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Biomedical subjects

D F Deen

Publications and source records attributed to D F Deen.

At least 127 records · Page 7Linked to original sources
PubMed1979

Cellular response of a rat brain tumor to a therapeutic carbon ion beam.

Clonogenic cell survival of in situ 9L brain tumors was measured in air-breathing rats and rats killed with nitrogen. Animals were irradiated with BEVALAC accelerated carbon ions in the plateau and spread-out Bragg peak regions of the specific ionization curve. The relative biological effectiveness (RBE) for carbon ions in the plateau was 1.2 +/- 0.1 for oxic cells and 1.3 +/- 0.1 for anoxic cells; in the Bragg peak the RBE was 1.6 +/- 0.1 for oxic cells and 2.0 +/- 0.1 for anoxic cells. The oxygen enhancement ratio (OER) in the plateau was 2.0 +/- 0.1, not significantly different from the 2.1 +/- 0.2 found for x rays. The OER in the Bragg peak was reduced to 1.7 +/- 0.1. For cells having the same radiobiological sensitivity as in situ 9L cells, the neon ion beam may be therapeutically superior; however, this does not preclude selection of the carbon ion beam in many clinical situations.

Animals↗
PubMed1979

Response of 9L tumor cells in vitro to spirohydantoin mustard.

The effects of spirohydantoin mustard (SHM), a potential antitumor agent for central nervous system tumors, in the in vitro 9L rat brain tumor model were studied. In cell culture medium at 37 degrees, the drug was totally detoxified within 30 min. Dose-response curves for exponentially growing and plateau-phase cells were similar and indicated that a small fraction of cells were resistant to SHM. When exponentially growing cells were treated with SHM (5 microgram/ml for 1 hr), recovery from potentially lethal damage occurred within 28 hr. When cells were perturbed by SHM, the S, G2, and M phases were prolonged, there was a G2 block, some cells entered mitosis, but few divided, and cells tended to accumulate in mid-S, then moved synchronously to G2-M. The rate at which cells moved was concentration dependent and was much slower at high concentrations. The ability of SHM to both synchronize cells and block DNA synthesis may be useful in multiagent therapy regimens.

Animals↗
PubMed1978

Perturbed cell kinetics of 9L rat brain tumor cells following dianhydrogalactitol.

Kinetic changes induced by dianhydrogalactitol (DAG) in cultured 9L rat brain tumor cells were studied using conventional autoradiography and flow cytometry. Cell cycle parameters for the untreated cell line were: G1, 8.5 hours; S, 8.2 hours; G2, 3.2 hours; M, 0.5 hour; and cell cycle time, 19.5--20 hours. Treatment with 5 micrograms/ml of DAG, which caused 89.8% cell kill as measured by the colony-forming efficiency assay, resulted in the following effects: (a) undisturbed progression of G2 cells toward mitosis; (b) disturbed progression of the cells in the S--G2 boundary; (c) extreme prolongation of DNA synthesis time; and (d) temporary accumulation in G2 phase of cells that were in G1 or S phase at the time of treatment.

Animals↗
PubMedDate not supplied

Radiosensitization of the RIF-1 murine flank tumor by desmethylmisonidazole (Ro 05 9963) during interstitial brachytherapy.

We have investigated the interaction of the nitroimidazole radiosensitizer desmethylmisonidazole (Ro 05 9963) with interstitial radiation using a clonogenic cell assay as the endpoint. Removable I-125 sources were implanted at right angles to the outer surface of globular RIF-1 tumors grown in the flanks of C3H/He mice. Desmethylmisonidazole was administered by continuous intraperitoneal infusion at a rate of 2.7 mg/gm body weight /24 hr. Tumor and serum drug levels were measured by high performance liquid chromatography. Tumor drug levels of 40--100 mugm/gm tumor tissue were achieved consistently. No appreciable cytotoxicity was produced by desmethylmisonidazole alone, but a radiosensitization effect with a dose modifying factor of 1.6 was found.

Animals↗
PubMedDate not supplied

Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption.

