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P W Sheldon

Publications and source records attributed to P W Sheldon.

At least 19 recordsLinked to original sources
PubMed1991

Excitatory responses to serotonin (5-HT) in neurons of the rat piriform cortex: evidence for mediation by 5-HT1C receptors in pyramidal cells and 5-HT2 receptors in interneurons.

As a prerequisite to pharmacological analysis of the excitatory effects of serotonin (5-HT) on piriform pyramidal cells and interneurons, this study first examined the physiological characteristics of these two cell types. Intracellular recordings confirmed that the subpopulation of 5-HT-activated cells located at the border of layers II and III are indeed interneurons. Voltage clamp recordings in pyramidal cells showed that the increase in excitability produced by 5-HT in these cells was the result of voltage- and Ca(2+)-dependent outward currents with the characteristics of IM and IAHP. Pharmacological studies were designed to discriminate 5-HT2 from 5-HT1C responses in interneurons and pyramidal cells of piriform cortex. The 5-HT antagonist spiperone, which has a much higher affinity for 5-HT2 receptors than for 5-HT1C receptors, blocked the excitatory effect of 5-HT at lower concentrations in interneurons (IC50 = 31 nM) than in pyramidal cells (IC50 = 2.1 microM). Similarly, ritanserin, a drug which also has a higher affinity for 5-HT2 than 5-HT1C receptors, blocked the effect of 5-HT at lower concentrations in interneurons (IC50 = 400 nM) than in pyramidal cells (IC50 = 8.1 microM). In contrast, LY 53857, an antagonist with higher affinity for 5-HT1C than for 5-HT2 receptors, blocked the effect of 5-HT at lower concentrations in pyramidal cells (IC50 = 26 nM) than in interneurons (IC50 = 364 nM). The 5-HT1C partial agonist/5-HT2 antagonist mCPP produced agonist-like effects in only 66% of pyramidal cells tested indicating that not all pyramidal cells may express 5-HT1C receptors. In that both spiperone and ritanserin have higher affinity for 5-HT2 receptors than for 5-HT1C receptors and LY 53857 has a higher affinity for 5-HT1C receptors than for 5-HT2 receptors, these data suggest that in piriform cortex excitatory effects of 5-HT are mediated by 5-HT1C receptors in pyramidal cells an by 5-HT2 receptors in interneurons.

Animals↗
PubMed1991

In vitro microdialysis: a novel technique for stimulated neurotransmitter release measurements.

A novel microdialysis technique suitable for parallel measurements of neurotransmitter release and single unit recordings from brain slices is presented. The effects of 3,4-methylenedioxymethamphetamine (MDMA) on slices of dorsal raphe nucleus and frontal cortex in a perfusion chamber for electrophysiological measures were studied. MDMA caused measurable release of serotonin which, in the case of the dorsal raphe, was of similar duration as the period of reduced cell firing induced by MDMA. Tryptophan potentiated the action of MDMA. Possible additional applications of this technique are discussed.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Serotonin (5-HT) induces IPSPs in pyramidal layer cells of rat piriform cortex: evidence for the involvement of a 5-HT2-activated interneuron.

In a slice preparation of rat piriform cortex, both intracellular and extracellular techniques were used to examine the pharmacological and electrophysiological actions of serotonin (5-HT). Bath application of 5-HT resulted in either depolarization (57%), hyperpolarization (34%) or no change (9%) in membrane potential of cells in the pyramidal cell layer (layer II) of piriform cortex. Additionally, when KCl-containing electrodes were used, 5-HT induced an increase in depolarizing synaptic potentials in 41% of these cells. It was concluded that these potentials were reverse inhibitory post-synaptic potentials (IPSPs) because they were blocked by bicuculline and tetrodotoxin. The induction of IPSPs by 5-HT was blocked by the 5-HT2-selective antagonist ritanserin. By recording extracellularly in the presence of 5-HT, a group of 5-HT-activated, putative interneurons was found at the border of layers II and III of piriform cortex, 5-HT but not norepinephrine activation was blocked by ritanserin. The actions of 5-HT were mimicked by the 5-HT2 agonist alpha-methyl-5-HT; the 5-HT2 partial agonist, 2,5-dimethoxy-4-methyl-amphetamine had a small agonist action of its own and blunted the effect of 5-HT. Activation of a larger group of putative interneurons by the more universal excitant N-methyl-D-aspartate showed that the 5-HT-activated interneurons represented 23% of the interneurons located on the border between layers II and III. We conclude that 5-HT induces IPSPs in layer II pyramidal cells by activating a subpopulation of interneurons at the border of layers II and III of piriform cortex.

