Outbred Albino Mice Research Articles

The time course of changes in the state of monoaminergic systems in the brain of mice under the acute hypoxia with hypercapnia

In socially isolated male outbred albino mice, the changes of monoaminergic systems under acute hypoxia with hypercapnia were studied. In cerebral cortex, hippocampus and striatum of the right and left sides of the brain, the concentrations of norepinephrine, dopamine, serotonin and their metabolites - dihydroxyphenylacetic, homovanillic and 5-hydroxyindoleacetic acids were investigated using the HPLC method. In isolated mice, which were not subjected to hypoxia with hypercapnia, higher levels of dopamine and serotonin in the left cortex were found. There was no asymmetry in monoamines and their metabolites in other studied brain structures. 10 min after the onset of exposure, acute hypoxia with hypercapnia resulted in a right-sided increase in norepinephrine levels and a decrease in dopamine levels in the striatum and serotonin levels in the hippocampus. In the cerebral cortex, 10 min after of hypoxic exposure beginning, there was a left-sided decrease in the dopamine content, while the original asymmetry found in the cortex of intact animals disappeared. In isolated mice perished of hypoxia with hypercapnia, almost all parameters returned to the control level. The exception was the ratio of serotonin metabolite level to the neurotransmitter, which in the right cortex became lower than in control animals. In white outbred mice, the brain monoaminergic systems are suggested to be relatively resistant to the negative consequences of hypoxia and hypercapnia, and corresponding shifts resulting in the reflex brain response to changes in the gas composition of the respiratory air.

Role of Rats ( Rattus norvegicus) in the Epidemiology of Toxoplasma gondii Infection in Grenada, West Indies.

Rodents are known to be reservoir hosts of Toxoplasma gondii infection for other animals, such as cats and pigs. From February to July 2017, 167 rats ( Rattus norvegicus) were trapped in Grenada, and serum, heart, skeletal muscle, and brain were examined for T. gondii infection by serological examination (modified agglutination test, 1:25) for T. gondii antibodies and for viable parasites by bioassay in mice. Samples of heart, skeletal muscle, and brain of all rats were bioassayed in Swiss Webster (SW) outbred albino mice and interferon gamma gene knockout (KO) mice. Toxoplasma gondii was isolated from heart and brain from 1 rat; this was the only seropositive rat. The T. gondii strain was avirulent for SW mice but killed KO mice. Tissue cysts were detected in the brains of SW mice, and tachyzoites were detected in the lungs of KO mice that died of acute toxoplasmosis. The strain was propagated in cell culture, and DNA derived from cell-cultured tachyzoites was genotyped using the 10 PCR restriction fragment length polymorphisms (SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico). The strain was a clonal Type III (ToxoDB genotype no. 2) strain. Although the prevalence of T. gondii in humans and animals in Grenada is high, rats seem to have little importance in the transmission of T. gondii on this island.

Sarcocystis cymruensis: discovery in Western Hemisphere in the Brown rat (Rattus norvegicus) from Grenada, West Indies: redescription, molecular characterization, and transmission to IFN-γ gene knockout mice via sporocysts from experimentally infected domestic cat (Felis catus).

Rodents are intermediate hosts for many species of Sarcocystis. Little is known of Sarcocystis cymruensis that uses the Brown rat (Rattus norvegicus) as intermediate hosts and the domestic cat (Felis catus) as experimental definitive host. Here, we identified and described Sarcocystis cymruensis in naturally infected R. norvegicus from Grenada, West Indies. Rats (n= 167) were trapped in various locations in two parishes (St. George and St. David). Microscopic, thin (< 1μm) walled, slender sarcocysts were found in 11 of 156 (7.0%) rats skeletal muscles by squash examination. A laboratory-raised cat fed naturally infected rat tissues excreted sporocysts that were infectious for interferon gamma gene knockout (KO) mice, but not to Swiss Webster outbred albino mice. All inoculated mice remained asymptomatic, and microscopic S. cymruensis-like sarcocysts were found in the muscles of KO mice euthanized on day 70, 116, and 189 post inoculation (p.i.). Sarcocysts from infected KO mice were infective for cats at day 116 but not at 70days p.i. By transmission electron microscopy, the sarcocyst wall was "type 1a." Detailed morphological description of the cyst wall, metrocytes, and bradyzoites is given for the first time. Additionally, molecular data on S. cymruensis are presented also for the first time. Molecular characterization of sarcocysts 18S rDNA and 28S rDNA, ITS-1, and cox1 loci showed the highest similarity with S. rodentifelis and S. muris. In conclusion, the present study described the natural infection of S. cymruensis in Brown rat for the first time in a Caribbean country and provided its molecular characteristics.

