PubMed Health⌕ Search

Biomedical subjects

L C Stephens

Publications and source records attributed to L C Stephens.

At least 109 records · Page 6Linked to original sources
PubMed1993

Protein C deficiency following hematopoietic stem cell transplantation: optimization of intravenous vitamin K dose.

Patients undergoing hematopoietic stem cell transplantation (HSCT) are dependent on i.v. vitamin K supplementation to prevent deficiency. Vitamin K deficiency may contribute to the development of a hypercoagulable state by limiting hepatic synthesis of fully functional carboxylated anticoagulant protein C (PC). The ratio of PC antigen (CAg) to PC measured in a clot-based functional assay (CFx) reflects the degree to which PC is carboxylated. The 133 patients undergoing HSCT received vitamin K 10 mg per week (low dose, 101 patients) or 5 mg per day (high dose, 32 patients) i.v. as their sole exogenous source of vitamin K. CAg and CFx were assayed before HSCT preparative regimen and again 14 days later. CAg and CFx fell significantly in both groups from day 0 to day 14 but there were no differences between the low-dose and high-dose vitamin K groups. For both groups, CAg correlated strongly with CFx at day 14 (p = 0.0001). At day 14, the CAg/CFx ratio for the low-dose group was significantly greater than for the high-dose group (1.26 +/- 0.4 vs 1.09 +/- 0.1, p < 0.0002), suggesting that low-dose patients had a higher proportion of incompletely carboxylated PC. The CAg/CFx ratio at day 14 correlated with serum albumin for the high-dose group (p = 0.05), but not the low-dose group (p = 0.09), suggesting that the change in ratio in the low-dose group was not simply due to a lack of protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens↗
PubMed1993

Biochemical modulation of radiation-induced apoptosis in murine lymphoma cells.

Considerable effort in our laboratory has been directed toward characterizing the role of apoptosis as a mode of cell death in model tumors irradiated in vivo. These studies have shown that apoptosis is an important response in some tumors, correlating with tumor growth delay and tumor cure. However, the response is heterogeneous among both the various tumors examined and the cells in a given tumor, suggesting that the propensity for cells to undergo apoptosis upon irradiation is regulated by unknown factors in tumors. To develop a model system for investigating these regulatory pathways in vitro at the molecular and biochemical levels, we have established cells from a tumor that displays a dramatic apoptotic response in vivo, the TH lymphoma, in cell culture. In this article, we review some of the results of our studies using this model system. To date, we have shown that the dose-response relationship and kinetics of the development of apoptosis for these cells in culture are similar to what we observed for the tumor response in vivo. Moreover, the roles of calcium and signal transduction pathways as important regulatory factors in radiation-induced apoptosis have been defined in this system. Ultimately such investigations may yield the insight necessary for designing protocols to modulate apoptosis biochemically in irradiated normal and tumor tissues to therapeutic advantage.

Animals↗
PubMed1993

Development of apoptosis in irradiated murine tumors as a function of time and dose.

In a previous paper (Radiat. Res. 127, 308-316, 1991), we reported that a moderately radiosensitive, transplantable murine ovarian carcinoma (OCaI) displayed apoptosis after irradiation whereas a radioresistant hepatocellular carcinoma (HCaI) did not. These initial observations have been followed up in this detailed analysis of the development of apoptosis in these two tumors as a function of time and dose. Histological sections of OCaI and HCaI carcinomas were scored at various times between 0.5 and 24 h after single doses of 2.5 or 25 Gy gamma radiation for the incidence of apoptosis. The percentage of nuclei undergoing apoptosis in untreated tumors was 5% in OCaI and 0.6% in HCaI. The peak in the number of apoptotic bodies occurred in the OCaI tumors 3-5 h after either dose. After 2.5 Gy, the peak incidence was about 20% and after 25 Gy it was about 30%. Irrespective of dose, HCaI tumors had an incidence of apoptosis of less than 3%. Based on the results of this time course, 4 h after irradiation was chosen for the determination of the dose response, over doses ranging from 2.5 to 25 Gy. The dose response for the OCaI tumors reached a plateau at 25-30% apoptotic nuclei after doses of about 7.5 Gy and above. Autoradiographic analysis of histological sections from mice injected with [3H]thymidine showed that some apoptotic bodies in the OCaI tumors arose from cycling cells. These results confirm that the apoptotic mode of cell death may represent an important response in some irradiated tumors.