Animals↗
PubMed1986

Induction of hypoxia in normal and malignant tissues by changing the oxygen affinity of hemoglobin--implications for therapy.

The drug BW12C, which increases the oxygen affinity of hemoglobin, reduces oxygen availability to tissues. This results in protection against radiation damage to the hemopoietic system and epidermal Langerhans cells in CBA mice. The drug also protects against beta-irradiation damage in pig epidermis. BW12C increases the hypoxic cell fraction in tumors and histological examination of an experimental T cell lymphoma shows that the induced hypoxia leads to tumor necrosis.

Aldehydes↗
PubMed1986

Analogues of RSU-1069: radiosensitization and toxicity in vitro and in vivo.

A series of nitroimidazoles containing aziridine and alkyl-substituted aziridine functions has been synthesized. The 2-nitroimidazole compounds examined all show greater radiosensitizing efficiency in vitro than misonidazole. The 4- and 5-nitroimidazole analogues are also more efficient than equivalent compounds which do not contain the alkylating aziridine moiety. All the compounds show increased toxicity towards hypoxic cells relative to aerobic cells, but this toxicity is reduced by alkyl-substitution of the aziridine ring. In vivo toxicity can also be reduced by modification of the aziridine function, but such alterations appear to have less effect upon the high radiosensitizing efficiency of these compounds in vivo. As a consequence of this study, compounds of potentially improved therapeutic utility compared to RSU-1069, the first reported member of this class, have been identified.

Animals↗
PubMed1985

The interaction between radiation and complexes of cis-Pt(II) and Rh(II): studies at the molecular and cellular level.

A range of Rh(II) carboxylates and cis-Pt(II) complexes have been examined for their ability to increase the radiation sensitivity of aerobic and hypoxic V79 cells in vitro. The transition metal complexes sensitize in both air and nitrogen, with the greater effect generally occurring in nitrogen. The cis-Pt(II) complexes only show small levels of sensitization with dose modification factors (DMFs) of no more than 1.2. In contrast, the Rh(II) complexes can give DMFs of 2.0. Radiation chemical experiments show the transition metal complexes to have substantially lower redox potentials than metronidazole and, in addition, neither type of complex undergoes electron transfer reaction or adduct formation on interaction with radicals derived from DNA bases. Thus, the inorganic complexes do not operate by mechanisms similar to those occurring with electron affinic or stable free radical sensitizers. The increase in radiation sensitivity for cells treated with the Rh(II) carboxylates, but not the cis-Pt(II) complexes, is attributed to the ability of the Rh compounds to deplete intracellular thiols. Further, the efficiency of sensitization by the Rh(II) complexes and their ability to interact with cellular thiols depends upon the nature of the carboxylate ligand and follows the order butyrate greater than propionate greater than acetate greater than methoxyacetate. The differences between the carboxylates may be due to differences in drug uptake. A combination of the Rh(II) complexes with misonidazole given to hypoxic cells irradiated in vitro gives an additive response. However, it was not possible to demonstrate a similar effect in tumours in mice given the combination of Rh(II) methoxyacetate and the misonidazole analogue RSU 1070.

Animals↗
PubMed1985

The effect of recovery from potentially lethal damage on the determination of repair and repopulation in a murine tumour.

Repair and repopulation following X irradiation of clamped-off murine anaplastic MT tumours was investigated using the established method of (Dn-D1)/(n-1). Repair was complete in 4 h, similar in extent to that reported in other tumours, and within the range of that reported for normal tissues. Subsequent repopulation commenced after 4 days and was equivalent to 1.8 Gy/day recovered dose, corresponding to a clonogenic cell number doubling time of 1.8 days. However, estimates of repair and repopulation may have been in error because the chronically hypoxic cells in this tumour alone have the ability to recover from potentially lethal damage (PLD) and so are more radioresistant than cells rendered acutely hypoxic by clamping. Because of this, even clamping off tumours at irradiation does not render all cell populations equally radioresistant, and so reoxygenation between fractions could result in an underestimate of repair and repopulation. Further, the differing sensitivity between acutely and chronically hypoxic cells renders the apparent OER a function of dose (i.e., oxygen not truly dose-modifying to chronically hypoxic cells). Consequently it is incorrect to assume a constant OER in order to compare repair in tumours irradiated under hypoxic conditions with that in normal tissues irradiated under aerobic conditions. It will be argued here that in the case of the present tumour neither reoxygenation nor the choice of OER will have qualitatively altered the conclusion reached from the conventional method.