Synthesis and Antidepressant Properties of 2-[3-Methyl-7-(Thietanyl-3)-1-Ethylxanthinyl-8-Thio] Acetic Acid Hydrazides

2-[3-Methyl-7-(thietanyl-3)-1-ethylxanthinyl-8-thio]acetic acid hydrazide was synthesized in two steps by our improved method. The structures of the synthesized compounds were confirmed by IR and NMR spectroscopic data. The acute toxicity was studied. The LD50 values were 700 mg/kg for outbred albino mice. Tail-suspension tests (TST) and forced swimming tests (FST) found that 2-[3-methyl-7-(thietanyl-3)-1-ethylxanthinyl-8-thio]acetic acid hydrazide exhibited antidepressant activity that was most pronounced at a dose of 12 mg/kg.

Синтез и антидепрессивные свойства гидразида 2-[3-метил-7-(тиетанил-3)-1-этилксантинил-8-тио]уксусной кислоты

По усовершенствованной нами методике в 2 стадии синтезирован гидразид 2-[3-метил-7-(тиетанил-3)-1-этилксантинил-8-тио]уксусной кислоты. Структура синтезированных соединений подтверждена данными ИК и ЯМР-спектроскопии. Изучена острая токсичность и определена ЛД50, которая для белых беспородных мышей составляет 700 мг/кг. В тестах «подвешивание мышей за хвост» (TST) и «принудительное плавание» (FST) установлено, что гидразид 2-[3-метил-7-(тиетанил-3)-1-этилксантинил-8-тио]уксусной кислоты оказывает антидепрессивное действие, наиболее выраженное в дозе 12 мг/кг.

Pathomorphism of Hantavirus infection under prolonged heat stress

to provide the morphological characteristics of experimental Hantavirus infection under heat stress conditions to identify the possibilities of its modeling in resistant laboratory animals. Experiments were carried out on outbred albino mice that were divided into 4 groups: 1) intact mice unexposed to heating; 2) those exposed to heating; 3) Hantavirus-infected animals unexposed to preheating; 4) those exposed to preheating. The animals in Groups 2-4 were long exposed to heat stress at a temperature of 30 °C for 3 hours during 3 days. Strain Aa 60343 (PM-79-95) of the Far East genovariant of Hantaan virus (the genus Hantavirus, family Bunyaviridae) from the collection of the G.P. Somov Research Institute of Epidemiology and Microbiology was used to induce infection. The animals in Groups 3 and 4 were intraperitoneally injected with 700 FFU of Hantavirus per mouse. Materials (lung, liver, kidney, and spleen) taken from Groups 2-4 animals were collected for histological examination on days 1, 3, 7 and 14 of observation. The intact albino mice in Group 1 showed no histopathological changes in the organs. After heat exposure, Group 2 animals were found to have an immunomorphological response in the interstitial tissues of the lung, liver and kidney in partial lymphoid hypoplasia of the spleen. There were no signs of inapparent infection in the presence of marked immunomorphological changes in the organs in Group 3 of hantavirus-infected animals unexposed to preheating. In Group 4, those exposed to preheating exhibited dystrophic and destructive changes in the target organs (lungs, kidneys) in the presence of immunodeficiency manifestations of manifestations that were more pronounced in dead animals. In an unresponsive model (adult albino mice), Hantavirus infection caused only obvious immunomorphological changes in the organs. Prolonged preheat stress in the hantavirus-infected animals promoted inapparent infection and morphological manifestations of induced secondary immunodeficiency that was responsible for the manifestation of an infectious process in some animals.

Determination of ceiling doses of Heligmosomoides bakeri infections in outbred albino mice: the maximum tolerated dose

