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Biomedical subjects

R D Snyder

Publications and source records attributed to R D Snyder.

At least 55 records · Page 3Linked to original sources
PubMed1993

Alterations in repair of alkylating agent-induced DNA damage in polyamine-depleted human cells.

Treatment of HeLa cells with the polyamine biosynthesis inhibitors difluoromethylornithine (DFMO) and/or methylglyoxal bis(guanylhydrazone) (MGBG) results in marked depression in levels of the cellular polyamines putrescine, spermidine and spermine. Cells in this polyamine-depleted state exhibited increased sensitivity to monofunctional alkylating agents, manifested as decreased cloning ability and retardation of the DNA excision repair process. DFMO treatment did not alter the initial level of interaction of radiolabeled alkylating agent with cellular DNA, but combined treatment with DFMO and MGBG reduced covalent binding, probably through effects on cell cycling. Polyamine supplementation had no effects on initial yield of DNA single-strand breaks in drug-treated cells. The repair defect appeared similar to that observed previously in polyamine-depleted cells following X-irradiation and UV irradiation, namely retarded sealing of DNA strand breaks. It was not possible to reverse the effects of these inhibitors by short periods of polyamine loading, despite the fact that all three polyamines could be restored to near-normal levels. These findings provide the first demonstration of altered response of polyamine-depleted cells to monofunctional alkylating agents and contribute to our understanding of altered responses of polyamine-depleted cancer cells to a variety of DNA-reactive chemotherapeutic drugs.

Alkylating Agents↗
PubMed1992

Effects of Captan on DNA and DNA metabolic processes in human diploid fibroblasts.

The fungicide Captan has been examined for its effects on DNA and DNA processing in order to better understand the genotoxicity associated with this agent. Captan treatment resulted in production of DNA single strand breaks and DNA-protein cross-links and elicited an excision repair response in human diploid fibroblasts. Captan was also shown to inhibit cellular DNA synthesis and to form stable adducts in herring sperm and human cellular DNA. Misincorporation of nucleotides into Captan-treated synthetic DNA templates was significantly elevated in an in vitro assay using E. coli DNA polymerase I, suggesting that DNA adduct formation by Captan could have mutagenic consequences. In sum, these studies demonstrate that Captan is capable of interacting with DNA at a number of levels and that these interactions could provide the basis for Captan's genotoxicity. The extreme cytotoxicity of this fungicide, however, could be due to other cellular effects since at the IC50 for cell killing, approximately 0.8 microM, none of the above genotoxic events could be detected by the methods employed.

Captan↗
PubMed1992

The cost of breast cancer recurrences.

Information about the costs of recurrent breast cancer is potentially important for targeting cost containment strategies and analysing the cost-effectiveness of breast cancer control programmes. We estimated these costs by abstracting health service and consumable usage data from the medical histories of 128 patients, and valuing each of the resources used. Resource usage and costs were summarised by regarding the recurrence as a series of episodes which were categorised into five anatomical site-based groups according to the following hierarchy: visceral, central nervous system (CNS), bone, local and other. Hospital visits and investigations comprised 78% of total costs for all episodes combined, and there were significant differences between the site-based groups in the frequency of hospital visits and most investigations. Total costs were most accurately described by separate linear regression models for each group, with the natural logarithm of the cost of the episode as the dependent variable, and predictor variables including the duration of the episode, duration squared, duration cubed and a variable indicating whether the episode was fatal. Visceral and CNS episodes were associated with higher costs than the other groups and were more likely to be shorter and fatal. A fatal recurrence of duration 15.7 months (the median for our sample) was predicted to cost $10,575 (Aus + 1988; or 4,877 pounds). Reduction of the substantial costs of recurrent breast cancer is likely to be a sizable economic benefit of adjuvant systemic therapy and mammographic screening. We did not identify any major opportunities for cost containment during the management of recurrences.

Adult↗
PubMed1991

Effects of polyamine analogs on the extent and fidelity of in vitro polypeptide synthesis.

