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R Snyder

Publications and source records attributed to R Snyder.

At least 55 records · Page 3Linked to original sources
PubMed1995

Benzene metabolism in rodent hepatocytes: role of sulphate conjugation.

1. Hepatocytes isolated from the adult male NMRI mouse or Wistar rat were incubated for 1 h with 0.5 mM 14C-benzene, the supernatant was separated from the cells, and analysed for benzene metabolites. Separately, formation of sulphate conjugates during benzene metabolism was studied in hepatocytes in the presence of 35S-sulphate. In addition sulphate conjugation of the benzene metabolites hydroquinone and 1,2,4-trihydroxybenzene was investigated in mouse liver cytosol supplemented with 3'-phosphoadenosine-5'-phospho-35S-sulphate. 2. Two novel metabolites, not detectable in rat hepatocyte incubations, were found in mouse hepatocytes, and were identified as 1,2,4-trihydroxybenzene sulphate and hydroquinone sulphate. Formation of the 35S-labelled conjugates could be demonstrated in incubations of mouse liver cytosol with hydroquinone or 1,2,4-trihydroxybenzene supplemented with 3'-phosphoadenosine-5'-phospho-35S-sulphate, and in mouse hepatocytes incubated with benzene and 35S-sulphate. 3. In comparison with hepatocytes from the Wistar rat, hepatocytes from the NMRI mouse were almost three times more effective in metabolizing benzene. The higher formation of hydroquinone, and the formation of trihydroxybenzene sulphate and hydroquinone sulphate, mainly contributed to the higher rate of benzene metabolism. 4. In conclusion, qualitative and quantitative differences in benzene metabolism may contribute to the higher susceptibility of mouse towards the myelotoxic and leucaemogenic action of benzene.

Animals↗
PubMed1995

Prevention of tumor formation in a mouse model of Burkitt's lymphoma by 6 weeks of treatment with anti-c-myc DNA phosphorothioate.

BACKGROUND: Transgenic mice bearing a murine immunoglobulin enhancer/c-myc fusion transgene (Emu-myc) provide a useful model for Burkitt's lymphoma. MATERIALS AND METHODS: Groups of 12 Emu-myc mice were treated prophylactically for 6 weeks after weaning with anti-c-myc DNA phosphorothioate (20 mg/kg/day), scrambled control DNA, or saline, delivered by micro-osmotic pumps. RESULTS: Half of the mice treated with saline or scrambled control DNA displayed palpable tumors by 8-9 weeks after birth, and 95% of them did so by 16 weeks, but 75% of the mice treated with antisense DNA were still free of tumors at the age of 26 weeks. Antisense therapy ablated MYC antigen in the spleens of tumor-bearing mice. Plasma physiological parameters indicated no acute toxicity. CONCLUSIONS: Long-term tumor resistance after anti-c-myc DNA therapy implies induction of a host response. Prophylactic anti-c-myc DNA therapy might prevent lymphoma in asymptomatic individuals displaying c-myc translocations.

Aging↗
PubMed1994

Penetration of topically applied ciprofloxacin, norfloxacin, and ofloxacin into the aqueous humor.

PURPOSE: To determine the intraocular penetration of topically applied fluoroquinolone antibiotics into aqueous humor. METHODS: Thirty-two patients undergoing cataract extraction received either 0.3% ciprofloxacin, 0.3% norfloxacin, or 0.3% ofloxacin topical drops. The patients were given two drops 90 minutes preoperatively and two drops 30 minutes preoperatively. At the time of surgery, 0.1 ml aqueous fluid was aspirated from the anterior chamber and immediately stored at -70 degrees C. RESULTS: Concentrations of ciprofloxacin, norfloxacin, and ofloxacin were determined using a broth dilution bioassay. Morganella morganii with a known minimal inhibitory concentration was used to assay ciprofloxacin and norfloxacin levels. Salmonella enteritidis with a known minimal inhibitory concentration was used to assay ofloxacin levels. Topically applied ciprofloxacin achieved a mean aqueous level of 0.072 microgram/ml (range, 0.02-0.153 microgram/ml). One sample was below the sensitivity of the bioassay. Topical norfloxacin achieved a mean aqueous level of 0.0570 microgram/ml (range, 0.046-0.10 microgram/ml). Seven samples did not reach the sensitivity of the bioassay. Topical ofloxacin achieved a mean level in the aqueous humor of 0.338 microgram/ml (range, 0.078-0.625 microgram/ml). There was no statistically significant difference in intraocular aqueous humor levels of ciprofloxacin versus norfloxacin (P > 0.05). Topical ofloxacin achieved aqueous humor levels significantly higher than either ciprofloxacin or norfloxacin (P < 0.004). CONCLUSION: Of the currently available topical fluoroquinolone antibiotics, ofloxacin achieves the highest aqueous humor concentrations.

