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Biomedical subjects

L M Adams

Publications and source records attributed to L M Adams.

At least 55 records · Page 3Linked to original sources
PubMed1987

Enhanced in vitro proliferation and in vivo tumorigenic potential of mammary epithelium from BALB/c mice exposed in vivo to gamma-radiation and/or 7,12-dimethylbenz[a]anthracene.

Virgin female BALB/c mice were exposed in vivo to whole body gamma-radiation and/or to 7,12-dimethylbenz[a]anthracene (DMBA) p.o. Mammary epithelial cells were isolated and assayed for carcinogen altered cell populations both in vitro by an epithelial focus assay and in vivo by injection into cleared fat pads of syngeneic host mice. Five groups of mice were exposed as follows: (a) sham controls; (b) 50-rad gamma-radiation; (c) 100-rad gamma-radiation; (d) 75 micrograms DMBA; or (e) 50-rad gamma-radiation followed in 1 week by 75 micrograms DMBA. Mammary epithelial cells were isolated and assayed at 24 h and at 1, 4, 16, and 52 weeks after in vivo exposure. Four to 12 mice per treatment per time point were individually assayed. Altered in vitro growth potential was characterized by the proliferation of carcinogen exposed (but not control) cells as epithelial foci which persisted at least 12 weeks in primary culture. Epithelial foci which could then be subcultured at least four times were termed subculturable epithelial foci. Altered in vivo morphogenic potential was characterized by dysplastic or neoplastic growth in host fat pads. With increased time in situ between exposure and assay, cell populations emerged which exhibited both increased in vitro subculturability and enhanced tumorigenic potential including a host response upon injection in vivo. Further, combined radiation and DMBA resulted in higher frequencies of subculturable epithelial foci than either treatment alone. The relevance of these progressive cellular changes to the process of mammary tumor development is discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Characterization of an inbred strain of the SENCAR mouse that is highly sensitive to phorbol esters.

An inbred strain of SENCAR mice was developed that is more sensitive to two-stage skin carcinogenesis protocols than the outbred parental stock. These mice, registered as SSIN/UTSP, were compared to the SENCAR in initiation-promotion protocols using the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 22 weeks at dose levels of 0.5, 1.0 and 2.0 micrograms. With 0.5 microgram of TPA, the number of papillomas in the SSIN was 3-fold higher than in the SEN-CAR; the tumor incidence was 100 versus 60%, respectively. Similar, although less dramatic, results were found with 1.0 and 2.0 micrograms of TPA. In two-step promotion protocols using TPA twice weekly for 2 weeks and 2 micrograms mezerein twice weekly for 15 weeks the SSIN produced approximately 50% more tumors than the SENCAR at 0.5 microgram of TPA. At 2 micrograms of TPA the tumor response between the two mice was not significantly different. Epidermal hyperplasia was considerably greater in the SSIN at 0.5 microgram of TPA as was ornithine decarboxylase activity. These TPA-sensitive inbred mice should be useful in investigations on the biochemical and genetic factors involved in skin tumor promotion.

Animals↗
PubMed1986

Effects of anti-promoters and strain of mouse on tumor promoter-induced oxidants in murine epidermal cells.

The induction of oxidant production in mouse epidermal cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) can be suppressed by many, but not all, known inhibitors of mouse skin tumor promotion. Members of the anti-oxidant category that were tested were ranked in the following order, 7,8-benzoflavone greater than butylated hydroxyanisole greater than ascorbic acid. In the retinoid category, retinoic acid was only moderately effective, while the trimethoxymethylphenyl analog had at least twice the inhibitory activity. Among the six protease inhibitors examined, tosylphenylalanine chloromethylketone and tosyllysine chloromethylketone were effective in diminishing the response while tosylarginine methylester, antipain, leupeptin and soybean trypsin inhibitor were ineffective, suggesting that proteases are probably not involved in the oxidant response. Several agents, trifluoperazine, trisialoganglioside and diolein, that have been shown to suppress TPA activity in other cell systems were also found to suppress the oxidant response. Finally, the extent of the oxidant response was found to correlate with sensitivity to TPA tumor promotion among the three strains of mice tested: SSIn greater than SENCAR greater than C57BL/6J.

Animals↗
PubMed1985

Phospholipase C mimics tumor promoter-induced chemiluminescence in murine epidermal cells.