Animals↗
PubMed1992

Increased therapeutic efficacy induced by tumor necrosis factor alpha combined with platinum complexes and whole-body hyperthermia in rats.

This study examined the effect of a trimodality therapy of the combination of recombinant human tumor necrosis factor alpha (TNF), whole-body hypertheria (WBH), and cis-diamminedichloroplatinum(II) (CDDP) or cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA) on a fibrosarcoma and normal tissue in F344 rats. TNF (1 x 10(5) units/kg) increased the antitumor effect of both CDDP (1.5 mg/kg) + WBH (2 h at 41.5 degrees C) and CBDCA (30 mg/kg) + WBH. Tumor growth delay, which was 1.9 days for CDDP + WBH and 2.7 days for CBDCA + WBH (P less than 0.01 compared to control), was significantly increased to 2.9 days with TNF + CDDP + WBH and 5.4 days with TNF + CBDCA + WBH (P less than 0.05). WBH, TNF, CDDP or CBDCA alone, TNF + CDDP, TNF + CBDCA, or TNF + WBH had no significant effect on tumor growth. In contrast, administration of TNF did not enhance the CDDP- or CBDCA-mediated dose limiting normal tissue toxicity. CDDP + WBH-mediated acute renal injury and CBDCA + WBH-mediated acute myelosuppression, as determined by blood urea nitrogen and peripheral blood cell counts, respectively, were not increased with the addition of TNF to either dual modality therapy. Histopathologically, addition of TNF produced no significant alterations in the kidney and the bone marrow as compared to CDDP + WBH or CBDCA + WBH. These data show that TNF enhanced the platinum + WBH-mediated antitumor effect without increasing normal tissue toxicity, suggesting that TNF may increase the therapeutic efficacy of CDDP or CBDCA combined with WBH.

Animals↗
PubMed1992

Initiation and post-initiation chemopreventive effects of diallyl sulfide in esophageal carcinogenesis.

Diallyl sulfide (DAS), one of a number of organosulfur compounds accounting for the flavor and smell associated with garlic, has been shown to inhibit a number of chemically induced forms of cancer. In this study, DAS was examined for its chemopreventive effects in both the initiation and post-initiation phases of nitrosomethylbenzylamine-induced esophageal carcinogenesis in the Sprague-Dawley rat. Although highly inhibitory during initiation, DAS is ineffective when given after the carcinogen. DAS, though not effective as a preventive in post-initiation, was not found to promote esophageal carcinogenesis.

Allyl Compounds↗
PubMed1992

Impact of spinal cord repair kinetics on the practice of altered fractionation schedules.

The kinetics of repair of sublethal lesions in the spinal cord was assessed in detail using a rodent model. Experiments were designed to obtain the fractionation sensitivity, alpha/beta, and to quantify the kinetics of repair after a clinically relevant fraction size. Pairs of 2-Gy fractions at intervals ranging from 0 to 24 h were given from Monday through Friday, to cumulative doses of 40-84 Gy. In addition, two groups of animals received 1.5 or 1.2 Gy twice a day at 8-h intervals, 5 days a week, to total doses of 66-90 Gy and 67.2-98.4 Gy, respectively. All irradiations were followed by a top-up dose of 16 Gy. Analysis of the experimental data revealed that a bi-exponential repair model fit the experimental data significantly better than did the mono-exponential model (p = 0.002). The repair half times obtained were 0.7 (0.2-1.3) h and 3.8 (2.6-4.9) h, respectively. The proportion of injury repaired by the longer half time was estimated to be 0.62 (0.37-0.86). The data showed that delivering 2 fractions per day at 6- or 8-h intervals instead of one per day led to a 16.5% (11.8-21.1%) and 13.5% (9.1-17.8%) reduction in the tolerance, respectively. Finally, the results indicated that when incomplete repair between fractions was accounted for, the linear-quadratic (LQ) model was valid in describing fractionation response down to 1.2 Gy per fraction.

Animals↗
PubMed1992

The relationship between apoptosis and atrophy in the irradiated lacrimal gland.

