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Biomedical subjects

S J Proctor

Publications and source records attributed to S J Proctor.

At least 145 records · Page 8Linked to original sources
PubMed1988

Methylprednisolone, etoposide, vindesine, and chlorambucil (PEEC) alone or alternating with CHOP as initial or salvage therapy for non-Hodgkin's lymphoma.

A novel cytotoxic drug combination, PEEC, has been tested in the initial or salvage treatment of lymphomas. The PEEC combination alone is active in high grade or intermediate grade NHL with two complete and two partial remissions out of four patients so treated. When combined with standard CHOP therapy using an alternating regime, seven out of 11 patients obtained a complete remission and four partial remission. Ten patients were well, off treatment, beyond one year from presentation. The combination was less impressive, however, as salvage therapy with two partial responses in a heavily pre-treated group of nine patients.

Adult↗
PubMed1988

Skin explant culture as a model for cutaneous graft-versus-host disease in humans.

An in vitro skin explant model for graft-versus-host disease (GVHD) in humans has been used to study the role of effector T cells in the histological pathogenesis of GVHD. In 11 of 12 experiments clear GVHD changes of grades II-IV were induced in HLA-mismatched skin explants cultured with allogeneic T cells sensitized by in vitro mixed lymphocyte culture. The role of effector T cells was investigated by comparing results before and after removal of CD3 positive cells, and CD4 positive and CD8 positive T cell-subsets by antibody and complement cytolysis from responder populations. Only total removal of CD3 positive T cells prevented histopathological lesions of GVHD in the skin biopsy specimens. The results also demonstrated that the CD4 positive population caused the greatest degree of GVHD in vitro in skin biopsy specimens and direct infiltration into skin by cells is not required for changes to become evident. These results confirm the early results on animal models and demonstrate the use of the skin explant model as a tool for studying the biology of GVHD in humans.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Reduced levels of drug-induced DNA cross-linking in nitrogen mustard-resistant Chinese hamster ovary cells expressing elevated glutathione S-transferase activity.

We have reported previously (C. N. Robson et al., Cancer Res., 46: 6290-6294, 1986) the isolation of a Chinese hamster ovary cell line, designated CHO-Chlr, that exhibits resistance to bifunctional nitrogen mustards while maintaining the normal parental level of sensitivity to several other alkylating agents. We have compared the rate of formation and repair of DNA cross-links induced by mechlorethamine in CHO-Chlr and parental CHO-K1 cells, both in intact cells and in isolated nuclei. Equimolar doses of mechlorethamine induce significantly fewer DNA interstrand cross-links in CHO-Chlr cells than in CHO-K1 cells, but levels of DNA-protein adducts are approximately equivalent in the two lines. There is a correlation between the relative resistance of CHO-Chlr cells to mechlorethamine (34-fold) and the amount of drug required to induce approximately equal numbers of DNA interstrand cross-links in the two cell lines. This strongly implicates DNA-DNA adducts in the cytotoxic action of mechlorethamine. DNA cross-linking studies on isolated nuclei reveal only minor differences between the two lines even with identical drug treatments. The rate of cross-link repair is comparable in the two cell lines. These results, taken together with our earlier observation that the rate of drug accumulation is identical in these two lines, suggest that enhanced cytoplasmic drug detoxification is the underlying resistance mechanism in CHO-Chlr cells. We have measured cellular glutathione S-transferase activity, using both the general substrate 1-chloro-2,4-dinitrobenzene, and substrates with some specificity for the different classes of transferase isoenzymes. Total enzyme activity (as measured with 1-chloro-2,4-dinitrobenzene) is elevated 3-fold in the resistant cells. A 2- and 5-fold increase, respectively, in activity against ethacrynic acid and cumene hydroperoxide is detectable in CHO-Chlr cells. This elevation in catalytic activity in the resistant cells is reflected in higher levels of both the Yf- and Ya-type transferase subunits.