Vascular endothelial growth factor (VEGF) is an important mediator of the intense angiogenesis which is characteristic of glioblastoma. While genetic manipulation of VEGF/VEGF receptor expression has previously been shown to inhibit glioblastoma growth, to date, no study has examined the efficacy of pharmacologic blockade of VEGF activity as a means to inhibit intracranial growth of human glioblastoma. Using intraperitoneal administration of a neutralizing anti-VEGF antibody, we demonstrate that inhibition of VEGF significantly prolongs survival in athymic rats inoculated in the basal ganglia with G55 human glioblastoma cells. Systemic anti-VEGF inhibition causes decreased tumor vascularity as well as a marked increase in tumor cell apoptosis in intracranial tumors. Although intracranial glioblastoma tumors grow more slowly as a consequence of anti-VEGF treatment, the histologic pattern of growth suggests that these tumors adapt to inhibition of angiogenesis by increased infiltration and cooption of the host vasculature.

Animals↗
PubMedDate not supplied

A hypoxia-regulated adeno-associated virus vector for cancer-specific gene therapy.

The presence of hypoxic cells in human brain tumors is an important factor leading to resistance to radiation therapy. However, this physiological difference between normal tissues and tumors also provides the potential for designing cancer-specific gene therapy. We compared the increase of gene expression under anoxia (<0.01% oxygen) produced by 3, 6, and 9 copies of hypoxia-responsive elements (HRE) from the erythropoietin gene (Epo), which are activated through the transcriptional complex hypoxia-inducible factor 1 (HIF-1). Under anoxic conditions, nine copies of HRE (9XHRE) yielded 27- to 37-fold of increased gene expression in U-251 MG and U-87 MG human brain tumor cell lines. Under the less hypoxic conditions of 0.3% and 1% oxygen, gene activation by 9XHRE increased expression 11- to 18-fold in these cell lines. To generate a recombinant adeno-associated virus (rAAV) in which the transgene can be regulated by hypoxia, we inserted the DNA fragment containing 9XHRE and the LacZ reporter gene into an AAV vector. Under anoxic conditions, this vector produced 79- to 110-fold increase in gene expression. We believe this hypoxia-regulated rAAV vector will provide a useful delivery vehicle for cancer-specific gene therapy.

Adenoviridae↗
PubMedDate not supplied

Potentiation of BCNU-induced cytotoxicity and sister chromatid exchanges by dibromodulcitol in vitro.

Dibromodulcitol (DBD) is an anticancer agent that is cytotoxic against animal and human brain tumors in vivo. Clinical trials of combination therapy with radiation, DBD, and a nitrosourea have shown some efficacy, but the mechanisms that lead to enhanced cytotoxicity are poorly understood. We investigated the effects of pretreatment with DBD on cell survival and sister chromatid exchange (SCE) caused by subsequent treatment with 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) in 9L rat brain tumor cells. Pretreatment of 9L cells for 24 hr with 5 microM DBD potentiated the cell kill produced by a 1-hr treatment with BCNU; the dose enhancement ratio was 1.7 at the 10% survival level. Treatment of 9L cells for 24 hr with 1 microM DBD induced 39 +/- 12 SCEs/metaphase. There was a 50-75% increase in BCNU-induced SCEs, compared with BCNU alone, after a 24 hr pretreatment with DBD. Thus DBD potentiation of BCNU cytotoxicity appears to be related to increased DNA damage.

Animals↗
PubMedDate not supplied

Recovery from potentially lethal damage induced by spirohydantoin mustard on 9L cells in vitro.

Spirohydantoin mustard (SHM) has been shown to cross the blood-brain barrier in dogs and has shown activity against mouse brian tumors in vivo and against 9L rat brain tumor cells in vitro. Factors influencing the recovery of monolayer 9L cells from SHM-induced potentially lethal damage were studied. The pattern of recovery was similar in exponentially growing and plateau-phase cultures. Recovery occurred in either Earle's balanced salt solution (EBSS) or depleted medium (DM), and was inhibited in fresh medium (FM). The recovery process had a half-life of approximately 4 hours and was completed within 18 hours. The enhancement of survival was dependent on drug concentration and temperature. The magnitude of recovery decreased as the temperature was lowered and was inhibited at ambient temperature, which suggested that an enzymatic repair process was responsible for recovery. The distribution of cells through the cell cycle after SHM treatment was determined using a flow cytometer. Incubation of exponentially growing and plateau-phase cells in either EBSS or DM impeded the progression of cells from G1 into S phase, but cells incubated in FM progressed into S phase by 24 hours. We conclude that the recovery occurred primarily when cells were in G1 phase and potentially lethal damage would be fixed when cells initiate DNA synthesis within 18 hours after administration of SHM. Therefore, optimal therapeutic benefit may depend on drug scheduling.