Animals↗
PubMed1984

Intestinal microflora as potential modifiers of sensitizer activity in vivo.

Treatment of mice (some bearing Lewis Lung tumors), with penicillin (PEN) at 500 mg/l drinking water for one week prior to treatment with misonidazole (MIS), resulted in: the elimination of their anaerobic cecal flora; a decrease in MIS-induced neurotoxicity; an increase in pharmacological exposure to MIS; a decrease in MIS chemopotentiation; a probable increase in MIS radiosensitization; an increase in MIS induced hypothermia. Assuming no chemical interaction between PEN and MIS, these observations indicate that the intestinal microflora can influence the activity of MIS in vivo. Therefore their influence should be considered in all sensitizer-related studies in vivo. The observed reduction in the neurotoxic but not the radiosensitizing potential of MIS following PEN treatment indicates a therapeutic benefit.

Animals↗
PubMed1984

Potentiation of cyclophosphamide cytotoxicity in vivo: a study with misonidazole and fifteen other 1-substituted 2-nitroimidazoles.

It has recently been reported that compounds more lipophilic than misonidazole are better potentiators of CCNU tumor cytotoxicity in vivo. There is now a need to extend these studies to include other tumors and cytotoxic drugs. In the present study we have shown that misonidazole (MISO) can potentiate cyclophosphamide cytotoxicity in the Lewis lung carcinoma but not in the B16 melanoma. Further studies in the Lewis lung carcinoma, using 15 1-substituted 2-nitroimidazoles possessing a range of octanol:water partition coefficient (P) (from 0.18- greater than 100) have shown that potentiation increases with increasing lipophilicity. The most efficient compounds at administered dose levels of 1.0 and 2.0 mumol/g were Ro-07-1902, benznidazole (Ro-07-1051) and RSU 1050 which possess octanol:water partition coefficients in the range of 2.5-10. However, on the basis of an equitoxic administered dose (1/2LD50/2d), little difference in potentiation is seen over the range of P studied.

Animals↗
PubMed1984

RSU 1069, a 2-nitroimidazole containing an alkylating group: high efficiency as a radio- and chemosensitizer in vitro and in vivo.

Electron affinity as measured by the one-electron reduction potentian, E7(1), is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E7(1) = 398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater in vitro than that of misonidazole, e.g., 0.2 mM RSU 1069 gives an enhancement ratio of greater than 2.0 compared to 1.4 for the same concentration of misonidazole. Radiosensitization studies with the MT tumor in vivo also showed RSU 1069 to be a more efficient sensitizer than misonidazole. An administered dose of 0.08 mg/g RSU 1069 yielded an enhancement of 1.8 to 1.9 using tumor cell survival and tumor cure as end-points. At least a 10-fold higher dose of misonidazole is required for a similar degree of sensitization. Low doses of RSU 1069 also radiosensitize the Lewis lung and B16 experimental tumors. The ability of RSU 1069 to potentiate the cytotoxic action of melphalan and other cytotoxic drugs towards the MT tumor was also examined. RSU 1069 (0.08 mg/g) given to mice 1 hour before melphalan gave an enhancement of 2.8.

Animals↗
PubMed1984

The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice.

Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour.

Animals↗
PubMed1984

Effect of the nitroimidazole Ro 03-8799 on the activity of chemotherapeutic agents against a murine tumour in vivo.

