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J Hilton

Publications and source records attributed to J Hilton.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effect of dosing vehicle on the dermal absorption of fluazifop-butyl and fomesafen in rats in vivo.

One important factor which may influence the extent and rate of percutaneous absorption is the dosing vehicle. The purpose of the experiments described was to compare the effect of dosing vehicles of different polarities on the absorption of two herbicides across rat skin in vivo. Rats were dosed dermally with either fluazifop-butyl (logP(oct) 4.5) or fomesafen sodium salt (logP(oct) -1.2) in propylene glycol (PG), octanol (OCT), or ethyl decanoate (ED), and the amount of radioactivity excreted in urine was determined. Absorption rates were estimated from the urinary excretion data and from blood kinetic data derived from intravenously dosed rats. For fluazifop-butyl the average rate of absorption (x10(-2) micrograms/hr-1 +/- SE) was not greatly influenced by the dosing vehicle (OCT, 2.94 +/- 0.08; ED, 3.66 +/- 0.10; PG, 3.95 +/- 0.32) despite relatively large differences in solubility (PG, 38 mg/ml; OCT, and ED, > 600 mg/ml). These results were consistent with the finding that there was at most only a twofold difference in the epidermal membrane:vehicle partition coefficients (km). In contrast, the absorption rate of fomesafen from PG (1.98 +/- 0.04) was approximately half that of ED (3.98 +/- 0.06) and OCT (4.49 +/- 0.08) for the first 30 hr after application and was in keeping with solubility data (PG, 638 mg/ml; OCT, 12 mg/ml; ED, < 10 mg/ml). At later time points the absorption of fomesafen from PG increased; this is discussed in relation to the penetration-enhancing properties of PG.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1994

Serological responses induced in mice by immunogenic proteins and by protein respiratory allergens.

It is known that a variety of materials, including both low molecular weight chemicals and proteins, is able to induce occupational respiratory allergy. We have shown previously that exposure of mice to chemical respiratory sensitizers results in both a marked increase in the serum concentration of IgE and the appearance of specific IgE antibody. In the present study we have examined the characteristics of immune responses induced in mice following intraperitoneal exposure to 3 protein respiratory allergens, ovalbumin (OVA), a lipase from Aspergillus oryzae (LP) and an amylase from Bacillus subtilis (AM) and to a fourth protein, bovine serum albumin (BSA), which is considered usually not to cause respiratory sensitization. Under conditions where all proteins provoked IgG antibody responses, only OVA, LP and AM elicited specific IgE antibody. As judged by passive cutaneous anaphylaxis (PCA) assay, BSA failed to induce an IgE response. In contrast to chemical respiratory sensitizers, the protein allergens examined here failed to cause a substantial increase in the serum concentration of IgE; OVA and AM induced no increase in serum IgE and LP only a comparatively modest increase relative to control values. In conclusion, these data demonstrate that while protein respiratory allergens are able to provoke specific IgE antibody, they fail to cause a marked increase in the concentration of this immunoglobulin in the sera of treated mice. It would appear, therefore, that the mouse IgE test, which seeks to evaluate chemical respiratory sensitization potential as a function of induced changes in the concentration of serum IgE, will be inappropriate for the identification of protein respiratory allergens. Nevertheless, identification of protein allergens may be possible by exploiting the observations reported here that such proteins induce in mice specific IgE antibody responses.

Allergens↗
PubMed1994

High performance liquid chromatography of carbon-11 labeled thymidine and its major catabolites for clinical PET studies.

The identity and pharmacology of the rapidly formed radiolabeled metabolites formed following i.v. injection of C-11 thymidine (TdR) labeled in the 5-methyl-position are being studied in animal models and patients with cancer. A high performance liquid chromatographic (HPLC) procedure has been developed for the separation of these metabolites including thymine, dihydrothymine, beta-ureidoisobutyric acid, and beta-aminoisobutyric acid from plasma and tissue extracts. Information obtained regarding the pharmacokinetics of the metabolites are being used to generate mathematical models for C-11 TdR incorporation rates into DNA.

Animals↗
PubMed1994

Vehicle effects on in vitro percutaneous absorption through rat and human skin.