Atrophy is generally considered to be a true late effect of radiation. However, in serous glands, atrophy was thought to be a consequential late effect because serous cells die within hours of irradiation and the apparent effects of atrophy are observed contemporaneously with radiation treatment. Therefore, to determine the pathogenesis of atrophy in serous glands, it is necessary to differentiate between parenchymal loss as a result of direct radiation death of serous cells and parenchymal loss as a result of serous cell death that is secondary to fibrosis, vascular damage, or precursor cell death. The lacrimal glands of 62 rhesus monkeys have been irradiated to single doses of 2.5 to 20 Gy and examined at intervals of 4 hr to 112 days postirradiation. Serous cells (nuclei) and acini were counted in at least 30 high power fields per (dose, time) point. At each dose and time of sacrifice, the average number of nuclei per acinus and the average number of acini per high power field were calculated. Also at each dose and time, the distribution of the number of nuclei per acinus was examined to determine how the frequency of acinar sizes changed as a function of irradiation. The number of cells per acinus appears to rise initially, but this is likely a result of the degranulated cells being physically smaller, yielding an artificially higher count. Within 4 days after 12.5 Gy, the average number of nuclei per acinus approaches control values and remains within the range of controls for at least 112 days. The number of acini per high power field decreases steadily for 30 days after 12.5 Gy. From 30 to 112 days, there is some recovery of this number, but it remains well below control values. At 24 hr, the number of nuclei per acinus shows a distinct dose response up to 20 Gy. However, at 30 days there is no evidence of a dose response for this parameter. These results indicate that even though serous cells die in significant numbers within hours of irradiation, the atrophy of the lacrimal gland (and by extension, the parotid gland) is a result of the death of the serous stem cell or precursor. Consequently, protection of serous cells from radiation apoptosis will not diminish serous gland atrophy.

Animals↗
PubMed1992

A role for calcium in regulating apoptosis in rat thymocytes irradiated in vitro.

Thymus-derived lymphocytes undergo death after gamma-irradiation via a pathway termed apoptosis, or programmed cell death. An early step in this pathway is the production of nucleosome-sized fragments of DNA. DNA fragmentation was used as the endpoint in these investigations to examine apoptosis in lymphocytes extracted from the rat thymus and irradiated in vitro. In unirradiated thymocytes the level of DNA fragmentation rose to 15% by the first hour of culture, where it remained approximately constant until the fifth hour. In contrast, thymocytes irradiated with a dose of 2.5 Gy exhibited a large and dramatic increase in DNA fragmentation beginning 2 h postirradiation. DNA fragmentation measured 6 h after irradiation was detected after as little as 0.25 Gy and reached a maximum of 90% with 10 Gy. Metabolic control of DNA fragmentation after irradiation was evidenced by the suppression of DNA fragmentation when thymocytes were incubated with cyclohexamide or actinomycin D. When gamma-irradiated thymocytes were incubated with the Ca2+ chelator EGTA, DNA fragmentation was reduced significantly. BAPTA-AM, a highly specific intracellular Ca2+ chelator, essentially eliminated DNA fragmentation in cells irradiated with 2.5 Gy and, unlike EGTA, eliminated the background level of fragmentation in unirradiated samples. Therefore, our data are consistent with the possibility that Ca2+ serves as a second messenger to induce DNA fragmentation in irradiated thymocytes, suggesting a common pathway for cells prompted to enter apoptosis from seemingly dissimilar interval events.

Animals↗
PubMed1992

Radiation-induced apoptosis of oligodendrocytes in vitro.

It has been suggested that glial cells and/or their progenitors are the primary target cells for radiation-induced demyelination. Cultures of terminally differentiated oligodendrocytes, immature oligodendrocytes, and O-2A progenitor cells were generated from the cerebral cortex and spinal cord of perinatal rat pups. Irradiation of cultures of terminally differentiated oligodendrocytes resulted in a significant increase in the percentage of apoptotic cells from 15% in control to 30% in irradiated samples, with the maximum increase induced by 10 Gy. This increase in apoptosis could be observed by 1 h after irradiation with the maximum level reached at 3-6 h. Apoptotic cells were not detected before or after irradiation of cultures of O-2A progenitor cells or immature oligodendrocytes. These data suggest that radiation-induced apoptosis of terminally differentiated oligodendrocytes may be involved in early demyelination.