Animals↗
PubMed1987

Interaction of cimetidine with oral melphalan. A pharmacokinetic study.

The effects of pretreatment with cimetidine (200 mg three times daily, 400 mg at night) on the pharmacokinetics of oral melphalan (10 mg) have been investigated in patients with multiple myeloma. Cimetidine pretreatment reduced the bioavailability of oral melphalan by approximately 30% (P less than 0.05). The elimination rate of melphalan from plasma was significantly increased by cimetidine (P less than 0.05), the half-life being reduced from 1.94 +/- 0.55 h to 1.57 +/- 0.53 h. Cimetidine appeared to reduce the interindividual variability in melphalan absorption, but at the cost of reduced bioavailability.

Administration, Oral↗
PubMed1987

Short course intermediate dose intravenous melphalan therapy in myeloma--relation to early emergence of drug resistance (phase II study).

Intermediate dose intravenous melphalan at a dose of 15 mg/m2 x 4 given at 21-day intervals has been evaluated in 20 consecutive patients. The aims were to assess the time to obtain maximal response, duration of response and response to reintroduction of intravenous melphalan on relapse. Median time to maximal response was 17 weeks. Four patients achieved a complete response with complete disappearance of paraprotein. On relapse, reintroduction of intravenous melphalan was unsuccessful in causing a reduction of paraprotein, suggesting that resistance to this dose of melphalan occurs early even in responding patients.

Drug Evaluation↗
PubMed1987

Activation of B chronic lymphocytic leukaemia cells by Branhamella catarrhalis.

Cells from the blood of patients with chronic lymphocytic leukaemia were cultured in the presence of two polyclonal activators of human B cells, the bacteria Branhamella catarrhalis (Bc) and Staphylococcus aureus Cowan 1 (SAC). Although the magnitude of the responses varied, cells from seven of the eight patients studied were induced to proliferate in response to Bc. In contrast, the response to SAC was low or negligible in seven of the eight patients, and only one patient responded well to this mitogen. Bc was also effective in inducing secretion of IgM in cells from seven of the eight patients, and this was unaffected by removal of T cells. Fractionation of CLL cells on density gradients showed that the highest level of IgM production was induced in cells with a low buoyant density, whilst cells with a high buoyant density secreted little or no immunoglobulin in response to Bc. Together, these results demonstrate that Bc is an effective, T-independent activator of both DNA synthesis and immunoglobulin production in CLL cells.

Aged↗
PubMed1986

Defective in vitro immunoglobulin production in response to pokeweed mitogen in patients with Hodgkin's disease pretreatment and in remission.

In vitro production of IgG and IgM from peripheral blood lymphocytes and B-cell enriched fractions was assessed in a group of Hodgkin's disease (HD) patients and normal controls using pokeweed mitogen (PWM) stimulation. Our studies demonstrated a significant (P less than 0.01) reduction in the absolute number of helper (OKT4 positive) T cells and a significant alteration in the helper/suppressor T-cell ratio (0.89 +/- 0.15) compared to normal (1.83 +/- 0.31). Results from PWM stimulation experiments demonstrated that HD patients produced significantly lower IgG (P less than 0.01) and IgM (P less than 0.01) levels than controls. Synthesis of IgM but not IgG induced by PWM was subnormal after addition to patient B-cell cultures of autologous irradiated T cells or allogeneic irradiated normal T lymphocytes. Irradiated T cells from HD patients were as effective as normal T cells in helping PWM induced IgG and IgM synthesis by normal B cells. Our results suggest that in HD impaired circulating B-cell function is partly due to T-suppressor cell activity and furthermore that B-cell subpopulations producing different immunoglobulin isotypes may either be defective or vary in their susceptibility to T-cell suppression.

Adult↗
PubMed1986

Interferon responses of peripheral blood mononuclear cells from normal and leukaemic children.