Administration, Topical↗
PubMed1994

A perspective on benzene leukemogenesis.

Although benzene is best known as a compound that causes bone marrow depression leading to aplastic anemia in animals and humans, it also induces acute myelogenous leukemia in humans. The epidemiological evidence for leukemogenesis in humans is contrasted with the results of animal bioassays. This review focuses on several of the problems that face those investigators attempting to unravel the mechanism of benzene-induced leukemogenesis. Benzene metabolism is reviewed with the aim of suggesting metabolites that may play a role in the etiology of the disease. The data relating to the formation of DNA adducts and their potential significance are analyzed. The clastogenic activity of benzene is discussed both in terms of biomarkers of exposure and as a potential indication of leukemogenesis. In addition to chromosome aberrations, sister chromatid exchange, and micronucleus formation, the significance of chromosomal translocations is discussed. The mutagenic activity of benzene metabolites is reviewed and benzene is placed in perspective as a leukemogen with other carcinogens and the lack of leukemogenic activity by compounds of related structure is noted. Finally, a pathway from exposure to benzene to eventual leukemia is discussed in terms of biochemical mechanisms, the role of cytokines and related factors, latency, and expression of leukemia.

Animals↗
PubMed1993

Benzene metabolism by reconstituted cytochromes P450 2B1 and 2E1 and its modulation by cytochrome b5, microsomal epoxide hydrolase, and glutathione transferases: evidence for an important role of microsomal epoxide hydrolase in the formation of hydroquinone.

Benzene metabolism was investigated using two purified rat hepatic MFO systems containing either cytochrome P450 2B1 or cytochrome P450 2E1. Studies performed over a wide substrate concentration range indicate that cytochrome P450 2B1 represents a relatively low-affinity form of cytochrome P450 with respect to benzene metabolism while cytochrome P450 2E1 is substantially more efficient at low benzene concentrations (apparent Km value 0.17 mM). Cytochrome b5 stimulated benzene metabolism by both cytochromes P450 2B1 and P450 2E1. With cytochrome P450 2E1 the stimulation of benzene metabolism by cytochrome b5 was very pronounced (up to 6-fold) at low concentrations of benzene and was most effective (up to 15-fold) with respect to formation of hydroquinone. The metabolites observed in these studies were phenol and hydroquinone. Cytochrome P450 2E1 metabolized phenol with an affinity and capacity comparable to those of benzene. Hydroquinone was the major product formed at all substrate concentrations, while some catechol was formed at all substrate concentrations, while some catechol was formed at higher concentrations of phenol. Phenol metabolism was also stimulated by cytochrome b5. The metabolism of benzene by cytochrome P450 2E1 in the presence of the major microsomal epoxide hydrolase, mEHb, yielded phenol, hydroquinone, and benzene dihydrodiol. Interestingly, the addition of mEHb did not lead to a decrease of the toxicologically important metabolite hydroquinone as might be expected from sequestration of the intermediate benzene oxide to the vicinal dihydrodiol pathway but rather led to a marked (more than 4-fold) increase in the formation of hydroquinone, suggesting catalysis by mEHb of a predominant attack at the homoallylic position rather than at a carbon atom which forms the epoxide ring of benzene oxide. The addition of glutathione transferases plus glutathione did not yield GSH conjugates during benzene metabolism. However, metabolism of phenol by cytochrome P450 2E1 in the presence of glutathione yielded a nonenzymatically formed glutathione conjugate derived from hydroquinone or from an oxidative product of hydroquinone.

Animals↗
PubMed1993

Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer.

BACKGROUND: The antioestrogen tamoxifen and progestins act via different receptors and may therefore have complementary effects against human breast cancer. This possibility was tested in a randomized study which compared the effects of tamoxifen, standard-dose megestrol acetate, and these two agents in combination, in patients with metastatic breast cancer. PATIENTS AND METHODS: 184 post-menopausal patients with metastatic breast cancer were randomized to initial treatment with either tamoxifen (TAM) 40 mg daily, megestrol acetate (MA) 160 mgm daily, or the combination of the two administered simultaneously. Patients crossed over to the alternative single agent on relapse or disease progression. Patients were evaluated for response, time to initial and ultimate treatment failure, and survival. RESULTS: There were no significant differences between the three groups with respect to response rates, nor the other parameters. Patient survival was significantly associated with age > 60 years, ER positive status, and the absence of visceral metastases. CONCLUSIONS: TAM and MA are both equally effective in response induction as initial treatments and the combination has no advantage. Sequential treatment is still optimal, TAM being the preferred initial agent in view of the reported side effects with MA.

Aged↗
PubMed1993

Proliferative and histologically malignant struma ovarii: a clinicopathologic study of 54 cases.

