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Biomedical subjects

A Livingstone

Publications and source records attributed to A Livingstone.

At least 19 recordsLinked to original sources
PubMed1992

Presentation of antigen by mixed isotype class II molecules in normal H-2d mice.

A panel of DBA/2 T cell hybridomas specific for the sperm whale myoglobin epitope 110-121 was found to recognize antigen presented by the mixed isotype class II molecule E alpha dA beta d. The response was blocked by monoclonal antibodies specific for E alpha and A beta d chains; in addition, the hybridomas responded to antigen presented by L cells expressing E alpha A beta d molecules, and made no response with L cells expressing I-Ad or I-Ed molecules. Two more groups of hybridomas isolated from DBA/2 and B10.D2 mice immunized with myoglobin also recognized peptide 110-121 presented by E alpha d A beta d. Thus, although it is expressed at biochemically undetectable levels on spleen cells, the E alpha d A beta d molecule is an important presenting element in normal H-2d mice making a conventional immune response to a protein antigen. These results suggest that high levels of class II expression are not a prerequisite for T cell activation.

Animals↗
PubMed1992

Phase I study of high dose 5-fluorouracil and high dose Leucovorin with low dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies.

Twenty-eight patients with refractory advanced malignancies were treated with a 24 hr infusion of 5-fluorouracil (5-FU), Leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable for the assessment of toxicity and anti-tumor activity. PALA was administered as intravenous bolus over 15 min at a fixed dose, 250 mg/m2 24 hr before the start of 5-FU and LV infusions. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 2600 mg/m2. LV was administered in a fixed dose of 500 mg/m2 concurrently with 5-FU over a 24-hr period. The course was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among dose-limiting toxic effects. Other toxicities observed were hand-foot syndrome, hair loss of scalp/eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. Maximum tolerated dose (MTD) of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated at 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose de-escalation, a majority of whom contained 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients had been previously treated. Eight patients achieved a partial response, all of whom were previously treated, except three patients. A complete response was observed in a patient with pancreatic carcinoma, previously untreated. Overall response rate for the patients who were treated at the 5-FU dose of 2100 mg/m2 or 2600 mg/m2 is 9 of 18 patients (50%).

Adult↗
PubMed1991

A phase I, II study of high-dose 5-fluorouracil and high-dose leucovorin with low-dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies.

Twenty-eight patients with refractory advanced malignancies were treated with a 24-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable to assess toxicity and antitumor activity. The PALA was administered as an intravenous bolus over 15 minutes at a fixed dose (250 mg/m2) 24 hours before the start of the 5-FU and leucovorin infusions. Initially the dose of 5-FU was 750 mg/m2; this was increased incrementally to 2600 mg/m2. The LV was administered in a fixed dose of 500 mg/m2 concurrently with the 5-FU over a 24-hour period. This regimen was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among the dose-limiting toxicities. Others were hand-foot syndrome, hair loss of the scalp and eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. The maximum tolerated dose of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated with 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose reductions, but most received 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients were treated previously. Eight patients had a partial response; five of these were treated previously. A complete response was observed in one patient with pancreatic carcinoma, previously untreated. The overall response rate for patients treated with 2100 or 2600 mg/m2 of 5-FU was nine of 18 patients (50%). Three of four previously untreated patients with pancreatic cancer responded to this treatment (two responded partially, and one had a complete response). One of three heavily pretreated patients with non-small cell lung cancer had a partial response as did a patient with breast cancer. Four of ten patients with colorectal cancer responded to the treatment (four partial responses), of whom three had been treated previously.

Adult↗
PubMed1991

Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes.

It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.

Animals↗
PubMed1991

Genetic analysis of diabetes in the nonobese diabetic mouse. I. MHC and T cell receptor beta gene expression.

Backcross nonobese diabetic (NOD) ((NOD x SWr)F1 x NOD) mice (108 females and 105 males) were typed for MHC, TCR V beta, and monitored for 350 days for the onset of diabetes. The presence of "antipolar" antibodies in the sera and the occurrence of insulitis was examined in a proportion of these backcross mice. There was no difference in the incidence of diabetes in mice heterozygous for TCR V beta b/a vs those homozygous for TCR V beta b/b. Among the 17 diabetics (all female) detected in this backcross, 14/17 were H-2nod/nod but 3/17 were H-2nod/q. This supports a previous observation suggesting that the MHC-linked diabetogenic gene originally thought to be recessive may rather be dominant but have a low penetrance in the heterozygous state. Antipolar autoantibodies were found in both female and male backcross mice, and were similarly distributed in diabetic and nondiabetic mice. There appeared to be no correlation between the level of these auto-antibodies and development of diabetes. The incidence and severity of insulitis was linked to MHC but no influence of TCR genes on insulitis nor an association between insulitis and antipolar antibodies could be demonstrated in this study. Further analyses of H-2nod/nod intercross mice homozygous for TCR V beta a or TCR V beta b are currently underway.

Animals↗
PubMed1987

The effect on human neuroblastoma spheroids of fractionated radiation regimes calculated to be equivalent for damage to late responding normal tissues.