Animals↗
PubMed1992

Neutron RBE for primate spinal cord treated with clinical regimens.

The RBEs of high-energy neutrons given in 9 or 12 fractions for cervical spinal cord injury in rhesus monkeys was determined using photons at 2.2 Gy per fraction as the reference radiation. Because the dose-response functions were not parallel, the RBE was not constant but rather increased with dose or, equivalently, with the probability of myelopathy. This required the development of a novel method of determining the RBE versus level of response. The RBE is presented as a function of probability of myelopathy from 0.1 to 99%. At a 50% incidence of myelopathy, the RBE (+/- 1 SE) was 5.22 +/- 0.15. A difference in the histopathology of lesions induced by photon and neutron treatments was observed.

Animals↗
PubMed1991

Protective effect of ICRF-187 against normal tissue injury induced by adriamycin in combination with whole body hyperthermia.

The use of [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) as a protective agent against normal tissue toxicity caused by combined Adriamycin (ADR) and whole body hyperthermia (WBH; 2 h at 41.5 degrees C) was assessed in a rat model. The effect of ICRF-187 on the antitumor response induced by the combination of ADR and WBH was also investigated in order to assess alterations in the therapeutic index of this combined therapeutic modality treatment. ICRF-187 significantly reduced ADR-mediated body weight loss, renal toxicity, and cardiomyopathy under both normothermic and hyperthermic conditions as shown by morphological and functional assays. ADR-induced neuropathy (seen only in normothermic rats) was also ameliorated by ICRF-187. Although this study did not show a pronounced effect of ICRF-187 on ADR-induced acute myelosuppression, ADR-mediated chronic anemia, leukocytosis, and thrombocytosis were reduced by ICRF-187 in both normothermic and WBH-treated rats. The effect of ICRF-187 on antitumor response was evaluated with a tumor growth delay assay using an in vivo transplantable fibrosarcoma. ICRF-187 caused no significant change in tumor growth delay induced by either ADR alone or ADR combined with WBH. Indeed, the only complete tumor regression following treatment resulted from the combination of ICRF-187 plus ADR plus WBH. Thus, ICRF-187 significantly increases the therapeutic index of the combined modality treatment of ADR and WBH by selectively reducing normal tissue toxicity without interfering with antitumor efficacy.

Animals↗
PubMed1991

Effect of adriamycin combined with whole body hyperthermia on tumor and normal tissues.

Thermal enhancement of Adriamycin-mediated antitumor activity and normal tissue toxicities by whole body hyperthermia were compared using a F344 rat model. Antitumor activity was studied using a tumor growth delay assay. Acute normal tissue toxicities (i.e., leukopenia and thrombocytopenia) and late normal tissue toxicities (i.e., myocardial and kidney injury) were evaluated by functional/physiological assays and by morphological techniques. Whole body hyperthermia (120 min at 41.5 degrees C) enhanced both Adriamycin-mediated antitumor activity and toxic side effects. The thermal enhancement ratio calculated for antitumor activity was 1.6. Thermal enhancement ratios estimated for "acute" hematological changes were 1.3, whereas those estimated for "late" damage (based on morphological cardiac and renal lesions) varied between 2.4 and 4.3. Thus, while whole body hyperthermia enhances Adriamycin-mediated antitumor effect, normal tissue toxicity is also increased, and the potential therapeutic gain of the combined modality treatment is eroded.

Animals↗
PubMed1991

Effect of carboplatin combined with whole body hyperthermia on normal tissue and tumor in rats.

The antitumor activity and normal tissue toxicity of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin) in combination with whole body hyperthermia (WBH) (41.5 degrees C, 120 min.) were examined in an F344 rat model. Carboplatin data were compared with those of cis-diamminedichloroplatinum (II) (cisplatin). At 37 degrees C, carboplatin showed minimal activity against a rat fibrosarcoma, but when combined with WBH, the antitumor effect-of the drug was greatly enhanced. The major carboplatin-induced acute toxicity at both normothermic and hyperthermic temperatures was marked hypocellularity of the bone marrow. A significant decrease in peripheral blood platelet counts was caused by the maximum tolerated doses (MTD) of carboplatin alone and with WBH. While the lethal dose of carboplatin alone caused only minimal renal damage, mild acute tubular necrosis was observed at the MTD of carboplatin with WBH, although no significant increase in blood urea nitrogen occurred. Therapeutic ratios of the combined chemotherapy and WBH modalities were calculated by comparing tumor growth response at the MTD of drug alone and drug combined with WBH. The combination of the nephrotoxic cisplatin with WBH resulted in a therapeutic ratio of only 0.8, whereas when carboplatin was combined with WBH, a value of 3.0 was obtained, representing a 3- to 4-fold increase over cisplatin in the therapeutic ratio. These data indicate that the less nephrotoxic carboplatin in combination with WBH improves therapeutic gain and may provide a more promising clinical combination for cancer treatment than cisplatin combined with WBH.