Treatment of newborn murine epidermal cells with phospholipase C results in the generation of a chemiluminescence response similar to that previously described for phorbol ester tumor promoters. Based on inhibitor studies, the oxidant, believed to be superoxide anion, is most likely generated from lipoxygenase metabolism of arachidonic acid. The specificity of the response to phospholipase C from C. perfringens and not from B. cereus or phospholipase A2 suggests specific phospholipids are involved. The response observed appears to arise from the phospholipid-protein kinase c model for phorbol ester binding and activity.

Animals↗
PubMed1985

Patterns of exploration in rats distinguish lisuride from lysergic acid diethylamide.

In order to further validate a previously proposed animal model of the effects of LSD in humans, doses of 5, 15, 30 and 60 micrograms/kg lisuride (a non-hallucinogenic congener of LSD) were studied using a behavioral pattern monitor (BPM). The BPM provided both quantitative measures of crossovers, rearings, and holepokes and qualitative measures of spatial patterns of locomotion. A holeboard chamber connected to a homecage provided two test situations. Rats were tested either with (free exploration) or without access to the homecage (forced exploration). In both situations, lisuride exhibited a biphasic dose-response curve for horizontal locomotion (low dose suppression and high dose enhancement), while rearing was significantly reduced at all doses. Lisuride also produced a dose-dependent increase in the perseverative quality of locomotor patterns. A comparison of these results with our previous studies with lysergic acid diethalmide (LSD) indicate that, with the exception of rearings, lisuride fails to mimic LSD's characteristic effects on exploratory activity. Rather, lisuride exhibited many similarities to the dopamine angonist apomorphine.

Animals↗
PubMed1985

Behavioral effects of xylamine-induced depletions of brain norepinephrine: interaction with LSD.

Male rats were treated with a combination of systemic fluoxetine and intraventricular xylamine (under ether anesthesia) to deplete brain norepinephrine (NE) in the projection areas of the locus coeruleus. Four days later, control and lesioned rats were tested following injections of either saline or 80 micrograms/kg LSD in a Behavioral Pattern Monitor which recorded the sequential patterns of their locomotor and investigatory (holepokes) responses. Liquid chromatographic measures of brain monoamines confirmed that xylamine reduced hippocampal NE by 80.8% and hypothalamic NE by 26% without affecting levels of serotonin or dopamine. Relative to controls, NE-depleted rats exhibited repetitive spatial patterns of locomotion with no alteration in the amount or rate of habituation of locomotor activity. Lesioned animals made fewer rearings and holepokes, particularly early in the hour test session. When given 80 micrograms/kg LSD, sham-lesioned rats exhibited the expected decreases in entries into and time spent in the center of the chamber, an increase in time spent in the corners, and fewer holepokes and rearings early in the session. With the exception of the effect on rearings and holepokes, the effects of LSD were diminished in rats depleted of brain NE. These results indicate that this profile of behavioral effects of LSD, which has been interpreted as a potentiation of neophobia, may be dependent upon the noradrenergic projections of the locus coeruleus.

Animals↗
PubMed1985

Effects of DOM and DMT in a proposed animal model of hallucinogenic activity.

A previously proposed animal model of lysergic acid diethylamide's (LSD) effects in humans was tested for its applicability to other hallucinogens, 2,5-dimethoxy-4-methyl amphetamine (DOM) and N,N-dimethyltryptamine (DMT). Both "free" and "forced" exploration tests in a behavioral pattern monitor were used to determine the effects of these hallucinogens on the normal tendencies of rats to avoid novel and central areas, respectively. The effects of DOM (0.3-1.0 mg/kg) were quite similar to those previously reported for LSD. Specifically, DOM reduced crossovers, holepokes, and rearings when rats were tested in a novel environment. In a familiar environment, only rearing activity was reduced with minimal effect on ambulation. Like LSD, entries into the central area were reduced in both situations. DOM also produced a dose-dependent reduction of entries into the novel chamber in a free exploration test. Pretreatment with the serotonin (5-HT) antagonist cyproheptadine (1.0 mg/kg), which does not block the psychological effects of hallucinogens in humans, selectively blocked DOM's reduction of rearings without altering DOM's reduction of center entries, crossovers, or holepokes. Like LSD and DOM, DMT (0.5, 1.0, and 2.0 mg/kg) produced a selective reduction of entries into the center region when rats were forced to explore a novel holeboard chamber. All three doses also selectively reduced holepoke responses without affecting crossovers or rearings. In conclusion, enhanced avoidance of novel and central areas appears to be a valid indicator of hallucinogenic activity since LSD, DMT, and DOM all share this property. Conversely, the reduction of rearings produced by LSD and DOM is not a suitable model behavior since the effect is not produced by DMT and cyproheptadine is capable of selectively blocking this effect.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1985

A proposed animal model for hallucinogens based on LSD's effects on patterns of exploration in rats.