The maximum dose of Heligmosomoides bakeri that can be tolerated by outbred albino mice was determined. Due to the extensive works of the author of this study with Heligmosomoides bakeri infections in the outbred albino mice, researchers have often contacted him for guides in choosing safe working dose levels of the parasite. This study was conducted in order to be able to advise accurately such requests and making available such results by publication for easy and wide access. This was done in two separate experiments in which maximum infection levels of 1000 L3 and 4000 L3 respectively were used. In Experiment I all infected mice survived. However, in Experiment II, some mortalities occurred in mice infected with 2500 – 4000 L3 H. bakeri. Though only proportionate to a certain point, there was generally an increase dose increase faecal egg counts (FEC) and worm burden (WB) response pattern. Also observed was an increase dose increase in PCV and bodyweight decline. This is an indication that these parameters are dependent on the infection dose levels. This fact was supported by the high morbidity and high mortality rate that occured at higher doses. The results therefore suggest that adult mice up to 8 week-old can survive infection with 2000 L3 H. bakeri and below. The infection dose of 2000 L3 is therefore the ceiling dose of H. bakeri in such adult or older mice. Dose levels as high as 2500 L3 and above were lethal to the mice. In designing experiments with the H. bakeri-mouse model for the study of GI nematode parasites only doses of 2000 L3 and below should be considered. Infection doses of H. bakeri greatrer than 2000 L3 may lead to earlier death of the mice when enough data might not have been taken.

Controlled Local Hyperthermia and Magnetic Hyperthermia of Surface (Skin) Cancer Diseases

Average size of hematite and magnetite micro and nanopowders and polydispersity index, zeta potential and distribution of particles were studied. Analysis showed that average size of the obtained particles for magnetite is 740.9 nm, for hematite particles 30 - 35 nm. Alternate current feed source was created for hyperthermia. Proceeding from the requirements of the objectives, the U type MnZn material magneto conductors were selected, in which 10.0 and 8.0 mm width gaps were cut and glass test tubes with magnetite or hematite suspensions were placed in them. Series of experiments at various field intensity and frequencies showed that for efficient magnetic hyperthermia therapy more powerful device was needed with frequency of up to 10 Mega Hertz to achieve the temperature 43°C - 45°C necessary for full activation of Neel and Brown mechanisms in particles. At the next stage, on the basis of experimental material the anticancer mono-therapeutic effect of hyperthermia and its adjuvant action in poly chemotherapeutic treatment was presented by the use of a device created by us “Lezi”. As a result of the experiment it was shown that in all animals (outbred albino mice, 3 months old) inhibition of cancer growth was fixed and intratumoral necrosis was developed, while after 7 and 10 sessions tumors were ulcerated, which refers to positive effect of the experiment (Conclusion of Pathologicanatomical Laboratory “PATGEO”, Tbilisi, Georgia ).

Role of Nicotinic and Muscarinic Cholinoreceptors in the Realization of the Cholinergic Anti-Infl ammatory Pathway during the Early Phase of Sepsis

Stimulation of nicotinic and muscarinic cholinoreceptors (nAChR, mAChR) in outbred albino mice with nicotine and aceclidine, respectively, in single equilethal doses 0.5 DL(50)6 h before sepsis induction significantly reduced animal mortality due to a decrease in blood concentrations of proinflammatory cytokines IL-1β, IL-6, and MIP-2. Stimulation of mAChR (injection of aceclidine) stimulated the neutrophilic phagocytic and metabolic activity. Realization of the cholinergic anti-inflammatory pathway (stimulation of the peripheral nicotinic cholinoreceptors (α7nAChR) and central muscarinic cholinoreceptors (mAChR) was modulated by stimulation of the muscarinic cholinoreceptors of the phagocytic monocytic system cells.

Effects of Reversible Inhibition of Cholinesterase and Nicotine on Mouse Mortality and Blood Levels of Proinflammatory Cytokines during the Early Phase of Sepsis

Experiments on outbred albino mice have shown that proserine (reversible cholinesterase inhibitor) and nicotine (nicotinic receptor agonist) in a equivalent dose of 0.2 DL(50)injected 2 h before sepsis induction significantly reduced animal mortality from experimental infection due to reduction of blood concentrations of proinflammatory cytokines TNF-α, IL-1β, and IL-6.

Influence of pregnancy and lactation on the parasitological and clinico-pathological responses of out-bred albino mice to Heligmosomoides bakeri infection administered at different trimesters of pregnancy

