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Biomedical subjects

G A Currie

Publications and source records attributed to G A Currie.

At least 37 records · Page 2Linked to original sources
PubMed1978

Repopulation of gamma-irradiated Lewis lung carcinoma by malignant cells and host macrophage progenitors.

Cellular repopulation in Lewis carcinoma irradiated with 60Co gamma-rays was examined by performing sequential cell-survival estimations using an in vitro soft-agar-colony assay. Following local irradiation (15--35 Gy) two distinct types of colony were seen: compact colonies with tightly packed cells and diffuse colonies with widely dispersed cells. Maximal diffuse colony formation in vitro was only obtained in the simultaneous presence of adequate numbers of compact colonies. After whole-body irradiation only compact colonies were observed. Only-cell survival data from compact colony counts correlated with cell survival estimated by the lung colony assay and we conclude that compact colonies are produced by clonogenic tumour cells. Cytochemical and immunological evidence showed that diffuse colonies were composed of macrophages. After local irradiation the initial kill of clonogenic tumour cells was dose dependent. At each dose level, repopulation began immediately and proceeded with a doubling time of about 1 day. Macrophage colony-forming cells (macrophage progenitors) per tumour were initially reduced by about 3 decades, but recovered very rapidly to reach pretreatment levels within 2 days. We conclude that at least two populations of clonogenic cells are present in Lewis lung carcinoma, tumour cells that repopulate irradiated tumours by in situ proliferation and host-macrophage progenitors that repopulate locally irradiated tumours by infiltration. The hazards of confusing host and tumour cell colonies in in vitro assay systems are stressed.

Cell Survival↗
PubMed1978

Differential arginine dependence and the selective cytotoxic effects of activated macrophages for malignant cells in vitro.

Normal and neoplastic cells from 4 species (man, rat, mouse and hamster) were examined for their dependence on exogenous L-arginine in tissue culture. The malignant cells required a higher concentration of L-arginine in the medium than their normal counterparts (with similar doubling times) to maintain optimal proliferation. Complete arginine deprivation resulted in equal growth inhibition of normal and malignant cells, but more rapid cytolysis of the malignant cell. Deprivation of L-arginine, followed 24 h later by rescue with L-arginine, allowed normal cells to proliferate, but the reproductive capacity of the malignant cells was irreversibly impaired. Since the cytotoxic activity of LPS-activated macrophages was associated with the release of arginase and was abrogated by excess L-arginine, it is suggested that the biological basis for the selective effects of such macrophages may reside in the L-arginine dependence of the target cells.

Animals↗
PubMed1978

Monocytes and macrophages in malignant melanoma. II. Lysis of antibody-coated human erythrocytes as an assay of monocyte function.

Peripheral blood mononuclear cells will lyse antibody-treated human erythrocytes. Using Group A red cells and a hyperimmune anti-A1 serum, we have devised a microassay for the cytolytic capacity of mononuclear cell suspensions. The effector cells responsible for red-cell lysis are mononuclear, adherent and phagocytic, and their activity is blocked by aggregated IgG. Their presence correlates well with non-specific esterase-containing cells and we conclude that they are monocytes. Dose-response curves of red-cell lysis plotted against numbers of monocytes were used to derive a simple parameter expressing the number of monocytes needed to lyse 15% of the 51Cr-labelled red cells. The assay was applied to a group of 27 normal controls and 36 patients with a histologically proven diagnosis of malignant melanoma. The results indicate that monocytes from patients show significantly greater lytic activity than those from the controls. These data suggest that monocytes from cancer patients are in some way activated, and that other defects in monocyte function which have been detected in cancer patients (defective chemotaxis and maturation) may be associated with monocyte "activation".

Antibody-Dependent Cell Cytotoxicity↗
PubMed1978

Specific active immunotherapy does not prolong survival in surgically treated patients with stage IIB malignant melanoma and may promote early recurrence.

A prospective trial with concurrent controls was designed to assess the effects of specific active immunotherapy in patients receiving intermittent cytotoxic chemotherapy (DTIC + Vincristine) as an adjuvant to surgery in Stage IIB malignant melanoma. The treated group received monthly irradiated allogeneic melanoma cells and BCG, and the controls BCG only. Sixteen patients in the treatment arm had a median relapse-free interval of 5 months, compared to 8 months in 12 controls given chemotherapy and BCG, and because of this we felt that continuation of the study was unjustified on ethical grounds. Although all the controls who relapsed did so at distant sites, 7/11 patients given specific active immunotherapy relapsed initially within the lymphatic drainage area of the primary tumour. The median intervals from starting treatment to relapse at distant sites, and the median survival were identical in the 2 groups. We conclude that immunotherapy comprising irradiated allogenic melanoma cells as employed in this study does not prolong survival in surgically treated Stage IIB malignant melanoma and may even promote early, local relapse.

Adult↗
PubMed1977

Monocytes and macrophages in malignant melanoma. I. Peripheral blood macrophage precursors.