We studied the effects of three vehicles (propylene glycol, octanol and ethyl decanoate) with differing polarity on the in vitro percutaneous absorption of three chemicals (fluazifop-butyl, dimethyl phthalate and fomesafen sodium salt) with a range of physico-chemical properties. Absorption rate measurements were made from high vehicle volume (200 microliters/cm2) and low vehicle volume (< 10 microliters/cm2) applications. For the lipophilic fluazifop-butyl absorption rate was highest from the more polar vehicle propylene glycol, but this effect was only significant under high-volume conditions. There was a variable vehicle effect on absorption of the intermediate chemical dimethyl phthalate. The largest vehicle effect was seen for the more hydrophilic fomesafen sodium salt where absorption was fastest from the least polar vehicle ethyl decanoate. These results support the hypothesis that the absorption process can in part be predicted from a knowledge of solute solubility. Vehicle effects were greater from high volume applications than from those more comparable to occupational exposure conditions.

Animals↗
PubMed1994

Multimodality correlative study of canine brain tumors. Proton magnetic resonance spectroscopy, positron emission tomography, and histology.

RATIONALE AND OBJECTIVES: Structural/functional relationships in an induced canine brain tumor were studied using proton-magnetic resonance spectroscopy (1H-MRS), positron emission tomography (PET), and histology. METHODS: Proton-MRS and PET data of implanted canine brain tumors were correlated with quantitative analysis of the tissue composition within the MRS and PET regions of interest (ROIs). Linear regression analysis was employed to correlate the 1H-MRS and PET data with the percent tumor and the percent total lesion (comprising tumor plus associated pathology ie, edema, cysts, hemorrhage, inflammation) within the ROI. RESULTS: Using 1H-MRS, N-acetyl aspartate concentrations were indirectly correlated with the amount of tumor (P = .058), as well as the amount of tumor plus associated pathology (P = .032) within the ROI. Total creatine concentrations were indirectly correlated with the amount of tumor and the amount of tumor plus associated pathology within the ROI (P < .05). Lactate concentrations were directly correlated with the amount of tumor (P = .053) and the amount of tumor plus associated pathology (P = .058) within the ROI. Using PET, Oxygen metabolic rates were indirectly correlated with the amount of tumor and with the amount of tumor plus associated pathology within the ROI (P < .05). Glucose metabolic rates were directly correlated with both the amount of tumor and with the amount of tumor plus associated pathology at P < .05. Proton-MRS measured concentrations of choline and PET measured values for blood flow, and oxygen extraction showed correlations with the amount of tumor and with the amount of tumor plus associated pathology at P > or = .08. CONCLUSIONS: The PET and MRS data were complementary with respect to suggesting anaerobic glucose metabolism for the tumor. Unlike other tumors, no increase in choline was noted in the canine tumor.

Animals↗
PubMed1993

Mechanistic relationship among mutagenicity, skin sensitization, and skin carcinogenicity.

Twenty organic Salmonella mutagens, seven of which (including benzo[a]pyrene) are established skin carcinogens, and one of which (2-chloroethanol) is a well-defined noncarcinogen to skin, have been evaluated for skin-sensitizing activity using the local lymph node assay. The relative mutagenicity of the agents to Salmonella was also established. Fourteen of the chemicals were positive in the local lymph node assay, including the seven skin carcinogens. 2-Chloroethanol was inactive as a sensitizing agent. We suggest that a variety of factors contributes to the lack of sensitizing activity of the remaining six bacterial mutagens: extremes of intrinsic chemical reactivity, high water solubility reducing dermal translocation, and inappropriate dermal metabolism. Two reference skin-sensitizing agents (an oxazolinone and fluorescein isothiocyanate) were established as in vitro clastogens after their recognition as nonmutagens to Salmonella. These data imply that mutagenicity, rather than simply activity in the Salmonella assay, is a primary stimulus for electrophilic sensitization and carcinogenic initiation in the skin. We conclude that genotoxicity data for an agent can provide indications of the agent's potential to induce skin sensitization and that genotoxins which are skin-sensitizing agents have an enhanced potential to initiate skin carcinogenesis. We suggest that common, albeit individually distinct, structure-activity relationships underpin genotoxicity, skin sensitization, and the initiation of skin carcinogenesis. These relationships should simplify the hazard evaluation of chemicals and contribute to a reduction in animal usage. Several predictions of skin carcinogenicity are made based on the data presented.