Human peripheral blood mononuclear cell cultures (PBMC) stimulated with Sendai virus or K562 cells produce a mixture of interferons. Temperature and pH stability characteristics and reactions with monospecific antibodies indicate that PBMC cultures from adults produce interferons alpha and gamma in approximately equal proportions. PBMC cultures from children produce lower levels of interferons with a higher proportion of type alpha. The ability of PBMC cultures from children with acute lymphoblastic leukaemia (ALL) to produce interferon was determined. Little or no gamma interferon was induced by either Sendai virus or K562 cells. Cultures from some children with ALL produced alpha interferon but mean levels were significantly lower than from normal children. A group of older children with ALL who had completed their course of therapy and were off treatment produced levels of interferon indistinguishable from those of normal children. This in vitro deficit, possibly induced by chemotherapy, may reflect an in vivo deficit and may contribute to the impaired handling of viruses seen in children being treated for ALL.

Adolescent↗
PubMed1986

Subpopulations of thyroid autoantibody secreting lymphocytes in Graves' and Hashimoto thyroid glands.

Lymphocytes isolated from Graves' and Hashimoto thyroid tissue by enzymatic (dispase) digestion or mechanical disaggregation were markedly different in terms of their ability to synthesize thyroid autoantibodies in culture. Dispase digestion, followed by removal of thyroid follicular cells, gave a lymphocyte population with a high T:B cell ratio (6:1). However, the ability of these cell suspensions to synthesize microsomal (Mic) and thyroglobulin (Tg) antibodies spontaneously was significantly increased compared with lymphoid suspensions isolated by mechanical means. Spontaneous synthesis of thyroid autoantibodies was not markedly enhanced in cell suspensions prepared from patients' lymph node tissue by digestion compared with mechanical disaggregation. Further, Mic and Tg antibody production by thyroid lymphocytes prepared using dispase was inhibited by pokeweed mitogen (PWM) whereas in most cases suspensions prepared from the same tissues by mechanical dispersion synthesized low or undetectable levels of autoantibodies whether PWM was present or absent. Digestion of tissue debris remaining after mechanical removal of lymphocytes gave suspensions which had an increased proportion of suppressor/cytotoxic T cells compared with suspensions produced mechanically or by digestion alone; however, in terms of spontaneous autoantibody synthesis and PWM induced inhibition, these suspensions were similar to these obtained by digestion alone. It would therefore seem that enzymatic digestion of thyroid tissue resulted in the isolation of a lymphoid population which was different from that extracted by mechanical disaggregation. The digestion process appears to permit the recovery of lymphocytes closely associated with thyroid follicular cells and our studies suggest that it is this population which makes the major contribution to autoantibody synthesis.

Adult↗
PubMed1985

Inhibition of natural killing and antibody-dependent cell-mediated cytotoxicity by the plasma protease inhibitor alpha 2-macroglobulin (alpha 2M) and alpha 2M protease complexes.

Over the past few years increasing attention has been given to the relationship between the immune response and proteases. The aim of our present study was to examine the dose-response effect of purified alpha 2-macroglobulin (alpha 2M) with varying degrees of protease (trypsin) saturation on natural killing (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC). The results demonstrated that alpha 2M with 50% trypsin saturation (fast alpha 2M) was more inhibitory in both assays than alpha 2M with no bound protease (slow alpha 2M).

Antibody-Dependent Cell Cytotoxicity↗
PubMed1985

Recognition of a chronic relapsing form of Hodgkin's disease in a population of patients demonstrating no second tumours.

Of 167 patients with Hodgkin's disease seen in a single centre between December 1972 and December 1982, only one has developed a myelodysplastic state. Between 1972 and 1977, therapy consisted of radiotherapy alone for early-stage disease, combined-modality treatment for intermediate-stage disease and chemotherapy alone using mustine, vinblastine, prednisone and procarbazine (MVPP) for advanced disease. Seventy-one per cent of these patients are disease-free at 5-10 years. From 1978, chlorambucil was substituted for mustine in the chemotherapy schedule (CLVPP). Combined-modality therapy has been used more frequently for patients with Stage III disease since 1978. Complete remission rates for patients treated with MVPP and CLVPP alone were 79% and 78%, respectively. Eight patients (5%) have been designated as a clinical subgroup of 'chronic relapsing' Hodgkin's disease. This chronic relapsing subgroup received substantially more chemotherapy than the remainder and one of these patients has developed a myelodysplastic state. Patients within the chronic relapsing group can be recognised and it is possible to obtain and maintain substantial remissions with fewer courses of chemotherapy than is currently the norm.

