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Biomedical subjects

D C Cox

Publications and source records attributed to D C Cox.

At least 19 recordsLinked to original sources
PubMed1996

Elimination of EL-4 and L1210 murine tumors by 1,3-bis (2-chloroethyl)-1-nitrosourea requires an intact immune response.

The chemotherapeutic agent 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) is commonly used to treat several types of human cancers. Recent investigations have suggested that elimination of tumor by BCNU is dependent on more than the cytotoxic activity of the drug. We have extended those findings by showing that cyclosporin A (CS) can inhibit the BCNU-mediated rejection of EL-4 or L1210 tumors in mice. It was shown that mice could be cured of EL-4 or L1210 ascites tumors with a single intraperitoneal injection of BCNU. When CS, an inhibitor of the activation of T lymphocytes, was administered to mice that had received either EL-4 or L1210 tumor and were treated with BCNU, nearly all the mice died by Day 60. When CS was administered to BCNU-treated mice starting at 1, 2 or 3 weeks after tumor injection, inhibition of the BCNU therapy did not occur. Finally, the ability of animals that had been cured of tumor by the BCNU therapy to reject a lethal challenge dose of homologous tumor was shown to be CS insensitive. These results suggest that the BCNU-mediated elimination of tumor from mice requires a functional immune response in addition to the cytotoxic activity of this chemotherapeutic agent.

Animals↗
PubMed1995

Reovirus type 3 chemoimmunotherapy of murine lymphoma is abrogated by cyclosporine.

We have previously shown that the combined modalities of reovirus type 3 and the chemotherapeutic agent 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) synergize to cause the rejection of various murine tumors. Resistance of surviving animals to challenge with homologous but not heterologous tumor suggested that tumor was eliminated through an immune-mediated mechanism. In this study, we showed that mice undergoing therapy-mediated rejection of tumor were able to reject subsequent weekly challenges with EL-4 but not L1210 tumor cells. The mechanism underlying this therapy was investigated using cyclosporine (CS) to suppress immune responsiveness. A dose-related inhibition of therapy was observed with total inhibition occurring at 30 mg/kg/day. Delayed administration of CS at day 14 or later after tumor administration resulted in little or no inhibitory effect. The resistance of cured mice to EL-4 tumor challenge was not affected by CS, which is consistent with the reduced ability of CS to affect secondary immune responses. In addition, CS did not alter natural killer cell activity in mice receiving the BCNU/reovirus therapy. These results suggest that there is an obligatory immune response produced by the BCNU/reovirus therapy which arises early after the administration of the therapy.

Animals↗
PubMed1993

Tumor necrosis factor-alpha induction by reovirus serotype 3.

We have reported previously that reovirus, when used in combination with 1,3-bis(chloroethyl)-1-nitrosourea (BCNU) chemotherapy, mediates the rejection of murine ascites tumors. Surviving animals reject a challenge with the same, but not a different, tumor, which suggests that tumor-specific immunity is induced by the treatment regimen. The present study was designed to characterize the interaction between reovirus and murine peritoneal macrophages, both in vitro and in vivo, to determine whether such a relationship may play a role in immune modulation resulting in tumor rejection. The results demonstrated that reovirus can efficiently infect peritoneal macrophages in vitro and stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha). In vivo administration of reovirus, however, did not produce high levels of infection in peritoneal exudate cells, even though the cells were stimulated to express detectable levels of membrane TNF-alpha. These results suggested that infection is not necessary for TNF-alpha expression and this hypothesis was supported by the observation that this expression was also stimulated in vitro by UV-inactivated reovirus. These findings suggest that one mechanism for immune stimulation by reovirus may be through the induction of TNF-alpha.

Analysis of Variance↗
PubMed1992

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)/interleukin-2 chemoimmunotherapy of murine L1210 leukemia.