Animals↗
PubMed1991

Radiation apoptosis of serous acinar cells of salivary and lacrimal glands.

Xerostomia and xerophthalmia are common and potentially serious local side effects of radiotherapy for head and neck cancer. Clinical observations supported by experimental findings show that radiation, even in low doses, causes acute diminutions of saliva and tears by rapidly killing the serous cells of the salivary and lacrimal glands, respectively. Serous acini of salivary and lacrimal glands have similar developmental, morphologic, and functional characteristics. Serous acinar cells are functionally mature, secretory epithelial cells that normally do not divide and are long lived. Irradiation of the salivary and lacrimal glands of rhesus monkeys resulted in selective death of serous acinar cells within 24 hours. The paradigm for acute radiation seroadenosis is intermitotic or interphase cell death caused by apoptosis.

Animals↗
PubMed1991

The coronary artery response to implantation of a balloon-expandable flexible stent in the aspirin- and non-aspirin-treated swine model.

Intracoronary stents may potentially alleviate some of the problems associated with coronary angioplasty. Since the anatomy and physiology of swine coronary arteries closely resemble those of humans, the response to implantation of the Glanturco-Roubin, balloon-expandable, flexible stent was studied in this model. Additionally, the effect of aspirin, 1 mg/kg/day orally, on this response was evaluated. Eighteen Hanford minature swine underwent stenting of the left anterior descending coronary artery. Two died within 24 hours of stent implantation. The 16 survivors were put to death at 4 (n = 4), 11 (n = 4), 28 (n = 4), 56 (n = 3), and 180 (n = 1) days. Angiographically, reduction of stent lumen diameter of 0.1 to 1.3 mm was observed and was maximum at 11 days, with gradual improvement at subsequent time periods. Scanning electron microscopy, transmission electron microscopy, and light microscopy showed early disruption of subjacent endothelium, and adherence of platelets to exposed subendothelium and stent wires. Microthrombi were readily apparent. At 11 days, intimal thickening, made up predominantly of smooth muscle cells with abundant extracellular matrix, was observed and covered the stent wires. At 28 days, regression of intimal thickening was apparent and a confluent endothelium with flow-directed orientation was seen. At 56 and 180 days, the luminal surface was smooth; intimal thickening averaged 525 microns over the stent wires and 55 microns away from the wires. Findings in aspirin-treated animals were similar to results in those that did not receive aspirin. Thus in this swine model, stent implantation results in a time-dependent and self-limited vascular response.

Angioplasty, Balloon, Coronary↗
PubMed1991

Hepatic pathology of the colon carcinogen, azoxymethane, in Hanford-Moore miniature pigs.

Azoxymethane (AOM) is commonly used in colon carcinogenesis studies in rodents. In an attempt to develop a large animal model of human colon cancer, AOM was given to Hanford-Moore miniature pigs. Six pigs were injected intraperitoneally with a single dose of AOM of either 5, 10, 20, 40 or 55 mg per kg body weight. Within 48 h, severe signs of toxicity and death occurred in animals receiving greater than 20 mg per kg AOM. After 30 days, all surviving animals were killed and necropsied. Acute hepatic necrosis with haemorrhage was the major toxic effect of AOM in all animals receiving doses exceeding 20 mg per kg. In a second, longer-term experiment, eight pigs were injected with either 20 mg per kg AOM weekly or 10 mg per kg AOM every other week or a combination of both treatments. Chronic toxic effects were limited to the liver. No colon tumours were observed. It is concluded that this particular species demonstrates marked hepatic sensitivity to the toxic effects of AOM.

Animals↗