A micro-assay designed to assess the capacity of peripheral blood mononuclear cells to differentiate in vitro into mature macrophages is described. In patients with "final common pathway" malignant melanoma, there was a highly significant deficiency in macrophage precursors (MPs). By conventional morphological criteria such patients did not show a significant monocytopenia. Serum factors do not seem to contribute to the MP defect in the patients. We conclude that these patients have an intrinsic functional defect in their peripheral blood monocytes, but the mechanisms responsible for this defect are as yet unknown.

Adhesiveness↗
PubMed1977

Inhibition of leukaemia blast cell motility as a test for specific antibody in acute adult myelogenous leukaemia.

Migration studies of acute myelogenous leukaemia blast cells in autologous diagnostic and remission sera from a series of 11 patients have demonstrated two factors. A factor of less than 70 000 molecular weight appears to potentiate blast cell migration whereas the other of molecular weights 100 000-250 000 inhibits blast cell migration relative to a standard non-immune AB serum. The low molecular weight fraction was found in the serum of patients prior to relapse while the greater molecular weight fraction was possibly an IgG antibody that increased in concentration with length of remission. The inhibitory factor was found in patients following immunotherapy and in one patient who received chemotherapy alone. An inhibitory factor was also consistently found in patients in overt clinical relapse following on remission induction and maintenance therapy.

Adult↗
PubMed1976

Spontaneous shedding and antibody induced modulation of histocompatibility antigens on murine lymphomata: Correlation with metastic capacity.

The lability of cell surface histocompatibility antigens of 2 murine lymphomata was examined. These 2 tumours differ greatly in their capacity to metastasize in syngeneic hosts. Cells of the metastatic lymphoma released histocompatibility antigens in vivo and in vitro at a greater rate than cells of the non-metastasizing lymphoma. Antigen/antibody complexes formed by the addition of allo-antiserum to intact cells disappeared more rapidly from the surface of cells of the metastatic line. We propose that the instability of surface antigens may be an integral feature of malignant cells and that there may be a quantitative relationship between the lability of membrane components and the capacity of the tumour to metastasize.

Animals↗
PubMed1976

Serum lysozyme as a marker of host resistance. I. Production by macrophages resident in rat sarcomata.

With progressive growth of syngeneic sarcomata in rats there was a rise in serum levels of lysozyme which correlated with their immunogenicity and their macrophage content. By an examination of lymph/blood differences in normal and in tumour bearing rats and of the production of lysozyme by cells obtained from the tumours and maintained in vitro, it is apparent that the macrophages resident in a tumour mass make a massive contribution to the elevation in serum lysozyme concentrations. Tumour cells did not release detectable lysozyme activity. Tumour amputation led to a rapid fall in lysozyme levels. Irradiation of the host rats abolished the lysozyme response and the subsequent development of metastases in these rats was associated with a rise in serum lysozyme. The serum concentration of this enzyme reflects the macrophage content of a tumour mass and the draining lymph nodes. We conclude that under well defined conditions serum lysozyme activity may be a useful marker of macrophage mediated host responses to a tumour.

Animals↗
PubMed1976

Serum lysozyme as a marker of host resistance. II. Patients with malignant melanoma, hypernephroma or breast carcinoma.

Serum lysozyme activity was measured in groups of untreated patients with malignant melanoma, hyperneophroma and breast carcinoma. Significant elevation of serum levels of the enzyme was confined to patients with localized disease. In the presence of metastatic disease such elevation was not detected. The rise in serum lysozyme activity was not due to renal damage or any infective process and in the case of malignant melanoma was shown to be associated with infiltration of the tumour mass by macrophages. In vitro studies demonstrated that the macrophages resident in a tumour mass are responsible for relasing lysozyme in large amounts. It is proposed that the elevation of serum lysozyme in these cases may be an indicator of macrophage-mediated host resistance and that the measurement of macrophage products such as lysozyme in the extracellular fluid may under well defined conditions provide useful clinical information concerning host reactions.

Adenocarcinoma↗
PubMed1975

Activated macrophages release a factor which lyses malignant cells but not normal cells.

When rat macrophages are activated by exposure to bacterial endotoxin they acquire the capacity to lyse sarcoma cells in tissue culture. Although showing no immunological specificity this lytic effect was only detectable on malignant cells; normal cells were unaffected. This tumor-selective lytic effect is mediated by a labile supernatant product.

Animals↗
PubMed1975

Active immunotherapy as an adjunct to chemotherapy in the treatment of disseminated malignant melanoma: a pilot study.

In patients with disseminated malignant melanoma an optimal method of immunization with irradiated tumour cells was developed by reference to an in vitro assay for circulating specific serum inhibitors of cell mediated cytotoxicity. This immunization protocol consisted of the intradermal inoculation of 2 times 10(7) irradiated allogeneic melanoma cells admixed with 50 mug of percutaneous BCG. This method of immunization induced a significant but transient fall in the specific inhibitory effects of the sera on tumour directed cytotoxic activity of the patients' lymphocytes. In a pilot group of 30 patients with disseminated malignant melanoma being treated with chemotherapy (DTIC and vincristine) the immunotherapy was given midway between courses of the cytotoxic drugs. There was a correlation between the effects on circulating inhibitor and clinical outcome. The number of objective regressions occurring in this small pilot group was surprisingly high (17/30) and these clinical effects, although obtained in a series without concurrent controls, are presented for discussion. We suggest that the approach illustrated by this study, employing in vitro assays of tumour directed immune responses, may provide a suitable rational basis for the use of active immunotherapy as an adjunct to chemotherapy in the treatment of malignant disease.