A series of polyamine analogs has been examined for their ability to support protein synthesis in an in vitro rabbit reticulocyte translation system. Diamines were found to stimulate protein synthesis to the greatest extent (8-12 fold). Triamines, tetraamines and pentaamines only stimulated 2-4 fold under these conditions although much lower concentrations were required. At elevated temperatures (45 degrees C), diamines were somewhat more active than at lower temperature but activity of longer chain polyamines was elevated very significantly. Polyamines with terminal benzyl or smaller alkyl groups had diminished activity. It is concluded that both charge and charge distribution determine the ability of polyamines to stimulate translation. Fidelity studies identified two classes of polyamines: those which are able to lower the optimal Mg2+ concentration required for amino acid misincorporation while not affecting extent of misincorporation relative to Mg2+ alone, and those which are sparing for Mg2+ and also stimulate extent of misincorporation.

Animals↗
PubMed1991

Modulation by Co(II) of UV-induced DNA repair, mutagenesis and sister-chromatid exchanges in mammalian cells.

In bacterial test systems, Co(II) has been shown to be antimutagenic in combination with several chemical and physical agents. To investigate whether such modulations also apply to mammalian cells, the effect of Co(II) on UV-induced mutagenesis, sister-chromatid exchanges as well as DNA damage and its removal was determined. Co(II) itself is weakly mutagenic at the HPRT locus and increases the frequency of sister-chromatid exchanges. Additionally, at both endpoints the metal ions enhance the genotoxicity of UV light. To discriminate between an enhancement of DNA damage and an interference with repair processes, the number of pyrimidine cyclobutane dimers was determined by HPLC. While the induction of these DNA lesions is not affected by Co(II), their removal is inhibited at concentrations of 75 microM Co(II) and higher. Analysis of the kinetics of strand-break induction and closure after UV irradiation by nucleoid sedimentation reveals an accumulation of strand breaks in the presence of Co(II). This indicates that either the polymerization or the ligation step in excision repair is affected. Since similar interactions with the processing of UV-induced DNA damage have been observed with other carcinogenic and/or mutagenic metal ions, this appears to be a common mechanism of metal genotoxicity.

Animals↗
PubMed1991

Synthesis and DNA-binding properties of polyamine analogues.

The synthesis of a series of novel polyamine analogues is reported. The DNA binding of these compounds and a variety of other polyamines were compared with their IC50 values against HeLa cell. There seemed to be no apparent correlation between the DNA binding and toxicity against HeLa cells.

Alkylation↗
PubMed1991

Anencephaly in the United States, 1968-1987: the declining incidence among white infants.

The ethical issues concerning the use of fetal tissue as a source for organ transplantation has focused interest on anencephaly. For reasons that are not entirely clear, the incidence of anencephaly has been declining. As anencephaly is easily recognized and invariably fatal, mortality figures provide an excellent reflection of incidence. In the United States, between 1968 and 1987, infant mortality rates per 100,000 live births due to anencephaly declined from 22.4 to 12.1 (46.0%) for male infants and from 32.7 to 16.6 (49.2%) for female infants. However, when separated by race, the mortality rate declined for white male infants from 25.0 to 13.3 (46.8%) but only decreased from 9.0 to 7.7 (14.4%) for nonwhite male infants. The mortality rate declined for white female infants from 36.7 to 17.6 (52.0%) and actually increased slightly from 12.8 to 13.2 (3.1%) for nonwhite female infants. Thus, the declining incidence of anencephaly reflects a declining incidence of affected white infants but not of affected nonwhite infants.

Anencephaly↗
PubMed1990

Effect of polyamine depletion on DNA damage and repair following UV irradiation of HeLa cells.