Animals↗
PubMed1993

Influence of sodium lauryl sulphate on 2,4-dinitrochlorobenzene-induced lymph node activation.

The influence of the anionic surfactant sodium lauryl sulphate (SLS) on the ability of the contact allergen 2,4-dinitrochlorobenzene (DNCB) to provoke draining lymph node cell proliferative responses, a correlate of skin sensitizing potential, has been examined in mice. Topical application of 10% SLS with 0.1% DNCB caused a more vigorous proliferative response than did exposure to 0.1% DNCB alone. Lower concentrations (0.1% or 1%) of SLS were ineffective and 10% SLS failed to influence proliferative responses to higher concentrations (0.5% or 1%) of DNCB. Using an in vitro model for measurement of percutaneous absorption 10% SLS was shown not to increase the skin penetration of 0.1% DNCB. We therefore examined the influence of SLS on the accumulation of dendritic cells (DC) in lymph nodes draining the site of exposure, an important early event during the induction phase of skin sensitization. The frequency of DC in draining nodes was measured following topical application of SLS, DNCB or a combination of both. Epicutaneous exposure to 0.1% DNCB caused only a modest increase in the number of lymph node DC. However, 10% SLS or a mixture of 10% SLS with 0.1% DNCB each resulted in a significant elevation of DC numbers. It is proposed that SLS augments the skin sensitizing potential of sub-irritant concentrations of DNCB via an increase in the number of immunostimulatory DC which reach the draining nodes.

Administration, Cutaneous↗
PubMed1993

Role of glutathione in cellular resistance to alkylating agents.

Both elevated glutathione levels and increased activity of the enzyme glutathione S-transferase have been associated with the resistance of cells to alkylating agents. We have demonstrated that one mechanism of this resistance is the inactivation of the alkylating agents by conjugation with glutathione. This conjugation can be catalyzed by glutathione S-transferase. For the nitrogen mustard agents we have studied, both the spontaneous and enzyme catalyzed reactions proceed through the aziridinium intermediates of the alkylating agents, and the alpha isoenzymes of GST are involved. In a study of cyclophosphamide resistant medulloblastoma cell lines elevated cellular concentrations of glutathione correlated well with the resistance of the cell lines.

Alkylating Agents↗
PubMed1993

Effect of 4-(diethylamino)benzaldehyde on ethanol metabolism in mice.

The compound 4-(diethylamino)benzaldehyde (DEAB) is a potent inhibitor of cytosolic (class 1) aldehyde dehydrogenase (ALDH) in vitro and can overcome cyclophosphamide resistance in murine leukemia cells characterized by their high content of ALDH. In this study, we examined the in vivo effect of DEAB in mice on ethanol metabolism and on antipyrine clearance as a measure of the microsomal mixed function oxidase activity. DEAB administered in doses of 50 and 100 mg/kg increased the blood acetaldehyde concentration and decreased the plasma acetate concentration in mice treated with ethanol. A pharmacokinetic approach demonstrated that DEAB in doses of 50 and 100 mg/kg inhibited the fraction of ethanol converted to acetate by 32.5 and 67.5%, respectively. This inhibition was comparable with that produced by disulfiram. DEAB produced optimal inhibition of ALDH 10-15 min after administration. DEAB did not change the half-life or the total clearance of antipyrine. We conclude that DEAB is a potent inhibitor of ALDH in vivo and has no effect on the mixed function oxidase activity as determined by antipyrine clearance.

Acetaldehyde↗
PubMed1992

Intrathecal 4-hydroperoxycyclophosphamide: neurotoxicity, cerebrospinal fluid pharmacokinetics, and antitumor activity in a rabbit model of VX2 leptomeningeal carcinomatosis.