Influence of pregnancy and lactation on the parasitological and some clinico-pathological responses of out-bred albino mice to single doses of Heligmosomoides bakeri (H.b) were studied. Fifty six pregnant and ten non-pregnant mice were used for the study. The pregnant mice were either infected in the first, second or third trimester depending on the experimental group and were either allowed to suckle or not following parturition. The ten non-pregnant mice served as uninfected controls. Faecal egg counts (FEC), bodyweights (BW), packed cell volume (PCV) and worm burdens (WB) were recorded. Both lactating and non-lactating mice infected in the first trimester had significantly higher WBs (F2,49 = 5.242, P = 0.001) and FECs (F2,37 = 4.314, P = 0.001 ) in comparison to their counterparts infected in the second and third trimesters. Generally, the WB of lactating mice was only marginally higher than those of non-lactating mice in the first and third trimesters. The FECs of non-lactating mice were generally higher than those of lactating mice. The PCV of lactating mice was lower than those of both non-lactating and uninfected control mice. The body weights of both lactating and non-lactating mice (infected) were lower compared to those of the uninfected control mice. No periparturient rise in FEC was observed nor did lactation influence FEC. Key words: Pregnancy, lactation, Heligmosomoides bakeri, outbred albino mice, parasitological and clinico-pathological responses.

Anxiolytic and Antidepressant Effects of Aqueous Tincture of the Aerial Part of Myosotis arvensis

Experiments on outbred albino mice showed a significant anxiolytic effect of aqueous tincture of the aerial part of Myosotis arvensis (L.) (Boraginaceae) in a single daily dose of 0.5 ml/kg. In a dose of 2 ml/kg, the tincture of M. arvensis aerial part exhibited an anxiolytic and antidepressant effect. In contrast to phenazepam, aqueous tincture of M. arvensis did not inhibit exploratory and motor activities.

Increased Helicobacter pylori-associated pathology in outbred mice coinfected with schistosomiasis

To the Editor Helicobacter pylori is a major gastroduodenal pathogen affecting about half of the world population (Taylor and Blaser 1991). It causes persistent gastritis and peptic ulceration and is directly linked to the development of various gastric malignant diseases (Huang et al. 1998; Uemura et al. 2001). Prevalence of H. pylori infection (Rowland et al. 2006) and the annual “true” reinfection rates (Zhang et al. 2009) are higher in developing countries than in developed countries and can vary by ethnicity, host genetics, place of birth, and socioeconomic factors. Differences in the incidence and severity of H. pylori infection can be attributed to differences in H. pylori strain virulence or the host’s capacity to control H. pylori infection due to altered immune responses caused by concurrent infection and/or environmental factors (Kusters et al. 2006). Helminth infections are estimated to infect three billion people worldwide (Crompton and Nesheim 2002). Schistosomiasis is helminth infection caused by the blood flukes of the genus Schistosoma. Despite intensive control efforts, disease caused by these worms remains a major public health concern in Egypt and +74 developing countries (Savioli et al. 1997). Although schistosomiasis is endemic in Egypt where H. pylori is a widespread problem and coinfections are frequent, limited data exist on the effects of schistosomiasis on the severity of H. pylori infection (Elshal et al. 2004). For the correct clinical management of H. pylori disease, obtaining thorough information on the other concurrent infections is essential. Here, we thought to compare the gastric pathologies in H. pylori-infected mice with concurrent Schistosoma mansoni infection with those infected with H. pylori alone. Eight-week-old CD1 age-matched female outbred albino mice (n=20) were obtained from Theodor Bilharz Research Institute, Cairo, Egypt. Mice were divided into four groups, each of five mice. Group (i) includes mice infected with S. mansoni and challenged with H. pylori 5 weeks after parasite infection, group (ii) includes mice challenged with H. pylori alone, group (iii) includes mice infected with S. mansoni alone, and group (iv) includes healthy noninfected control mice. Mice were infected with 60 S. mansoni cercariae of an Egyptian strain as described (Elsheikha et al. 2008). For challenge with H. pylori, mice were inoculated intragastrically with a single dose of 0.1 ml of Helicobacter suspension (10 bacteria) and then observed for an additional 2 weeks. All mice were euthanized at 7 weeks post-S. mansoni infection (i.e., 2 weeks after bacterial infection). Animal infection was conducted according to protocols approved by the Animal Care and Ethics Committee at Mansoura University, Egypt. Parasitol Res (2009) 105:297–299 DOI 10.1007/s00436-009-1486-x

Clinico-pathological effects of Schistosoma mansoni infection associated with simultaneous exposure to malathion in Swiss outbred albino mice