Adolescent↗
PubMed1985

Natural killer cell activity in childhood acute lymphoblastic leukaemia in remission.

Fifteen children with acute lymphoblastic leukaemia (ALL) in remission receiving maintenance chemotherapy and 12 ALL patients off treatment and in remission were tested for natural killer (NK) cell activity in vitro. Compared with a control population the children with ALL receiving maintenance chemotherapy had low levels of NK cell activity. This effect was not due to a specific reduction in NK cell numbers since proportions of mononuclear cells detected by the monoclonal antibodies HNK-1 (Leu-7) and Leu-11a were normal. Furthermore NK cell activity in patients could only be partially increased by pre-incubation of effector cells with interferon (alpha IFN). These studies confirm the lack of NK cell activity in children with ALL and show that this phenomenon is directly related to functional NK cell impairment. Our study has further shown that this effect is transient since ALL patients off treatment and in remission showed normal levels and augmentation of NK cell activity.

Acute Disease↗
PubMed1985

Acute lymphoblastic leukaemia in adults in the northern region of England--a study of 75 cases.

Over a ten-year period we have studied 75 cases of adult acute lymphoblastic leukaemia (ALL). Sixty of the cases were seen from 1979 to 1984 and represent an unselected series of all known cases in a region of 3 000 000 people. Study of these patients has given further insight into the heterogeneous, clinical and cytological nature of adult ALL. Three protocols have been used and results are presented indicating that conventional approaches to treatment in this disease are unsatisfactory. Not all patients could be entered on protocols but these patients are included to give the overall perspective of this disease in clinical practice. A new strategy is proposed which envisages abandoning traditional maintenance chemotherapy in favour of either allogeneic marrow transplant or autologous transplant in first remission in the post-consolidation phase. Preliminary results of this flexible approach are given.

Acute Disease↗
PubMed1985

Thyroid autoantibody synthesis by lymphocytes from different lymphoid organs: fractionation of B cells on density gradients.

Lymphocytes from thymus, blood, lymph nodes and thyroid tissue of patients with autoimmune thyroid disease have been assessed for their ability to synthesize thyroid autoantibodies spontaneously or following stimulation by Pokeweed mitogen (PWM). Blood and thymic lymphocytes synthesized IgG and microsomal or thyroglobulin antibodies of IgG class in response to PWM (and were therefore probably B-memory cells), while thyroid lymphocytes frequently secreted autoantibodies spontaneously. Lymph node lymphocytes resembled blood lymphocytes in terms of increased production of IgG in response to PWM; however, spontaneous secretion of thyroid autoantibodies was observed in some lymph node suspensions, and the magnitude of the increment in thyroid autoantibodies synthesized in response to PWM was lower than that observed for blood lymphocytes. Fractionation of B-cell enriched populations on density gradients and subsequent incubation of the fractions with T cells and PWM demonstrated that, whereas blood B cells capable of synthesizing autoantibody were found in both medium and low density fractions, lymph node precursors of thyroid autoantibody-secreting cells were associated almost exclusively with the light fractions. The presence in lymph nodes of small numbers of low density B cells, compared with a much higher proportion of the heterogeneous population capable of secreting IgG, could account for the discrepancy between the IgG and autoantibody response to PWM. Further, it seems likely that the density difference in the autoantibody precursor population of lymph nodes and blood is related to the difference in the state of activation of B cells in these lymphoid organs.

Adult↗