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R Snyder

Publications and source records attributed to R Snyder.

At least 19 recordsLinked to original sources
PubMed1996

Effects of benzene metabolite treatment on granulocytic differentiation and DNA adduct formation in HL-60 cells.

Reactive metabolites of benzene (BZ) play important roles in BZ-induced hematotoxicity. Although reactive metabolites of BZ covalently bind to DNA, the significance of DNA adduct formation in the mechanism of BZ toxicity is not clear. These studies investigated the covalent binding of the BZ metabolites hydroquinone(HQ) and 1,2,4-benzenetriol(BT) using the DNA [32P]postlabeling method and explored the potential relationship between DNA adduct formation and cell differentiation in human promyelocytic leukemia (HL-60) cells, a model system for studying hematopoiesis. Maturation of HL-60 cells to granulocytes, as assessed by light and electron microscopy, was significantly inhibited in cells that were pretreated with HQ or BT prior to inducing differentiation with retinoic acid (RA). The capacity of RA-induced cells to phagocytose sheep red blood cells (RBC) and to reduce nitroblue tetrazolium (NBT), two functional parameters characteristic of mature, differentiated neutrophils, was also inhibited in cells pretreated with HQ or BT. These BZ metabolite treatments induced DNA adduct formation in HQ- but not in BT-treated cells. These results indicate that whereas HQ and BT each block granulocytic differentiation in HL-60 cells, DNA adducts were observed only following HQ treatment. Thus DNA adduct formation may be important in HQ but not in BT toxicity.

Benzene Derivatives↗
PubMed1996

Promoter elements that mediate the pH response of PCK mRNA in LLC-PK1-F+ cells.

The onset of metabolic acidosis causes an increased transcription of the renal phosphoenolpyruvate carboxykinase (PCK) gene. When transgenic mice carrying a bovine growth hormone (bGH) gene driven by the -460 to +73 segment of the PCK promoter were made chronically acidotic, the bGH mRNA was increased twofold after 4 days. Confluent and well-differentiated cultures of LLC-PK1-F+ cells exhibit a 2.5-fold increase in PCK mRNA when transferred to acidic media (pH 6.9, 10 mM HCO3-) for 16 h. Confluent cultures transfected with PCK-490 CAT exhibit an increase (3.5-fold) in chloramphenicol acetyltransferase (CAT) activity when shifted to acidic medium for 48 h. Mutation or deletion of the P2 element causes a four- to fivefold decrease in basal CAT activity but does not affect the pH response. In contrast, mutations of the P3(II) element or the CRE-1 cAMP-response element have little effect on basal activity but cause a 50% decrease in the pH response. Other deletions or mutations have little effect on either activity. Thus changes in the activity or levels of the protein(s) in the renal proximal tubule that binds to the P3(II) and CRE-1 elements may mediate increased transcription of the PCK gene during metabolic acidosis.

Animals↗
PubMed1996

Survival after trauma pneumonectomy: the pathophysiologic balance of shock resuscitation with right heart failure.

Emergency pneumonectomy for trauma has a high mortality. Although exsanguination is a major factor leading to death, mortality remains high even after adequate resuscitation and is thought to be related to pulmonary edema and right heart failure. We present a series of nine patients who underwent pneumonectomy at Harbor-UCLA from penetrating (7) and blunt (2) trauma. Two patients survived; three initially survived the surgery but died postoperatively of hypoxemia and right heart failure; four died intraoperatively (2 from right heart failure and 2 from exsanguination). One survivor required open cardiac massage for asystole. Careful attention to prevent volume overloading before and during trauma pneumonectomy and maintaining a negative fluid balance postoperatively may contribute to survival in these patients.

Adolescent↗
PubMed1995

The hematotoxic effects of 6-hydroxy-trans,trans-2,4-hexadienal, a reactive metabolite of trans,trans-muconaldehyde, in CD-1 mice.