To investigate whether infection of Swiss outbred mice with the digenetic fluke Schistosoma mansoni is influenced by exposure to environmental pollutants, experimentally infected mice were exposed to 200 and 400 mg/kg of malathion. Pathology of liver and spleen, worm burden and levels of key hematological, biochemical and liver enzymes parameters of these mice were evaluated and were compared with data from infected, unexposed mice, uninfected, exposed mice as well as with data from uninfected, unexposed mice. Oral administration of malathion to mice infected with 20, 40 or 60 S. mansoni cercariae adversely affect architecture of liver and spleen and critically alter hematological, biochemical, histological and hepatic enzymes parameters significantly more than the controls. Alterations observed in infected, exposed mice included (i) higher mortality rate; (ii) severe pathologies in liver and spleen; (iii) increased serum level of bilirubin and alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes; (iv) decreased serum level of albumin and total proteins; and (v) decreased red blood cell count (RBC), lymphocytes, leucocytic count, and hemoglobin content. The number of recovered adult worms of S. mansoni or their oviposition capacity did not seem to be affected with malathion treatment. Statistical analysis revealed that the increase alteration in hepatic functions is correlated with increasing the number of S. mansoni cercariae and malathion doses. Such alterations were more significant in mice treated with the higher dose of malathion or infected with the largest numbers of S. mansoni cercariae. These data indicate that schistosomiasis can be exacerbated by simultaneous malathion exposure, which in turn adversely impact the clinical and pathological outcome of the disease.

Outcomes of Schistosoma mansoni infection in outbred albino mice exposed to Larvin contaminant

The present study tested the hypothesis that mice exposed to Schistosoma mansoni and treated with the insecticide Larvin have an increased risk of accelerated liver damage. To investigate this hypothesis, adverse effects resulting from treatment with Larvin were compared between S. mansoni-exposed and nonexposed outbred albino mice. The effects of concurrent treatment with Larvin on the progress and outcomes of S. mansoni infection were assessed via macroscopic and microscopic examination of liver and spleen, evaluation of several hematological, biochemical and hepatic enzymes parameters, and effect on worm burden. Oral administration of 1/5 and 1/10 LD(50) of Larvin to S. mansoni-exposed mice induced (1) hepatomegaly and splenomegaly; (2) prominent lymphocytic aggregation in liver replacing large areas of bridging necrosis; (3) increased serum level of bilirubin and alanine aminotransferase-aspartate aminotransferase enzymes; (4) decreased serum level of albumin and total proteins; and (5) decreased RBC, hemoglobin content, leukocyte, and lymphocyte counts. No significant effect on worm burden or oviposition was noted as a result of Larvin treatment compared to controls. All doses used in mice either for infection with S. mansoni cercariae or treatment with Larvin resulted in dose dependent alterations in hepatic functions of the tested mice. These alterations were most profound in mice exposed to S. mansoni and receiving Larvin treatment. The present findings support our hypothesis and show that concurrent S. mansoni infection with exposure to Larvin adversely affect liver functions and seriously alter hematological, biochemical, and hepatic enzymes parameters in outbred albino mice. These findings warrant further investigation and reinforce the need to minimize exposure to insecticide in both natural field settings and the broader environment.

Effects of apolipoproteins on dalargin transport across the blood-brain barrier

Antinociceptive activity of dalargin (7.5 mg/kg) adsorbed on poly(butyl)cyanoacrylate nanoparticles with different coating was studied on outbred albino mice by the tail-flick test. poly(butyl)cyanoacrylate nanoparticles without coating did not increase the antinociceptive activity of dalargin and hence, did not increase its transport across the blood-brain barrier. poly(butyl)cyanoacrylate nanoparticles coated with apolipoprotein B, apolipoprotein E, and polysorbate 80 increased the transport of dalargin across the blood-brain barrier. Delivery of dalargin to the brain was most effective in case of using poly(butyl)cyanoacrylate nanoparticles with polysorbate 80 coating and subsequent supercoating with apolipoprotein E.

Susceptibility of neonate mice born to Schistosoma mansoni-infected and noninfected mothers to subsequent S. mansoni infection

The present study tested the hypothesis that prenatal exposure of neonate Outbred albino mice to Schistosoma mansoni antigens (Ags) or antibodies (Abs) modulates their immunity against postnatal responses to infection. Persistence of maternal S. mansoni Abs and/or Ags in mice born to S. mansoni-infected mothers (IF-IMs) and noninfected mothers (IF-NMs) for up to 8 weeks after delivery was investigated. A higher level of anti-S. mansoni IgG Ab was detected in sera of 1-week-old mice born to IF-IM compared to controls. Then, immunoglobulin (Ig)G gradually decreased to the eight week. No anti-S. mansoni IgM Ab was detected in sera of these offspring at any week after delivery. Schistosoma Ags were detected in liver and kidney tissues of mice born to infected mothers. However, Ags decreased markedly till the sixth week in the liver but increased significantly at the sixth week in the kidney. Eight-week-old mice born to infected and noninfected mothers were infected with 200 S. mansoni ceracriae. Their sera and livers were collected for testing IgG and granuloma formation 6 weeks postinfection. Worms were collected via portal perfusion and counted. Anti-S. mansoni IgG level, size and number of liver granuloma, and worm burden were significantly reduced in the offspring of infected mothers. These data suggest that in utero exposure of Outbred albino mice to S. mansoni may attenuate the pathogenesis of S. mansoni in subsequent challenge.

