested cannabinoids reduced the frequencies of both DOI-induced HTR and ESR in a dose-dependent fashion. HU-210 was the most potent inhibitor of HTR, whereas CP 55,940 was most effective against ESR. The ID(50) potency order of cannabinoids in blocking the HTR is: HU-210 > CP 55,940 > WIN 55,212-2 > Delta(9)-THC > Delta(8)-THC, which is identical to their published order of potency in producing the tetrad of behaviors in mice. On the other hand, they had the following ID(50) potency order against the ESR: CP 55,940 > HU-210 > WIN 55,212-2 > Delta(9)-THC > Delta(8)-THC. The tested cannabinoids were 3-30 times more potent in preventing the ESR than the HTR. The data show that cannabinoids inhibit 5-HT(2A) receptor-mediated functions in a potent but differential manner.

Amphetamines↗

PubMed2001

Peripheral and preemptive opioid antinociception in a mouse visceral pain model.

Recent studies suggest that opioids can produce analgesia through peripheral mechanisms following inflammation of peripheral tissue. This study examined whether opioids administered prior to inflammation can produce antinociception by peripheral mechanisms in a model of visceral pain. Mice were injected intraperitoneally (i.p.) with 1% acetic acid to evoke abdominal writhing, a standard model of visceral pain. The number of writhes that occurred during 30 min after acetic acid were determined. Intraperitoneal injection of morphine sulfate (60, 90, 100 or 120 microg/0.3 ml) or the peripherally acting opioid loperamide (0.12, 0.36, 1.2 or 3.6 mg/0.3 ml) given 5 min after acetic acid decreased writhing in a dose-dependent fashion. Morphine (100 microg) produced an 70% attenuation in the number of writhes while loperamide (1.2 mg) decreased writhing by 56%. These antinociceptive effects were blocked by pretreatment with the opioid receptor antagonists naloxone (10 mg/kg) and its quarternary version naloxone methiodide (10 mg/kg). To determine whether opioids produced preemptive antinociception via peripheral mechanisms, mice received i.p. injections of morphine (1, 5, and 10 microg/0.3 ml) or vehicle 5 min before acetic acid. Doses of 5 and 10 microg morphine inhibited the number of writhes by 51 and 93%, respectively. The highest dose (10 microg) was ineffective when given intravenously 5 min before acetic acid, suggesting that antinociception following i.p. administration was acting via peripheral mechanisms. These data demonstrate that low doses of opioids, given before or after acetic acid, produce visceral antinociception through peripheral mechanisms. This may be clinically relevant for the management of postoperative abdominal pain.

Acetic Acid↗

PubMed1998

Gene therapy of epithelial ovarian cancer using adenoviral vectors.

Ovarian cancer is the fourth most common cause of death in women. Gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment has been successfully applied in the treatment of different cancers in experimental animals and in humans. In a recent report, we have demonstrated that the HSV-tk/GCV system can be used efficiently to kill human epithelial ovarian cancer cells (Gynecol Obstet Invest 1997;43:268-75). In this work, we wanted to test the ability of the HSV-tk/GCV to treat ovarian cancer in an animal model.The immune-deficient nude mice model was employed, and mice were injected intraperitoneally with the human epithelial ovarian cancer cell line OVCAR3, 10(8) cell/mouse. The mice were divided into three different groups, groups 1 and 2 were treated by intraperitoneal injection of adenovirus carrying the HSV-tk gene (ad-tk) on day 3 after cell implantation. Group 1 received 2 x 10(8) pfu/mouse; group 2 received 20 x 10(8) pfu/mouse. Group 3 did not receive any viral injection and served as our negative control. All mice received GCV 10 mg/kg IP bid for 6 days. All mice were hosted in the same facilities and had access to food and water ad libitum. Mice in group 3 started to show clinical manifestations of disease by day 10, and all mice were dead by day 21 (16 +/- 1.5). At this point mice in groups 1 and 2 appeared perfectly healthy. Autopsy done on group 3 mice demonstrated multiple cancer implants in the abdominal cavity plus hemorrhagic ascitis. In contrast, autopsy on sample mice from groups 1 and 2 at the same time point failed to demonstrate any macroscopic or microscopic cancer.On further follow-up, mice in groups 1 and 2 started to show cancer-related signs, eg, weight loss, movement difficulty, poor reflex response, and finally death. Survival varied between 50 and 101 days with a mean of 66 +/- 17 days for group 1 and 74 +/- 13 days for group 2. Autopsy done on treated mice demonstrated multiple cancer implants and ascitis. In conclusion, a single injection of ad-tk/GCV was able to improve survival in an ovarian cancer mouse model from an average of 16 days to 74 days. Trials with multiple injection in a novel immune-competent mouse model of ovarian cancer are underway in our laboratory.