We reviewed 54 cases of struma ovarii with histologic features diverging from the normal pattern of benign thyroid tissue. These 54 lesions were divided into proliferative struma (41 cases) and malignant struma (13 cases). The patients diagnosed with proliferative struma ovarii ranged in age from 18 to 84 years (average, 44 years). The most common clinical findings among the proliferative struma patients were a mass (58%) and acute abdominal pain (12%). Preoperative evidence of hyperthyroidism was noted in three of the patients with proliferative struma, whereas one additional patient presented with ascites and hydrothorax ("pseudo-Meigs' syndrome"). Proliferative struma differed from the usual struma ovarii in that they comprised areas of densely packed follicles or papillary formations that raised the possibility of malignancy. However, none of the lesions that we have designated as proliferative struma ovarii showed histologic evidence of overlapping "ground glass" nuclei, vascular space invasion, or mitotic activity that would have supported an unequivocal diagnosis of malignancy. None developed metastases or recurrent disease. The 14 malignant struma ovarii manifested the classical features of thyroid carcinoma (including the presence of overlapping "ground glass" nuclei lining papillary formations and vascular space invasion). Patients with malignant struma ovarii ranged in age from 30 to 77 years (average, 50 years). Their clinical presentations included a mass (78%) and acute abdominal pain (22%). One patient had clinical and laboratory evidence of hyperthyroidism. On follow-up, one patient had persistent disease with peritoneal involvement, but distant metastases did not develop in any of these patients. A diagnosis of malignant struma ovarii should be reserved for lesions that exhibit the full range of changes seen in thyroid carcinoma arising in the cervical thyroid. By requiring that these rigid criteria be adhered to, the diagnosis of malignant struma ovarii will probably become less frequent as the more commonly encountered proliferative struma ovarii are recognized.

Abdominal Pain↗
PubMed1993

The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group.

PURPOSE: In an effort to maintain the excellent long-term results achieved with combination chemotherapy for good-prognosis germ cell carcinoma, but to reduce the toxicities encountered, a randomized trial was conducted comparing cisplatin and vinblastine with or without bleomycin. PATIENTS AND METHODS: Two hundred eighteen assessable patients with a good prognosis were randomized to receive induction chemotherapy with cisplatin 100 mg/m2 intravenously (IV) day 1 and vinblastine 6 mg/m2 IV days 1 and 2 every 3 weeks (PV) with or without bleomycin 30 mg intramuscularly (IM) weekly (PVB) for a maximum of 12 weeks. Once maximum response was achieved, patients with a complete remission (CR) received two courses of consolidation chemotherapy, while those with residual abnormalities and normal tumor markers underwent surgical resection whenever possible. RESULTS: Toxicities encountered in this study were clearly greater for those patients who received bleomycin, with significantly more leukopenia, thrombocytopenia, anemia, alopecia, and renal and pulmonary toxicities. The proportion of patients who achieved CR and had no evidence of disease (resection of all viable malignancy) was 89% for PV and 94% for PVB (P = .29). After a minimum of 4 years of follow-up, relapses have occurred in 7% of patients who received PV and 5% who received PVB. A total of five patients on each therapy arm were successfully treated with further salvage chemotherapy and surgery. Thus, deaths from progressive malignancy have occurred in 15% of patients on PV and 5% on PVB (P = .02), a rate that was partly offset by the higher proportion of toxic deaths with PVB (P = .06). CONCLUSION: Despite the toxicities encountered with bleomycin in cisplatin-based combination chemotherapy for these patients, complete deletion of this drug compromises therapeutic efficacy.

Adolescent↗
PubMed1993

The toxicology of benzene.

Benzene is metabolized, primarily in the liver, to a series of phenolic and ring-opened products and their conjugates. The mechanism of benzene-induced aplastic anemia appears to involve the concerted action of several metabolites acting together on early stem and progenitor cells, as well as on early blast cells, such as pronormoblasts and normoblasts to inhibit maturation and amplification. Benzene metabolites also inhibit the function of microenvironmental stromal cells necessary to support the growth of differentiating and maturing marrow cells. The mechanism of benzene-induced leukemogenesis is less well understood. Benzene and its metabolites do not function well as mutagens but are highly clastogenic, producing chromosome aberrations, sister chromatid exchange, and micronuclei. Benzene has been shown to be a multi-organ carcinogen in animals. Epidemiological studies demonstrate that benzene is a human leukemogen. There is need to better define the lower end of the dose-response curve for benzene as a human leukemogen. The application of emerging methods in biologically based risk assessment employing pharmacokinetic and mechanistic data may help to clarify the uncertainties in low-dose risk assessment.

Animals↗
PubMed1992

Alterations in the morphology and functional activity of bone marrow phagocytes following benzene treatment of mice.