We have developed a chemoimmunotherapy regimen for the treatment of L1210-cell-induced ascites tumors in mice using a combination of sub-toxic doses of interleukin-2 (IL-2) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU is administered intraperitoneally 4 days after tumor implantation and followed 2 days later by single doses of human recombinant IL-2 for 3 consecutive days. An optimum survival of 84% was achieved using 1500 U IL-2. Reduced survival was observed when lower or higher IL-2 dosages were used. No therapy resulted when heat-inactivated IL-2 was used or when IL-2 was used without chemotherapy. Surviving animals were resistant to L1210 leukemia but not P815 mastocytoma tumor challenge suggesting the combined BCNU/IL-2 therapy stimulated tumor-specific immunity.

Animals↗
PubMed1988

Characteristics of reovirus-mediated chemoimmunotherapy of murine L1210 leukemia.

We have previously demonstrated the ability of reovirus to function synergistically with chemotherapy in the treatment of murine EL-4 lymphoma. This study characterizes this treatment regimen in the therapy of L1210 leukemia. Animals with an estimated tumor burden of 10(7) cells were treated with 9 mg/kg 1,3-bis(2-chloroethyl)-1-nitrosourea. Reovirus type 3, which had been quantitated either by particles or plaque-forming units (pfu), was administered 48 h after chemotherapy. Complete remission of tumor was observed in 80% of the animals which received either 10(11) particles or 10(9) pfu of reovirus. Cured animals were resistant to challenge with homologous tumor, but were susceptible to challenge with heterologous tumor. Reovirus undergoes limited replication at the tumor site, and virus-specific antibody appears only after disappearance of reovirus-infected cells and virus from the ascites fluid. Reovirus appears to function therapeutically by inducing a tumor-specific cytolytic immune response.

Animals↗
PubMed1988

Effects of cholesterol and 25-hydroxycholesterol on smooth muscle cell and endothelial cell growth.

Auto-oxidation products of cholesterol may play a role in atherogenesis. In order to determine whether cholesterol or 25-hydroxycholesterol, a cholesterol auto-oxidation product, affected growth of vessel wall cells, sparse and confluent cultures of rabbit thoracic aorta smooth muscle cells and human umbilical vein endothelial cells were exposed to these compounds for 88 hr. The compounds were administered at 10(-4), 10(-5), 10(-6) or 10(-7) M in either ethanol or fetal bovine serum (FBS) vehicle. Cells were counted electronically, and the results were expressed as the percent growth in experimental vs control wells. Cholesterol did not inhibit cell growth under any experimental condition. 25-Hydroxycholesterol had the following effects: inhibited confluent smooth muscle cell growth at 10(-4) M in ethanol vehicle only; inhibited sparse smooth muscle cell growth in a dose-related manner at 10(-4), 10(-5) and 10(-6) M in ethanol vehicle, but in FBS vehicle inhibited at only 10(-4) and 10(-5) M; inhibited confluent human umbilical vein endothelial cells at 10(-4) M in ethanol vehicle only; and inhibited sparse human umbilical vein endothelial cell growth at 10(-4) and 10(-5) M in ethanol vehicle only. Thus, rabbit aortic smooth muscle cell growth was more sensitive to inhibition by 25-hydroxycholesterol than human umbilical vein endothelial cell growth was.

Animals↗
PubMed1988

Cultured human endothelial cells treated with recombinant leukocyte A interferon. Tubuloreticular inclusion formation, antiproliferative effect, and 2',5' oligoadenylate synthetase induction.

Cultured human umbilical vein endothelial cells and human thoracic aorta endothelial cells were treated with 500, 1,000, and 2,000 IU/ml of recombinant leukocyte alpha-interferon for 2, 4, and 7 days. Tubuloreticular inclusions developed in treated human umbilical vein endothelial cells and human thoracic aorta endothelial cells. The size and number of tubuloreticular inclusions observed correlated with the dose and duration of treatment. Interferon treatment inhibited the rate of proliferation of both human umbilical vein endothelial cells and human thoracic aorta endothelial cells in a dose- and duration-dependent manner. Induction of the interferon-associated enzyme, 2'-5' oligoadenylate synthetase, also occurred. Since the endothelium is exposed to endogenous interferon present in certain pathologic conditions and to exogenous interferon administered in the treatment of several neoplastic or viral diseases, there is an increased need to understand the various effects of interferon on the endothelial cell.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Rejection of reovirus-treated L1210 leukemia cells by mice.