Journal Article↗

PubMed1998

Colon-specific genotoxicity of heterocyclic amines detected by the modified alkaline single cell gel electrophoresis assay of multiple mouse organs.

The in vivo genotoxicity of five heterocyclic amines-Trp-P-2 (13 mg/kg), IQ (13 mg/kg), MeIQ (13 mg/kg), MeIQx (13 mg/kg), and PhIP (40 mg/kg)-in the mucosa of gastrointestinal and urinary tract organs (stomach, duodenum, jejunum, ileum, colon, and bladder) was studied by the alkaline single cell gel electrophoresis (SCG) (Comet) assay. Male CD-1 mice were sacrificed 1, 3, and 8 h after intraperitoneal injection. All the heterocyclic amines studied yielded statistically significant DNA damage in the colon but not the small intestine (duodenum, jejunum, and ileum) or urinary bladder. In this study, five heterocyclic amines were injected intraperitoneally to avoid the consequences of ingestion. Thus, the extensive damage to colon DNA was concluded to be due, at least in part, to a systemic effect.

Amines↗

PubMed1996

Tocopherols, retinol, beta-carotene and fatty acids in fat globule membrane and fat globule core in cows' milk.

Milk fat globule membranes (MFGM) were isolated from milk from cows injected intraperitoneally with dl-alpha-tocopherol acetate. The fatty acid composition and content, and the contents of tocopherols, retinol and beta-carotene were determined and compared with the composition and content in the original cream sample. Intraperitoneal injection of 10 g dl-alpha-tocopherol acetate elevated the alpha-tocopherol content in the milk fat from 13-30 to 50-70 micrograms alpha-tocopherol/g milk fat 2-3 d after injection. The increase depended on the alpha-tocopherol status of the cow prior to injection. The concentrations of retinol and beta-carotene in the milk fat were unchanged after the alpha-tocopherol injections. MFGM fatty acids made up 18-27 g/kg total fatty acids in the milk fat. However, the proportions of monounsaturated and polyunsaturated fatty acids were higher in MFGM than in total milk fat, while the proportion of saturated fatty acids was lower in MFGM (P < 0.001). Thus, the long-chain polyunsaturated fatty acids in MFGM constituted approximately 40-70 g/kg total milk fat. alpha-Tocopherol was the only fat-soluble vitamin detected in MFGM; gamma-tocopherol, retinol and beta-carotene were detected only in the cream. A significant relationship between alpha-tocopherol contents in cream and MFGM was found: (alpha-tocopherol in MFGM fatty acids) = -1652 x (1/ln(alpha-tocopherol in cream fatty acids)3) + 97 (r = 0.857, P < 0.001) when the contents of alpha-tocopherol were expressed as microgram/g fatty acid. According to this equation the upper limit for incorporation of alpha-tocopherol into MFGM is 97 +/- 5 micrograms/g MFGM fatty acids. Thus, under normal farming conditions the alpha-tocopherol content will be highest in MFGM. However, in cream with an alpha-tocopherol concentration < 15 micrograms/g cream fatty acids the concentration in MFGM will be lower and furthermore will decrease rapidly. The possible importance of this relationship in relation to the oxidation of milk fat is discussed.

Animals↗