The effect of the 2-nitroimidazole Ro 03-8799 (8799) on the activity of 11 chemotherapeutic agents against the anaplastic MT tumour in mice has been determined by soft agar cloning. The 8799, whilst producing little cytotoxicity by itself, potentiated the cytotoxic actions of the alkylating agents melphalan and cyclophosphamide, and the nitrosoureas BCNU, CCNU and MeCCNU. This potentiation was influenced by the time interval between the administration of 8799 and the chemotherapeutic agents, and also by the site of tumour implantation. However, 8799 did not potentiate the cytotoxicities of the compounds CBDCA, cisplatin, adriamycin, vincristine, 5-fluorouracil and bleomycin. A review is included of the reported in vivo effects of nitroimidazoles on the chemotherapeutic agents investigated here.

Animals↗
PubMed1984

Radiation sensitization and chemopotentiation: RSU 1069, a compound more efficient than misonidazole in vitro and in vivo.

Electron affinity as measured by the one-electron reduction potential, E17, is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E17 = -398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater than that of misonidazole, e.g. 0.2 mM RSU 1069 gives an enhancement ratio of 2.2 compared to 1.5 for the same concentration of misonidazole. Radiosensitization studies with the MT tumour in vivo also showed RSU 1069 to be a more efficient sensitizer than misonidazole. An administered dose of only 0.08 mg g-1 RSU 1069 yielded an enhancement of 1.8 to 1.9 using tumour cell survival and tumour cure as end-points. The ability of RSU 1069 to potentiate the cytotoxic action of melphalan towards the MT tumour was also examined. RSU 1069 (0.08 mg g-1) given to mice 1 h before melphalan resulted in an enhancement of 3.0. In contrast, previous studies had shown with a series of nitroimidazoles including misonidazole that Ro 03-8799 was the most effective potentiating agent, but this only gave an enhancement of 2.3 at a 10-fold higher dose than RSU 1069. RSU 1069 is a compound of substantial promise both as a radiosensitizer and chemopotentiating agent and warrants further investigation.

Animals↗
PubMed1984

Thiol reactive nitroimidazoles: radiosensitization studies in vitro and in vivo.

Using Chinese hamster V79 cells in vitro a study has been made of the radiosensitizing properties of 4- or 5-nitroimidazoles substituted in the 2, 5 or 4 position with various halo, sulphur ether, sulphonamide, sulphonate, ether or nitro groups. Values of E17 (the one-electron reduction potential measured versus the normal hydrogen electrode at pH7) vary in the range -178 to -565 mV. All the compounds, with one exception, are more efficient radiosensitizers than would be predicted from their redox potentials, and the factor, C1.6/C1.6, by which a compound is more efficient has been calculated. The second-order rate constants, k2, for reaction of these nitroimidazoles with glutathione and/or dithiothreitol were determined. Within each class of nitroimidazole there is a trend for k2 to increase with increasing redox potential. However, there is no clear trend between k2 and C1.6/C1.6. The concentration required to cause a 50 per cent depletion of intracellular glutathione was determined for selected compounds, as was the ability of glutathione-S-transferase to catalyse reaction with thiols. These observations suggested that the relative thiol reactivity measured under chemically controlled conditions does not necessarily indicate thiol reactivity intracellularly. Studies using the MT tumour in mice showed that the high levels of radiosensitization seen in vitro could not be duplicated in vivo. This was attributed to thiol reactivity, resulting in low metabolic stability and rapid depletion of sensitizer in vivo.

Animals↗
PubMed1983

Radiosensitization in vivo: a study with an homologous series of 2-nitroimidazoles.

An homologous series of 1-(omega-morpholino)alkyl-2-nitroimidazoles, previously reported to be more efficient hypoxic cell radiosensitizers than misonidazole (MIS) in vitro, were evaluated in vivo using the murine Lewis Lung carcinoma. When given i.p. the compounds were 3-20 times more acutely toxic (LD50/2d) than MIS and this toxicity increased with both the number of methylene groups (n) in the side chain and the lipophilicity of the compounds. The compounds sensitized the tumour to single doses of X-rays. On the basis of equimolar administered dose, the most effective compounds, n = 2, 4 and 5, were as efficient as MIS. However, on the basis of the measured concentration of drug in the tumour at the optimum time of irradiation the compounds with n = 4 and n = 5 were less efficient than expected from previously published data in vitro. This is attributed to the basicity of the morpholino nitrogen in these compounds such that at physiological pH the compounds are primarily in an ionized form and hence poorly able to penetrate hypoxic cells.

Animals↗