L1210 leukemia cells were treated in vitro with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and reovirus to determine their interactive effects on rejection of these tumor cells by mice. The cells were treated with BCNU at concentrations of 0, 3, or 10 microM, incubated for 48 h, then treated with reovirus at a multiplicity of infection of 0, 10, 30, or 100 for 2, 6, or 12 h. The survival of mice injected with cells treated with any amount of reovirus, regardless of BCNU treatment, was greater than that of mice injected with untreated cells. Exposure of the cells to reovirus for 6 or 12 h increased the survival of mice injected with these cells as compared with that of mice injected with cells exposed to reovirus for 2 h. Of the survivors, 76% were resistant to subsequent challenge with untreated L1210 cells. These results suggest that activities associated with reovirus replication may cause modifications of L1210 cells that enable them to induce an immune response, thus facilitating their rejection. A lack of correlation between differences in DNA synthesis (measured by 3H-thymidine uptake) by treated cells and the ability of those cells to kill recipient mice indicates that rejection of cells treated with reovirus or BCNU is not due to a decrease in their ability to proliferate or, presumably, to generate lethal tumors. The survival of mice injected with treated L1210 cell preparations containing as few as 2.9% reovirus-infected cells was enhanced to the same degree as that of mice injected with those containing as many as 14.6% infected cells, indicating that modification of only a minor component of the tumor cell population is sufficient to alter the ability of the cells to generate a lethal tumor.

Animals↗
PubMed1985

Cellular integrity is required for inhibition of initiation of cellular DNA synthesis by reovirus type 3.

Synchronized HeLa cells, primed for entry into the synthesis phase by amethopterin, were prevented from initiating DNA synthesis 9 h after infection with reovirus type 3. However, nuclei isolated from synchronized cells infected with reovirus for 9 or 16 h demonstrated a restored ability to synthesize DNA. The addition of enucleated cytoplasmic extracts from infected or uninfected cells did not affect this restored capacity for synthesis. The addition of ribonucleotide triphosphates to nuclei isolated from infected cells stimulated additional DNA synthesis, suggesting that these nuclei were competent to initiate new rounds of DNA replication. Permeabilization of infected cells did not restore the ability of these cells to synthesize DNA. Nucleoids isolated from intact or permeabilized cells, infected for 9 or 16 h displayed an increased rate of sedimentation when compared with nucleoids isolated from uninfected cells. Nucleoids isolated from the nuclei of infected cells demonstrated a rate of sedimentation similar to that of nucleoids isolated from the nuclei of uninfected cells. The inhibition of initiation of cellular DNA synthesis by reovirus type 3 appears not to have been due to a permanent alteration of the replication complex, but this inhibition could be reversed by the removal of that complex from factors unique to the structural or metabolic integrity of the infected cell.

Antigens, Viral↗
PubMed1984

Collaborative study of the USP dissolution test for prednisone tablets with Apparatus 2.

Five lots of prednisone tablets that disintegrate within 5 min were collaboratively studied by 11 laboratories using USP Apparatus 2 under carefully controlled conditions. One lot gave complete dissolution. The reproducibility and repeatability of Apparatus 2 for the four lots still dissolving at the end of the test were 2.6 and 1.6% of label claim, respectively, for the 11 laboratories.

Chemistry, Pharmaceutical↗
PubMed1984

Systematic error associated with apparatus 2 of the USP dissolution test V: Interaction of two tableted prednisone formulations with glass and plastic vessels.