Adult↗
PubMed1974

Development of specific cell-dependent antibody during growth of a syngeneic rat sarcoma.

A micro-cytotoxicity assay was adapted for the detection of cell-dependent antibodies (CDA). Using normal rat spleens as the source of effector cells such CDA activity was readily demonstrable in allo-immune sera tested on cultured sarcoma cells. The same technique was then used to examine for tumour specific antibodies in the sera of Hooded rats bearing a "non-immunogenic" syngeneic metastasizing sarcoma. During the early stages of tumour growth, at Days 7 and 14, tumour specific CDA cytotoxicity was detectable at high titres. By Day 21, however, this activity had completely disappeared from the serum. This cell-dependent cytotoxicity was tumour specific in that it did not kill cells from an unrelated syngeneic sarcoma, and the activity was probably confined to immunoglobulin G as detected by molecular weight separation techniques. Following tumour amputation at Day 21, this type of specific antibody activity rapidly re-appeared in the serum. The presence of tumour specific CDA showed an inverse correlation with the presence of specific inhibitors of cell-mediated immunity in the same sera. At no stage in tumour growth could complement-dependent cytotoxicity be detected in tumour bearing rat sera.It is concluded that cell-dependent cytotoxic activity is not associated with conventional complement dependence, that this CDA type of assay is exquisitely sensitive and is suitable for the detection of anti-TSTA antibodies in tumour bearing rats.The possible significance of CDA activity in syngeneic tumour immunity is discussed briefly. The results suggest that the role of humoral immune mechanisms in host resistance to tumour growth needs re-appraisal.

Animals↗
PubMed1973

Influence of tumour growth on the evolution of cytotoxic lymphoid cells in rats bearing a spontaneously metastasizing syngeneic fibrosarcoma.

Regional and distant lymph node cells, thoracic duct cells and peripheral blood lymphocytes from rats bearing a spontaneously metastasizing and apparently non-immunogenic sarcoma were assayed for cytotoxic activity on microcultures of tumour cells at 7, 14 and 21 days of tumour growth. In the regional lymph nodes detectable cytotoxicity was present at 7 days and the overall activity remained constant at 14 and 21 days. At Day 7 of tumour growth the cytotoxic cell population in the regional node was tumour specific in its cytotoxic effect, very radiosensitive and could not be removed by nylon wool column purification. In contrast the cells in the regional nodes at Day 21 were nonspecifically cytotoxic and could be completely removed by nylon wool treatment. In the peripheral blood, cytotoxic lymphoid cells not removed by nylon wool, were detectable at all stages of tumour growth. The thoracic duct lymph cells were, however, without cytotoxic activity throughout the period of tumour growth studied. Distant lymph node cells were assayed for cytotoxicity and it was found that they acquired significant cytocidal properties only late in tumour growth. The sera from tumour-bearing rats were tested for inhibitory activity on the cytotoxicity of Day 7 regional lymph nodes from tumour-bearing rats. It was found that a specific inhibitor appeared in the serum and that its activity increased with tumour growth. The possible contributions of the changes in lymph node cytotoxicity and the development of specific serum inhibitors to continued growth and dissemination of the tumour are discussed.

Animals↗
PubMed1973

Effect of active immunization with irradiated tumour cells on specific serum inhibitors of cell-mediated immunity in patients with disseminated cancer.

The sera from patients with advanced cancer were tested for their specific inhibitory effects on the cytotoxicity of autologous lymphocytes on tumour cells in a microculture assay. By adding a standard volume of the sera to suspensions of well-washed lymphocytes the inhibitory effect was quantitated by comparison with the effect of normal allogeneic serum. Significant levels of inhibitory activity were detected in 7 patients (one massive primary melanoma, 4 with disseminated melanoma, one with metastatic hypernephroma and one with a recurrent leiomyosarcoma). The patient with a massive primary melanoma was treated by extensive surgical excision. This procedure was associated with the rapid and complete disappearance of the serum inhibitory effect. In the other cases surgical intervention was minimal and the serum inhibitor was unaffected. All 6 of these patients were then immunized with irradiated autologous tumour cells and the serum inhibitory activity assayed. In 5 cases the serum inhibitor rapidly became undetectable after a single immunization. The one patient who failed to respond in this manner had very extensive disease and died within 2 weeks of the study. Repeated monthly immunization in the case of recurrent leiomyosarcoma was associated with the maintenance of the serum inhibitory activity at very low levels and with good clinical progress. The response to a single immunization is transient, the inhibitor becoming detectable again at 14-21 days. The possible role of circulating antigen in this serum inhibitory activity is discussed, as is the potential value of assaying the sera of cancer patients for serum inhibitory activity, as a means of monitoring the effects of treatment.

Adenocarcinoma↗