Dissemination of tumor to the leptomeninges and cerebrospinal fluid represents a common pattern of metastasis for many cancers; however, few chemotherapeutic agents are available for intrathecal (i.t.) use and treatment results are often poor. We studied the neurotoxicity and pharmacokinetics of i.t. 4-hydroperoxycyclophosphamide (4-HC) in the rabbit and the activity of i.t. 4-HC in a VX2 rabbit model of leptomeningeal carcinomatosis to evaluate the potential use of 4-HC in the treatment of leptomeningeal tumors. Toxicity studies examined 4-HC doses ranging from 0.5 to 6.0 mumol administered by intraventricular injection weekly for 4 to 8 weeks. Clinical or histological neurotoxicity was not observed in rabbits treated with < 1.0 mumol 4-HC for 4 weeks. Clinical toxicity, characterized by lethargy, weight loss, seizures, or death, was apparent at doses > 2.0 mumol. Vasculitis of superficial arteries was observed in rabbits treated with > 1.0 mumol 4-HC. In cerebrospinal fluid pharmacokinetic studies, the mean drug half-life after intraventricular or intralumbar administration was 24.3 and 18.2 min. Regional inequities in drug exposure were apparent as area under the clearance curve values for cerebrospinal fluid distant from the injection site were lower than those of proximate sites (P < 0.001). Weekly intraventricular treatment of VX2 leptomeningeal tumor-bearing rabbits with 0.5 or 1.0 mumol of 4-HC resulted in an increased life span of 22.5 and 35%, respectively. These results indicate that i.t. 4-HC, at doses lower than those producing neurotoxicity in the rabbit, is effective treatment for VX2 leptomeningeal carcinomatosis.

Animals↗
PubMed1992

Hepsulfam sensitivity in human breast cancer cell lines: the role of glutathione and glutathione S-transferase in resistance.

Hepsulfam (NSC 329680, 1,7-heptanediol disulfamate) is an alkylating agent that showed excellent activity against mouse and human mammary carcinoma in preclinical studies. We therefore studied the cytotoxicity of this drug in six human breast cancer cell lines (AdrRMCF7, WTMCF7, Hs578T, MDA-MB-231, T47D, and MDA-MB-468). Clonogenic assays of these cell lines showed a range of sensitivity with the 90% inhibitory concentration ranging from 3.1 microM hepsulfam (MDA-MB-468) to 32.3 microM hepsulfam (AdrRMCF7) after 24-h exposure to the drug. To evaluate possible mechanisms responsible for this observed variation in sensitivity to hepsulfam, we have studied glutathione S-transferase (GST) activity and glutathione (GSH) in these cell lines. Total cytoplasmic GST activity correlated with sensitivity; the most sensitive cell lines had the lowest GST activity, while the two most resistant cell lines, AdrRMCF7 and Hs578T, had the highest GST levels of the six cell lines. Western blot analysis showed that the only detectable isoenzyme was GST-pi. The amount of GST-pi isoform correlated with hepsulfam sensitivity in the three most resistant cell lines and was undetectable in the three most sensitive cell lines. Cellular concentrations of GSH did not correlate with hepsulfam sensitivity. However, GSH depletion with buthionine sulfoximine increased sensitivity to hepsulfam in a dose-dependent fashion in all six cell lines. Evaluation by mass spectrometry revealed that glutathione can form conjugates with hepsulfam. We conclude that the GST/GSH detoxication system plays a role in the sensitivity of these breast cancer cell lines to hepsulfam.

Antimetabolites, Antineoplastic↗
PubMed1991

Structure and expression of the cytosolic aldehyde dehydrogenase gene in cyclophosphamide-resistant murine leukemia L1210 cells.

These investigations were performed to clarify the molecular basis for the enhanced expression of cytosolic aldehyde dehydrogenase (ALDH-1) enzymatic activity in the cyclophosphamide-resistant L1210/CPA murine leukemia cell line, as compared to the parental L1210/O strain. Western immunoblot analysis was performed using a 15-fold greater quantity of cytosolic protein from the L1210/O as compared to the L1210/CPA cell line. Nevertheless, ALDH-1 immunoreactive protein could be detected only in the L1210/CPA cells. Northern analyses, performed using total cellular and polyadenylated RNA, again demonstrated ALDH-1-specific transcripts only in the L1210/CPA cell line. This transcript was identical in size to the ALDH-1 message expressed by normal murine hepatocytes. On Southern analysis, no evidence of gene amplification, gene rearrangement, or significant mutations of length was detected. These studies suggest that the ALDH-1 protein produced by the L1210/CPA cell line is structurally normal. Moreover, overexpression of the gene does not appear to have arisen as a result of an incremental process, such as gene amplification. Rather, a qualitative abnormality in the regulation of this gene appears to exist in the L1210/CPA cells, which distinguishes them from L1210/O cells and from normal murine lymphocytes.