Copper‐status and age alter suckling rodent brain and heart catecholamine levels

Mice and rats were compared to determine differences in dietary copper (Cu) deficiency (Cu−) started during late gestation and/or lactation on catecholamine, norepinephrine (NE) and dopamine (DA), content in brain and heart. Limiting dopamine beta-monooxygenase (DBM) results in lower NE and higher DA in Cu− tissues compared to copper adequate (Cu+) tissues. Experiments were performed with Holtzman rats and Hsd:ICR (CD-1) outbred albino mice in which dams were fed a modified AIN-76A diet and drank deionized water or Cu supplemented water. Offspring were sampled at three time points between postnatal age 3 (P3) and P31. NE concentration increased with age in both heart and brain in Cu+ rodents. Cu− pups exhibited signs consistent with Cu deficiency, lower cuproenzyme and copper content, compared to Cu+ pups. For both rat and mouse tissue NE and DA changes were amplified at later ages in Cu− mice when Cu deficiency was limited to lactation only. Although dam Cu restriction began earlier in rats than mice, embryonic day 7 (E7) compared to E17, rat brain NE and DA alterations were not impacted as severely as mouse brain. This pattern was also true for heart NE reduction in Cu− rodents. However, Cu− mouse heart DA was impacted less than Cu− rat heart DA. Both mouse and rat models illustrate limiting DBM when dietary Cu is restricted during perinatal development. Within species, changes were more severe and proportional to the length of Cu deprivation. Both models may be useful to study the impact of Cu deficiency on altered catecholamines and their role in delayed development and altered behavior. Supported by NRI USDA CSR grant 2001-00998 and by NIH grant HD 39708.

Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24)

Aim of this study was to investigate the anticancer properties of the new lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24). In vitro, growth inhibition by KP772 was comparable for >60 tumour cell models with IC 50 values generally in the low μM range. KP772 induced tumour cell apoptosis indicated by chromatin condensation, caspase substrate cleavage and mitochondrial membrane depolarisation. DNA is unlikely to represent the primary molecular target of KP772, as no significant interaction or damage of DNA was detectable both in vitro and in living cells. Moreover, we found no evidence for induction of radical species. In contrast, KP772 potently inhibited DNA synthesis paralleled by a massive block of cell cycle in G 0/G 1 phase and a selective decrease of cyclin B 1. Although treatment with KP772 induced expression of p53 and p21 Waf1, transfection of wild-type p53 into knock-out cells only marginally enhanced the cytostatic activity of KP772. In vivo, the anticancer activity of KP772 against human DLD-1 colon carcinoma xenografts was comparable to that of cisplatin and methotrexate at doses not causing significant adverse effects. With regard to toxicity, the LD 50 and no-observed-adverse-effect levels (NOAEL) of KP772 in Sprague–Dawley rats were 21.6 and 7.5 mg/kg, in outbred albino mice 62 and 10 mg/kg, respectively. In summary, KP772 exerts anticancer activity via potent induction of cell cycle arrest and/or apoptosis and has promising in vivo anticancer activity against a human colon cancer xenograft. Together, these data suggest further development of KP772 as a new anticancer metal-drug.

Effect of melatonin, ascorbic acid, and succinic acid on the cumulative toxic effect of repeated treatment with gammafos (amifostine).

Daily treatment of outbred albino mice with gammafos in radioprotective doses of 300 and 500 mg/kg for 4 days produced a cumulative toxic effect. This effect was not observed after decreasing the dose of gammafos to 100 mg/kg. Repeated peroral administration of melatonin and ascorbic acid in a dose of 200 mg/kg 30 min before treatment with gammafos reduced its cumulative toxic effect. Succinic acid in a dose of 100 mg/kg was ineffective under these conditions. The cumulative death time for 50% animals receiving gammafos alone or in combination with melatonin, ascorbic acid, and succinic acid was 3.08, 4.29, 4.06, and 2.97 days, respectively.