Recently marketed glass vessels that are uniform and pass USP specifications were compared with uniform plastic vessels that also pass USP specifications. Two lots of prednisone tablets, Tablet 1 and Tablet 2, were tested in both types of vessels. Tablet 1 gave higher results (+12.7% of label claim) in glass vessels at 50 rpm but gave equivalent results in either vessel at 75 rpm. Tablet 2 gave equivalent results in either vessel at 50 rpm but gave higher results (+22% of label claim) in glass vessels at 75 rpm. The type of vessel used to obtain dissolution results for tablets should be specified.

Chemistry, Pharmaceutical↗
PubMed1983

Systematic error associated with apparatus 2 of the USP dissolution test III: limitations of calibrators and the USP suitability test.

The calibrator tablets now used in the USP suitability test do not reveal common sources of systematic error associated with Apparatus 2. When the apparatus was operated under conditions near or beyond USP tolerances, changes in the results of the USP calibrators were slight, whereas those of several samples of commercial prednisone tablets were significant. Thus, the USP calibrators and requirements do not guarantee suitability of the equipment for general dissolution testing of drug products.

Chemistry, Pharmaceutical↗
PubMed1983

Systematic error associated with apparatus 2 of the USP dissolution test IV: effect of air dissolved in the dissolution medium.

Acceptable concentrations of gases in a medium are not well defined in USP dissolution tests. A sample of 10-mg prednisone tablets, known to be sensitive to dissolved gases, was tested with batches of purified water that contained different concentrations of air. The data suggest that the results from Apparatus 2 can be influenced by the concentration of air in the dissolution medium unless the medium remains unsaturated with air for the duration of the test. The repeatability of means of six results was markedly improved when the air concentration in the medium was accurately controlled at the beginning of the test.

Air↗
PubMed1982

Systematic error associated with apparatus 2 of the USP dissolution test II: Effects of deviations in vessel curvature from that of a sphere.

Dissolution vessels made from glass or plastic are recognized by the USP as being suitable for dissolution testing. Glass vessels with a bottom inside curvature flatter than that of a sphere can cause a high bias in dissolution results; vessels with a steeper curvature can cause a low bias. The inside bottom curvature of plastic vessels adhered closely to the curvature of a sphere. The plastic vessels are preferable for use if the drug is not adsorbed and the vessel is not attacked by the dissolution medium. Bias in results between individual positions of a dissolution apparatus was traced to two shafts which were not vertical.

Chemistry, Pharmaceutical↗
PubMed1979

Semiautomated method for the analysis of formulations of chlorpheniramine maleate and brompheniramine maleate.

The determination of chlorpheniramine maleate and brompheniramine maleate in tablets, capsules, injections, and elixirs has been automated. The active ingredient is dissolved in dilute HCl. The dilute acid solution is sampled, made basic with dilute NaOH, and extracted with isooctane. The isooctane phase is resampled and the drug is re-extracted into dilute HCl. The absorbance of the acidic aqueous layer is monitored at 265 nm. The method is an automated version of the general USP XIX assay for salts of organic nitrogenous bases. The results from the semiautomated procedure agree well with the USP XIX and NF XIV official methods. Recoveries were 100% from an authentic tablet material. The system is linear from 0 to 300% of declared potency. The procedure is free from common excipient and dye interferences. Precision data are included for both the automated and official methods.

Autoanalysis↗
PubMed1978

Differential sensitivity of normal and transformed human cells to reovirus infection.

Normal and simian virus 40-transformed WI-38 cells exhibited a differential sensitivity to infection with type 3 reovirus. A progressive decrease in viability began 24 to 36 h after infection of transformed cells terminating in complete lysis of cultures by 96 h. Normal cells were productively infected and continued to produce and release virus for as long as 14 days after infection, but exhibited no detectable cytopathology. Inhibition of cellular DNA synthesis began 15 to 18 h after infection in transformed cells before development of cytopathology. No inhibition of DNA synthesis was detected in infected normal cells. No significant differences were noted in the adsorption or early replication characteristics of reovirus in normal and transformed cells. Virus replication and host cell DNA synthesis in normal and transformed human cells were compared to reovirus-infected L-929 mouse fibroblast cells.

Cell Division↗