Aldehyde Dehydrogenase↗
PubMed1991

Interaction of N,N',N''-triethylenethiophosphoramide and N,N',N''-triethylenephosphoramide with cellular DNA.

The antineoplastic agents N,N',N''-triethylenethiophosphoramide (thioTEPA) and N,N',N''-triethylenephosphoramide (TEPA) were studied for their interaction with the DNA of L1210 cells in the presence and absence of rat hepatic microsomes and NADPH. Alkaline elution was used to study 3 types of DNA lesions. When L1210 cells were incubated with thioTEPA alone, or with thioTEPA in the presence of microsomes and NADPH, no single-strand breaks were detected. However, incubation of L1210 cells for 2 h with thioTEPA, at concentrations greater than or equal to 100 microM, caused a dose-dependent increase in interstrand cross-linking that reached a maximum by 2 h after drug exposure. In the presence of rat hepatic microsomes and NADPH, this cross-linking was eliminated, but a different DNA lesion, alkali-labile sites, was produced. These alkali-labile sites were partially reparable with maximum repair achieved by 2 h after removal of drug. ThioTEPA was greater than 85% consumed by the microsomal incubation conditions employed, and TEPA was the only product of the microsomal metabolism of thioTEPA. Alkaline elution studies of L1210 cells that had been incubated with TEPA, alone or in the presence of microsomes and NADPH, demonstrated an elution pattern identical to that produced by thioTEPA in the presence of microsomes and NADPH. Lymphoblastoid cell lines derived from patients with Fanconi's anemia were far more sensitive to thioTEPA and mechlorethamine hydrochloride than were lymphoblasts derived from normal humans, but this hypersensitivity was not noted with TEPA or bleomycin. This is consistent with the known hypersensitivity of cells from patients with Fanconi's anemia to agents that produce interstrand cross-links and with the alkaline elution studies described above. In contrast, lymphoblastoid cell lines derived from patients with ataxia telangiectasia were no more sensitive to thioTEPA than were lymphoblasts derived from normal humans but were far more sensitive to bleomycin. One of these cell lines proved hypersensitive to TEPA, whereas the other was no more sensitive to TEPA than were lymphoblasts from normal humans. Our data imply that thioTEPA produces interstrand cross-links but that TEPA, the primary metabolite of thioTEPA, produces DNA lesions that are alkali labile.

Animals↗
PubMed1991

Specificity of isozymes of murine hepatic glutathione S-transferase for the conjugation of glutathione with L-phenylalanine mustard.

Glutathione S-transferase (GST) isozymes play a central role in the protection of cells from cytotoxic chemicals and have a putative role in the intrinsic and acquired resistance of tumors to cytotoxic drugs. We have isolated and purified GST isozymes from mouse liver (M. Warholm et al., Biochemistry, 25: 4119-4125, 1986) and analyzed the metabolic products of the reaction of L-phenylalanine mustard (L-PAM) with glutathione in the presence of GST isozymes, using reverse phase high performance liquid chromatography. At pH 6.5, the spontaneous conjugation of L-PAM and glutathione is suppressed and the major product at 60 min is the monochloro, monohydroxyl derivative of L-PAM. Addition of neither class mu nor class pi isozymes to the reaction has any effect on the metabolism of L-PAM. Only isozymes of the alpha GST class catalyze the conjugation of L-PAM with glutathione. In this case, the major metabolite at 1 h is the monochloro, monoglutathionyl conjugate. Increasing the amount of mu or pi isozyme in the reaction mixture has no effect on the metabolism of L-PAM, whereas increasing the amount of alpha isozyme completely supplants hydrolysis with conjugation. Thus, increased levels of class alpha GST isozyme may represent a specific mechanism whereby cells can acquire resistance to nitrogen mustards.