The utility of various measures of exploratory activity in rats was studied in order to develop an animal model of hallucinogens. A hole board chamber, connected by a door to a home cage, provided two test situations. Rats either were placed directly into the hole board with the door closed (forced exploration) or were placed in the home cage and, following adaptation, the door was opened (free exploration). The monitoring system provided both quantitative measures (crossovers, rearings, and hole pokes) and qualitative measures of locomotor patterns. A series of four experiments, with doses of 2-160 micrograms/kg LSD, revealed three major categories of effects, distinguishable on the basis of dose dependency, time course, or response to environmental manipulation: increased avoidance of novel and central areas, disruption of the spatial patterning of locomotion, and suppression of rearing. All three effects exhibited partial tolerance 24 hr after one injection of 30 micrograms/kg LSD and complete tolerance after five daily injections. The possibility that LSD's enhancement of neophobia in rats may be a valid analogue model of its intensification of affective reactions in humans is discussed.

Animals↗
PubMed1985

The first stage and complete promoting activity of retinoic acid but not the analog RO-10-9359.

Retinoic acid has the ability to act as either a weak first stage promoter or a weak complete promoter in the initiation-promotion protocol for skin carcinogenesis in the SENCAR mouse. The retinoid analog RO-10-9359 lacks this tumor promoting activity. Both retinoids however inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. Additional comparisons revealed that retinoic acid alone can induce dark keratinocytes, a characteristic of tumor promoters, while RO-10-9359 cannot. Retinoic acid but not RO-10-9359 can induce an immediate chemiluminescence response in human polymorphonuclear cells. Both retinoids, however, inhibit a TPA-induced response. Since the chemiluminescence response is believed to be due to oxygen free radical generation, the data suggest that the ability of retinoic acid but not RO-10-9359 to promote tumors and induce dark cells may be due to initial oxidative reactions at the cell membrane.

Animals↗
PubMed1985

Suppression of tumor promoter-induced chemiluminescence in mouse epidermal cells by several inhibitors of arachidonic acid metabolism.

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a stimulator of chemiluminescence (CL) in SENCAR mouse epidermal cells. The CL response is TPA dose dependent (8 to 800 nM) as well as proportional to the number of cells used. Treatment with 166 nM TPA results in a CL response that peaks by 15 min although a strong response persists for over 30 min. The CL response can be inhibited by superoxide dismutase and the superoxide dismutase mimetic copper(II) (3,4 diisopropylsalicylic acid)2, suggesting that the CL response may be due to or mediated by superoxide anions. Catalase, which is specific for H2O2, and mannitol, which is a scavenger for hydroxyl radicals, had negligible inhibitory effects. The CL response is also inhibited by retinoic acid and the analogue ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8- nonatetraenoate. A series of phorbol esters with different promoting abilities produced corresponding CL responses. The second stage tumor promoter mezerein is as effective as TPA in stimulating CL. Inhibitors of various parts of the arachidonic acid cascade were found to affect the TPA-induced CL response in a manner that corresponds to their effects in vivo tumor promotion experiments: agents which are predominantly lipoxygenase inhibitors, i.e., nordihydroguaiaretic acid, benoxaprofen, or agents which are effective against both lipoxygenase or cyclooxygenase, i.e., 5,8,11,14-eicosatetraynoic acid and phenidone, are effective in diminishing the CL response. Cyclooxygenase inhibitors, i.e., indomethacin and flurbiprofen, have no or a slight enhancing effect at low doses. These data suggest that at least a major part of the TPA-induced CL response is due to the metabolism of arachidonic acid, most probably by the lipoxygenase(s). This CL assay may provide a useful system for studying the involvement of oxidants in tumor promotion.

Animals↗
PubMed1985

Measurement of biological shape: a general method applied to mouse vertebrae.

A method is described for recording and analysing the projected shape of mouse vertebrae. The image of the shape is captured by a television camera, cleaned, digitized and subjected to mathematical analysis. A visual representation is obtained by reconstructing the shape in polar coordinates about its centre of area. Further statistical analysis of the whole shape is performed after a Fourier transform. This allows the shape to be represented by and reconstructed from 15 numbers. The method does not rely on homologous points or expert opinion and allows mean shapes to be constructed. It successfully distinguished between 92% of the test data, T1 and T2 vertebrae from two strains of mice.