Treatment of HeLa cells with the polyamine biosynthesis inhibitors, methylglyoxal bis(guanylhydrazone) (MGBG), difluoromethylornithine (DFMO) or a combination of the two, resulted in reduction in cellular polyamine levels. Analysis of UV light-induced DNA damage and repair in these polyamine depleted cells revealed distinct differences in the repair process relative to that seen in cells possessing a normal polyamine complement. Initial yield of thymine dimers and rate of removal of these lesions from cellular DNA appeared normal in polyamine-depleted cells. However, depleted cells exhibited retarded sealing of DNA strand breaks resulting from cellular repair processes, reduced repair synthesis and an increased sensitivity to UV killing. Incision at damaged sites was not affected since ara-C repair-dependent breaks accumulated in a normal fashion. Molecular analysis of inhibited repair sites by exonuclease III and T4 DNA ligase probes suggest that the strand interruptions consist of gaps rather than ligatable nicks, consistent with an interpretation of the repair defect being at the gap-filling stage rather than the ligation step. Observed patterns of differential polyamine depletion by DFMO and MGBG, and partial reversal of repair inhibition by polyamine supplementation, suggests that polyamine depletion per se, rather than some secondary effect of inhibitor treatment, is responsible for the inhibition of repair.

Colony-Forming Units Assay↗
PubMed1990

Neuropathy in Navajo children: clinical and epidemiologic features.

We describe a rare and apparently unique neuropathic syndrome among Navajo children living on the Navajo Reservation. Clinical features include sensorimotor neuropathy, corneal ulcerations, acral mutilation, poor weight gain, short stature, sexual infantilism, serious systemic infections, and liver derangement including Reye's syndrome-like episodes. Progressive CNS white matter lesions were diagnosed through magnetic resonance imaging. We identified 20 definite and 4 probable cases occurring between 1959 and 1986. Mean age at the time of 1st recognized symptom was 13 months (range, 1 month to 4 years 6 months). Ten individuals have died; 6 of the deaths occurred before 5 years of age. The incidence of this syndrome on the western Navajo reservation is 5 times higher than that on the eastern reservation (38 compared with 7 cases per 100,000 births). Although the etiology is unknown, this syndrome is consistent with an inborn error of metabolism, inherited in an autosomal recessive manner.

Adolescent↗
PubMed1989

Polyamine depletion is associated with altered chromatin structure in HeLa cells.

HeLa cells depleted of polyamines by treatment with alpha-difluoromethylornithine (DFMO), methylglyoxal bis(guanylhydrazone) (MGBG) or a combination of the two, were examined for sensitivity to micrococcal nuclease, DNAase I and DNAase II. The degrees of chromatin accessibility to DNAase I and II appeared enhanced somewhat in all three treatment groups, and the released digestion products differed from those in non-depleted cells. DNA released from MGBG- and DFMO/MGBG-treated cells by DNAase II digestion was enriched 4-7-fold for Mg2+-soluble species relative to controls. DNA released by micrococcal nuclease digestion from all three treatment groups was characterized as consisting of higher-order nucleosomal structure than was DNA released from untreated cells. At least some of the altered chromatin properties were abolished by a brief treatment of cells with polyamines, notably spermine. These studies provide the first demonstration in vivo of altered chromatin structure in cells treated with inhibitors of polyamine biosynthesis.

Chromatin↗
PubMed1989

Differential effects of 5-azacytidine and 5-azadeoxycytidine on cytotoxicity, DNA-strand breaking and repair of X-ray-induced DNA damage in HeLa cells.

The cytotoxicity, DNA-strand breaking ability, and effects on repair of X-ray-induced DNA damage by short treatments with 5-azacytidine (azaCyd) and 5-azadeoxycytidine (azadCyd) were examined in HeLa cells. azaCyd was shown to be an effective inhibitor of the repair of X-ray-induced DNA single-strand breaks whereas azadCyd did not have this effect. At high doses, both compounds also induced DNA damage by themselves. The cytotoxicity, inhibition of repair, and drug-induced DNA damage associated with azaCyd treatment were all reversed by the concurrent addition to the cells of cytidine or uridine but not by thymidine, deoxycytidine or deoxyuridine. Cytotoxicity and drug-induced strand breaks associated with azadCyd treatment were reversed to varying degrees with all nucleosides and deoxynucleosides. These results support the notion that these two antileukemic cytidine analogs may have different mechanisms of action in exerting their antiproliferative activity.

Antineoplastic Agents↗
PubMed1989

Inhibition of X-ray-induced DNA strand break repair in polyamine-depleted HeLa cells.