Benzene is a well-established hematotoxin that affects developing leukocytes and erythrocytes as well as bone marrow stromal cells. In the present studies we analyzed the effects of benzene on the morphology and functional activity of bone marrow phagocytes. Male Balb/c mice were treated with benzene (660 mg/kg) once per day for 3 days. Bone marrow cells were then isolated and fractionated by density gradient centrifugation. Using highly sensitive techniques in flow cytometry/cell sorting, we found that we could separate three distinct populations of bone marrow cells that differed with respect to size and density. Monoclonal antibody binding and cell sorting revealed a large, dense population that consisted predominantly of granulocytes, a smaller, less dense population of lymphocytes, and a population of intermediate size and density consisting of mononuclear phagocytes and precursor cells. Differential staining of sorted mononuclear phagocytes revealed that benzene treatment of mice caused a marked increase in the number of mature, morphologically activated macrophages in the bone marrow. Benzene treatment of mice also resulted in enhanced chemotaxis and production of hydrogen peroxide by bone marrow granulocytes and mononuclear phagocytes. In contrast, treatment of mice with the combination of hydroquinone and phenol (50 mg/kg each, 1 x/day, 3 days), two metabolites of benzene, resulted in a significant (p < or = 0.02) depression of granulocyte chemotaxis and had no effect on hydrogen peroxide production by bone marrow phagocytes compared to cells from control animals. Taken together these results demonstrate that benzene causes increased differentiation and/or activation of phagocytes in the bone marrow.

Animals↗
PubMed1991

Depression of iron uptake into erythrocytes in mice by treatment with the combined benzene metabolites p-benzoquinone, muconaldehyde and hydroquinone.

Using radio-iron uptake into erythrocytes as a measure of hematopoiesis, it was demonstrated that p-benzoquinone (BQ) and muconaldehyde (MUC) are potent inhibitors of bone marrow function in female mice. These two benzene metabolites reduced iron uptake at dosages of less than 5-6 mg kg-1. The combination of MUC and hydroquinone (HQ) (100 mg kg-1) was additive, reducing iron incorporation to an extent that was the sum of the effect of each chemical given alone. The combined effect of MUC and BQ was significantly less than additive, demonstrating antagonism in the response. Multiple regression was used to study the contributions of the components of binary mixtures of the benzene metabolites (METAB). Data obtained from standard curves of METAB and their mixtures are separable in regression analysis. Thus, for zero interaction of METAB, the responses would be simply additive, while positive and negative interaction would indicate synergy and antagonism, respectively. T-testing of the data resulted in non-significant values for the mixture MUC + HQ, indicating zero interaction and an additive response. The negative t-values obtained for the mixture MUC + BQ, however, indicate negative interaction or an antagonistic response. Since mutually exclusive agents share the same binding sites and occupation of a site by one agent excludes its occupation by another, they cannot interact in producing the effect; combinations of these agents show zero interaction and are simply additive. This suggests that HQ and MUC are mutually exclusive and share the same binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehydes↗
PubMed1991

Effects of neonatal deafening and chronic intracochlear electrical stimulation on the cochlear nucleus in cats.

Four newborn kittens were deafened by daily intramuscular injections of neomycin sulfate, beginning the day after birth and continuing for 14-16 days. At 10-16 weeks of age the deaf kittens were implanted unilaterally with a four wire intracochlear electrode array. The animals were stimulated daily (starting at 13-18 weeks of age), for a period of one hour, at 6 dB above the electrically evoked auditory brainstem response threshold. After 3 months of chronic intracochlear electrical stimulation, animals were studied in acute electrophysiological experiments and euthanized for histological studies. This study compares the stimulated and control cochlear nuclei (CN) of these deafened animals to the CN of four normal adult cats. Statistical comparisons of spherical cell densities in the anteroventral cochlear nucleus (AVCN), cross-sectional spherical cell areas, and volumes of the cochlear nucleus subdivisions were included in the analysis. The results indicate that, by all of these measures, the cochlear nuclei in neonatally deafened animals were significantly different from the cochlear nuclei of control animals. As a result of deafening, the density of spherical cells was decreased by 30%, the cross-sectional areas of spherical cells were reduced by 20%, and the volume of the cochlear nucleus was reduced by 25%. These changes were observed in both cochlear nuclei (ipsilateral to both stimulated and unstimulated ears) of the deafened animals. With the measures employed, no significant difference was demonstrated in comparisons between the deafened/unstimulated and the deafened/stimulated cochlear nuclei. That is, no reversal of the profound effects of deafening was observed in the cochlear nuclei as a consequence of chronic intracochlear electrical stimulation which was begun 11 to 16 weeks after deafening.

Animals↗