Animals↗
PubMed1984

Depletions of central norepinephrine by intraventricular xylamine in rats.

A series of neurochemical studies evaluated the selectivity of the depletions of norepinephrine produced by intraventricular injections of xylamine. Brain monoamines were assayed by liquid chromatography with electrochemical detection. With ether anesthesia, bilateral injections of 50 or 100 micrograms xylamine reduced hippocampal levels of norepinephrine and serotonin without affecting striatal dopamine or serotonin. The depletion of hippocampal norepinephrine was significant as soon as 24 h. Animals treated with the combination of 20 mg/kg fluoxetine and 100 micrograms xylamine had selective depletions of central norepinephrine with no significant changes in serotonin.

Animals↗
PubMed1984

Morphological and histological characteristics of mammary dysplasias occurring in cell dissociation-derived murine mammary outgrowths.

The morphological and histological characteristics of ductal dysplasias that were observed in mammary outgrowths derived from monodispersed mammary cells of carcinogen-treated mice are described. Mammary outgrowths were derived by injecting either 10(4) or 10(5) enzymatically dissociated mammary cells, obtained from control or carcinogen-treated BALB/c mice, into gland-free mammary fat pads of syngeneic hosts. The mammary dysplasias observed varied considerably in morphological and histological characteristics. The majority of the lesions were ductal in origin and were associated with epithelial hyperplasia which ranged from mild hyperplasia, in which only a few extra layers of epithelium were present, to severe hyperplasia, in which the ducts and end buds were occluded and distended with epithelial cells. In addition, papillary and lobular lesions were observed which were also associated with varying degrees of hyperplasia. The range of mammary dysplasias observed in these outgrowths closely resembles that of lesions associated with the pathogenesis of mammary carcinoma in mice, rats, and humans.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Survival of mammary epithelial cells from virgin female BALB/c mice following in vivo gamma irradiation.

To examine the cytotoxic effects of ionizing radiation on mouse mammary epithelial cells, a transplantation assay was used to generate a single-dose survival curve. In these experiments, virgin female BALB/c mice were irradiated with 0, 100, 300, 600, 900, 1200, or 1500 rad whole-body 137Cs radiation. Mammary glands of control and irradiated mice were removed and the mammary epithelial cells were enzymatically dissociated, either immediately or 24 hr following irradiation, serially diluted, and injected into gland-free mammary fat pads of 31/2-week-old virgin female BALB/c host mice. The number of cells required to give ductal growth at 10 weeks in half the fat pads (the mammary cell dose 50%, MCD50) was determined by a maximum likelihood procedure and the ratio of MCD50 for nonirradiated control cells to MCD50 for irradiated cells provided an estimate of cell survival. Fitting the data using a single-hit multitarget model resulted in an estimate for D0 of 250 rad with an n of 2.4. No significant difference in the results was obtained whether the cells were dissociated and transplanted immediately after irradiation or the cells were allowed to remain in situ for 24 hr following irradiation. Thus no "in situ repair" was detected for mouse mammary epithelial cells.

Animals↗
PubMed1982

LSD-induced alterations of locomotor patterns and exploration in rats.

A five exploration test was used to examine the effects of LSD on investigatory responding and locomotor activity in a novel environment. Rats were injected with 20-30 micrograms/kg LSD or saline prior to being placed in a home cage. After 10 min, a door was opened permitting entry into a larger holeboard chamber where crossovers, rearings, hole pokes, and routes of locomotion were monitored. When administered either 10 or 30 min prior to testing, LSD reduced the time spent in the holeboard chamber only during the first half of a 1-h session, resulting in a corresponding reduction in all holeboard activity measures. In the subsequent 30 min, LSD-treated rats maintained a steady level of responding, in contrast to the continual decrement exhibited by controls. Despite their initial avoidance of the holeboard, LSD-treated rats made consistently longer hole pokes into floor holes and showed a more diversified pattern of locomotion than did controls throughout the 1-h session. Most striking was the failure of LSD-treated rats to establish the stereotyped excursion routes, characteristic of controls, from the home cage to various parts of the holeboard. It is suggested that LSD potentiates both neophobic (avoidance) and investigatory responses to a novel environment by retarding the rate of behavioral habituation.

Animals↗