Multicellular tumour spheroids (MTS) are a useful in vitro model of human cancer. An experiment was designed to assess the likely therapeutic advantage of hyperfractionation--a proposed strategy in radiotherapy. A cell line (NB1-G) derived from human neuroblastoma was grown as MTS. This MTS line is radiosensitive with low capacity for repair of sublethal radiation damage. These properties make NB1-G a suitable line to test the theoretical advantage of hyperfractionation. MTS were irradiated using alternative fractionated regimens, with fraction sizes varying from 0.5 to 4 Gy. In each experiment, the total dose was chosen to make the regimens theoretically isoeffective for damage to late-responding normal tissues (calculated using the linear-quadratic mathematical model with alpha/beta = 3 Gy). The radiation responses of MTS were evaluated using the end-points of regrowth delay and "proportion cured". Regimens using smaller doses per fraction were found to be markedly more effective in causing damage to neuroblastoma MTS, as assessed by either end-point. These experimental findings support the proposal that hyperfractionation should be a therapeutically advantageous strategy in the treatment of tumours whose radiobiological properties are similar to those of the MTS neuroblastoma line NB1-G.

Cell Line↗
PubMed1987

Biological properties of a tumour cell line (NB1-G) derived from human neuroblastoma.

The properties of a new tumour cell line (NB1-G) derived from human neuroblastoma by xenografting in nude rats followed by adaptation to tissue culture are described. Studies using a panel of monoclonal antibodies demonstrate the neuro-ectodermal nature of the cells and support the diagnosis of the primary tumour as neuroblastoma. Cytogenetic studies have revealed a human karyotype with several chromosomal abnormalities. Genetic analysis by in situ DNA hybridization has demonstrated the presence of multiple copies of the N-myc gene. Approximately 20-30 fold amplification of the gene is observed on Southern blot analysis. The cell line has been adapted to growth as multicellular tumour spheroids as well as monolayer culture. Radiobiological studies on spheroids show the cells to be radiosensitive with low capacity for sub-lethal damage accumulation and repair. The cell line should be useful for fundamental studies of human neuroblastoma as well as experimental therapy in vitro.

Animals↗
PubMed1986

Radiation studies on multicellular tumour spheroids derived from human neuroblastoma: absence of sparing effect of dose fractionation.

In vitro experiments were carried out to compare the effects of single-dose and split-dose irradiation on a cell line (NB1-G) derived from human neuroblastoma and grown as multicellular tumour spheroids (MTS). The radiation response was evaluated in terms of regrowth delay; estimates of in situ cell survival were made by back-extrapolation of regrowth curves. These studies showed no significant difference in the effectiveness of single as compared to split dose irradiation i.e. no sparing effect of fractionation. If MTS constitute a realistic model for micrometastases in vivo, these results provide a radiobiological rationale for hyperfractionated treatment regimes in the adjuvant radiotherapy of neuroblastoma.

Cell Line↗
PubMed1986

Radiobiological considerations in the treatment of neuroblastoma by total body irradiation.

Neuroblastoma is a radiosensitive neoplasm for which total body irradiation (TBI) is presently under clinical consideration. Collated data on the radiobiology of human neuroblastoma cells in vitro (11 cell lines derived from seven patients) indicates moderate cellular radiosensitivity and low capacity for accumulation of sublethal damage (median survival curve parameters: Do = 104 cGy, Dq = 32 cGy, n = 1.36). Mathematical studies incorporating these parameters suggest that low dose fractionated TBI is unlikely to achieve significant levels of tumour cell kill. When high dose TBI is used in conjunction with bone marrow rescue a tumour "log cell kill" of 4-5 should be achievable. This effect would be additional to that achieved by chemotherapy. The optimum schedule for exploitation of radiobiological differences between neuroblastoma cells and the dose-limiting normal tissues has a hyperfractionated structure. Twice-daily treatments with fraction sizes in the region 120-150 cGy seems appropriate. Single dose treatments at high dose rate are contraindicated. Fractionated TBI with bone marrow rescue may be curative for some patients in clinical remission who are presently destined to relapse.

Cell Survival↗
PubMed1985

The radiosensitivity of human neuroblastoma cells estimated from regrowth curves of multicellular tumour spheroids.

Multicellular tumour spheroids may provide a suitable in-vitro model for micrometastases in vivo. In this paper, the results are reported of experimental studies on the radiation response of two lines of spheroids derived from human neuroblastoma. Spheroids of approximately 200-250 microM mean diameter were exposed to graded doses of X rays (50-350 cGy) and, following a static or regression phase, regrew at rates which approximated those of unirradiated spheroids. Clonogenic surviving fraction was estimated, at each dose level, by extrapolation of the regrowth curve to zero dose. It is proposed that this procedure is more suitable for regrowth curves of spheroids than in-vivo tumours, because of the absence in vitro of complicating factors which occur only in vivo. By this means, survival curves were deduced and were found (for both cell lines) to be almost exponential in form, with little indication of capacity for accumulation of sublethal damage (multitarget parameters: DQ values: 17 and 25 cGy; Do values: 104 and 81 cGy respectively). These results contribute to the evidence for high radiosensitivity of neuroblastoma cells in vitro and provide a rationale for the use of hyperfractionation in the clinical treatment of neuroblastoma by radiotherapy.

Cell Division↗