Animals↗
PubMedDate not supplied

Effects of the polyamine analogs BE-3-7-3, 3-8-3, and BE-3-8-3 on human brain tumor cell growth and survival.

Based on computer modeling, physicochemical studies of spermine-DNA interactions, and cell culture experiments, we hypothesized that polyamine analogs with hydrocarbon chain lengths differing from natural polyamines and a stronger affinity for nucleic acids than spermine should have a cellular antiproliferative effect. We tested three spermine analogs with long hydrocarbon chains, 1,16-diamino-4,12-diazahexadecane (3-8-3), 1,16-bis(ethyl)amino-4,12-diazahexadecane (BE-3-8-3), and 1,15-bis(ethyl)amino-4,11-diazapentadecane (BE-3-7-3) in human brain tumor cell lines U-251 MG, SF-126, and SF-188. Analog concentrations < or = 5 microM inhibited growth and colony-forming efficiency in each cell line by treatment day 5, with significant decreases in putrescine and spermidine, but not spermine, levels. These findings suggest that potentially cytotoxic polyamine analogs can be specified on the basis of their hydrocarbon chain length and DNA affinity.

Brain Neoplasms↗
PubMedDate not supplied

P53-independent apoptosis: a mechanism of radiation-induced cell death of glioblastoma cells.

PURPOSE: Radiation therapy, though routinely used in the treatment of patients with glioblastoma multiforme, is of limited efficacy in extending patients' lives. In this study we investigated the mechanism by which ionizing radiation causes death of glioblastoma cells in the hope of ultimately altering the intrinsic radioresistance of glioblastoma tumors. METHODS: Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Radiation-induced apoptosis was assayed by fluorescence-activated cell sorter analysis, terminal deoxynucleotide transferase labeling technique, and chromatin morphology. Cellular distribution within the cell cycle was quantitated by dual labeling with propidium iodide and bromodeoxyuridine. RESULTS: We examined whether in vitro clonogenic radioresistance of glioblastoma would reflect their susceptibility to radiation-induced apoptosis and their ability to undergo a G1 arrest--two cellular functions associated with wild-type p53 expression. We demonstrated that apoptosis contributed to the cytocidal effect of ionizing radiation on glioblastoma cells. The apoptosis observed in glioblastoma cell lines occurred in the absence of wild-type p53 expression. We identified a glioblastoma cell line expressing wild-type p53 and found that it did not exhibit radiation-induced apoptosis but rather underwent a prolonged G1 arrest not observed in any glioblastoma cell line lacking wild-type p53 expression. CONCLUSION: Apoptosis is an important component of the lethal effect of ionizing radiation on glioblastoma cells and does not require wild-type p53 expression. Glioblastoma expressing wild-type p53 exhibited no apoptosis, even after high radiation doses, but rather underwent a prolonged G1 arrest. The observation of p53-independent apoptosis and p53-dependent Gi arrest in glioblastoma cells have important radiobiologic and clinical implications.

Apoptosis↗
PubMedDate not supplied

Effects of Matrigel on the SF-767 malignant glioma athymic mouse tumor model.

Matrigel, an extracellular matrix material, has been used to promote growth of experimental tumors. SF-767, a human glioblastoma cell line, is used in brain tumor research. We investigated Matrigel induced changes in tumor latency, growth rate, cell yield, plating efficiency, and histology of SF-767 tumors in athymic mice. Low volume (0.1 ml) Matrigel did not increase growth rate in comparison with control tumors but appeared to promote uniformity in growth. High volume (0.5 ml) Matrigel increased the initial rate of tumor growth, increased cell yield and produced tumors with a centralized area of residual Matrigel and necrotic cells, with viable cells on the periphery of the mass. On average, tumors grown with Matrigel had shorter latency periods and lower plating efficiencies. We conclude that important characteristics of the SF-767 tumor model, which may be important when evaluating efficacy of anticancer agents, are altered by Matrigel.

Animals↗