Animals↗
PubMed1991

The murine local lymph node assay: results of an inter-laboratory trial.

The local lymph node assay is a novel predictive test for the identification of contact allergens. The collaborative study reported here was performed to evaluate the reliability of the method when performed in independent laboratories. Eight chemicals were examined in each of 4 participating laboratories and results compared with predictions of skin-sensitizing activity made from concurrent Magnusson and Kligman guinea-pig maximization tests performed in a single laboratory. The local lymph node assay has as its theoretical basis the fact that contact allergens induce T-lymphocyte proliferative responses. In practice, predictions of contact-sensitizing potential are made following measurement of proliferation in lymph nodes draining the site of exposure to chemical, and derivation of a stimulation index using control values as the comparator. Although in the present study there was some variation between laboratories with respect to the absolute stimulation indices recorded, it was found that with all chemicals each laboratory made the same predictions of sensitizing activity. Six chemicals (2,4-dinitrochlorobenzene, formalin, eugenol, isoeugenol, p-phenylenediamine and potassium dichromate) yielded positive responses, and two (methyl salicylate and benzocaine) were negative, in each laboratory. Furthermore, with 7 of the 8 chemicals tested there was no significant difference between laboratories in terms of the characteristics of the dose-response relationships recorded. With the exception of one chemical (benzocaine), predictions made with the local lymph node assay were in accord with those derived from guinea-pig maximization tests. These inter-laboratory comparisons demonstrate that the local lymph node assay is a robust and reliable method for the identification of at least moderate and strong contact allergens.

Allergens↗
PubMed1991

Assessment of the relative skin sensitizing potency of 3 biocides using the murine local lymph node assay.

The relative skin-sensitizing potency of 3 biocides, 5-chloro-2-methyl-4-isothiazolin-3-one (the major active ingredient in Kathon CG), 1,2-benzisothiazolin-3-one and 2-methyl-4,5-trimethylene-4-isothiazolin-3-one, was assessed using the murine local lymph node assay. Potency was ranked according to the lowest dose of material which, following epicutaneous exposure, induced a significant proliferation of T lymphocytes in the draining lymph nodes. The results showed that 5-chloro-2-methyl-4-isothiazolin-3-one was able to induce proliferative activity at significantly lower dose levels than the other 2 biocides and that it may therefore be a more potent skin sensitizer.

Animals↗
PubMed1990

Development and characterization of a cyclophosphamide-resistant subline of acute myeloid leukemia in the Lewis x Brown Norway hybrid rat.

Preclinical studies of resistance to alkylating agents in the Lewis x Brown Norway hybrid (LBN) rat model of acute myeloid leukemia (AML) have hitherto been limited by the sensitivity of LBN AML cells to cyclophosphamide (CY). We developed a CY-resistant subline of LBN AML by serial intravenous (IV) passage of AML cells followed by in vivo exposure to CY (100 mg/kg) 14 days later. After 18 and subsequent passages, CY-treated AML cells remained viable despite ex vivo incubation with 70 to 100 mumol/L 4-hydroperoxycyclophosphamide (4HC) or in vivo exposure to 100 to 300 mg/kg of CY. Once established, resistance to incubation with 4HC was stable in LBN AML cells after at least six serial in vivo passages without exposure to CY. Nevertheless, both control and CY-treated AML cells demonstrated similar dose-dependent sensitivity to 100 to 500 mumol/L phosphoramide mustard (PhM), the active alkylating end-product of CY activation in vivo. Levels of aldehyde dehydrogenase (ALDH), which inactivates CY by prevention of formation of PhM, were significantly elevated in these CY-resistant AML cells: cytosolic and particulate ALDH fractions from these cells were 11 to 13 times control with NAD cofactor and propanal substrate and three to four times control with NADP cofactor and benzaldehyde substrate. Further studies with this animal model of AML, in which resistance to CY is mediated by elevated ALDH activity, may elucidate mechanisms for effective elimination of drug-resistant leukemic cells ex vivo and in vivo.

Aldehyde Dehydrogenase↗