Treatment of HeLa cells with the polyamine biosynthesis inhibitors, alpha-difluoromethylornithine (DFMO) or methylglyoxal bis(guanylhydrazone) (MGBG), results in, depending on the conditions, partial or complete depletion of the cellular polyamines: putrescine, spermidine and spermine. In this compromised state cells exhibited a distinct deficiency in repair of X-ray-induced DNA strand breaks. The half-time for return of normal DNA sedimentation following 1.6 Gy was 9.5 min for untreated control cells and 22, 32 and 50 min for cells treated with MGBG, DFMO + MGBG and DFMO, respectively. Normal repair kinetics were restored to these cells upon a short incubation in media containing all three polyamines. The rapid early phase of repair following higher X-ray doses (16 Gy) was also delayed in polyamine-depleted cells but later repair occurring 1-4 h post-irradiation, representing chromatin reconstitution, was apparently normal.

DNA Repair↗
PubMed1989

Hyperthermia, polyamine depletion, and inhibition of X-ray-induced DNA strand break repair.

We have recently demonstrated that HeLa cells that had been depleted of polyamines by treatment with inhibitors of polyamine biosynthesis were deficient in their ability to repair X-ray-induced DNA strand breaks. Since it had previously been demonstrated that hyperthermic shock also inhibited strand break repair following X irradiation and that hyperthermia resulted in a leakage of polyamines from cells, it seemed of interest to examine whether the inhibition of repair by hyperthermia was related to this loss of cellular polyamines. In the present paper it is demonstrated that both polyamine depletion and hyperthermia inhibit strand closure, and that a combined treatment further reduces the rate of repair. In cells not depleted of polyamines, repair is restored to normal levels if hyperthermia treatment is followed by a 4-h incubation at 37 degrees C before X irradiation. In polyamine-depleted cells, this 37 degrees C incubation does not result in a return of repair ability. Polyamine supplementation was not effective in reversing hyperthermia-dependent repair inhibition, and, in fact, restoration of repair in control cells following hyperthermic shock corresponded to a time at which polyamines show a maximum decrease in those cells. These results suggest that the inhibition of repair and the increased radiosensitivity observed in hyperthermically treated cells is not related to polyamine depletion. However, data further suggest that polyamine-depleted cells may have other alterations, perhaps in chromatin, which render them more sensitive to thermal inhibition of repair.

Biogenic Polyamines↗
PubMed1988

Prospective nerve conduction studies in cisplatin therapy.

We studied nerve conduction prospectively in 38 women receiving cisplatin for gynecological malignancies. Decreased sensory nerve action potential amplitudes and prolonged sensory latencies were the only significant changes identified. This prospective electrophysiological study validates the clinical observation of frequent sensory symptoms and occasional sensory neuropathies associated with cisplatin therapy.

Action Potentials↗
PubMed1988

Role of active oxygen species in metal-induced DNA strand breakage in human diploid fibroblasts.

The ability of 6 metal salts to induce DNA damage in human diploid fibroblasts was examined. Cadmium, magnesium, manganese, chromium(VI), zinc and selenite were all shown to induce DNA strand breaks as measured by two independent assays. DNA strand breaks were repaired within 2-4 h after removal of metal and this repair appeared not to be sensitive to "long-patch" repair inhibitors. With the exception of selenite, metal-induced DNA damage appeared to be mediated via the formation of active oxygen species since oxygen scavengers when administered simultaneously with the metal, antagonized strand break formation. Selenite-induced DNA damage (as previously reported) was dependent on the formation of a selenite-glutathione conjugant and was not affected by oxygen radical scavengers. Scavenger treatment did not enhance cloning ability of metal-treated cells suggesting that DNA strand breaks may not be important in metal-induced cytotoxicity.

Cells, Cultured↗
PubMed1988

Möbius syndrome and transposition of the great vessels.

A case of Möbius syndrome was associated with transposition of the aorta and pulmonary artery, as well as acheiria. This combination of anomalies supports the hypothesis that Möbius syndrome is caused by an intrapartum insult during the fourth to seventh week of gestation and is consistent with the vascular theory of embryopathogenesis.

Abducens Nerve↗