6-Hydroxy-trans,trans-2,4-hexadienal (CHO-M-OH) is a metabolite of trans,trans-muconaldehyde (muconaldehyde or MUC), a microsomal hematotoxic ring-opened metabolite of benzene. In the present study, the toxicity of CHO-M-OH was examined. In order to assess potential toxic effects of CHO-M-OH on the maturation of erythroid cells in the bone marrow, 10-week-old male CD-1 mice were administered CHO-M-OH intraperitoneally and 59Fe incorporation into erythrocytes was measured. The uptake of 59Fe by erythroid cells was significantly inhibited at doses of 20, 25, and 30 mg/kg. There was no inhibition of 59Fe incorporation at a dose of 15 mg/kg. In other hematotoxicity studies, bone marrow cellularity, peripheral blood cells, and sulfhydryl contents in bone marrow cells were examined in mice administered CHO-M-OH intraperitoneally. An increase in the white blood cell count was observed in mice treated with 5 mg/kg/day for 16 consecutive days, while bone marrow cellularity and red blood cell parameters were not changed. Administration of 10 mg/kg/day for 16 consecutive days caused a significant decrease in sulfhydryls of bone marrow cells but no changes in bone marrow cellularity and peripheral blood parameters compared with controls. At a dose of 25 mg/kg/day for 4 days, there was a significant decrease in nucleated bone marrow cells. The white blood cell count, mainly lymphocytes, also significantly decreased. Our results indicate that CHO-M-OH is a hematotoxin in mice and conceivably could play a role in benzene toxicity.

Aldehydes↗
PubMed1995

Temporal resolution of neurons in cat inferior colliculus to intracochlear electrical stimulation: effects of neonatal deafening and chronic stimulation.

1. Cochlear implants have been available for > 20 yr to profoundly deaf adults who have lost their hearing after acquiring language. The success of these cochlear prostheses has encouraged the application of implants in prelingually deaf children as young as 2 yr old. To further characterize the consequences of chronic intracochlear electrical stimulation (ICES) on the developing auditory system, the temporal-response properties of single neurons in the inferior colliculus (IC) were recorded in deafened anesthetized cats. 2. The neurons were excited by unilateral ICES with the use of a scala tympani stimulating electrode implanted in the left cochlea. The electrodes were modeled after those used in cochlear implant patients. Responses of 443 units were recorded extracellularly in the contralateral (right) IC with the use of tungsten microelectrodes. Recordings were made in three groups of adult animals: neonatally deafened/chronically stimulated animals (192 units), neonatally deafened/unstimulated animals (80 units), and adult-deafened/prior normal-hearing animals (171 units). The neonatally deafened cats were deafened by multiple intramuscular injections of neomycin sulfate and never developed demonstrable hearing. Most of the deafened, chronically stimulated animals were implanted at 6 wk of age and stimulated at suprathreshold levels for 4 h/day for 3-6 mo. The unstimulated animals were implanted as adults at least 2 wk before the acute physiological experiment and were left unstimulated until the acute experiment was conducted. Prior-normal adults were deafened and implanted at least 2 wk before the acute experiment. 3. IC units were isolated with the use of a search stimulus consisting of three cycles of a 100-Hz sinusoid. Most units responded to sinusoidal stimulation with either an onset response or a sustained response. Onset units were the predominant unit found in the external nucleus, whereas sustained units were found almost exclusively in the central nucleus. The temporal resolution of sustained response units was measured with the use of pulse trains of increasing frequency and calculating the discharges/pulse. 4. The range of electrical pulse frequencies to which IC units responded in a temporally synchronized manner was comparable with that produced by acoustic stimulation. The discharge rate/pulse-versus-pulse frequency transfer functions of IC units were uniformly low-pass, although they varied widely in their cutoff frequencies. This variation in pulse response was partially correlated with the unit's response to sinusoids. Most onset neurons responded only to pulse frequencies below 20 pulses per second (pps). Most sustained units responded best to pulse frequencies < 100 pps, and most ceased to respond to pulse frequencies > 300 pps.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
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↗