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Biomedical subjects

S Siena

Publications and source records attributed to S Siena.

At least 109 records · Page 6Linked to original sources
PubMed1987

Amantadine potentiates T lymphocyte killing by an anti-pan-T cell (CD5) ricin A-chain immunotoxin.

The studies described in this report demonstrate that 1-adamantanamine hydrochloride (amantadine) is a potent enhancer of the cytotoxic activity of the anti-pan-T lymphocyte (CD5) T101 monoclonal antibody conjugated to purified ricin A-chain (T101-immunotoxin; T101-IT). We also demonstrate that T101-IT in the presence of amantadine does not induce immunotoxin-mediated cytotoxicity in nontarget cells such as human marrow hematopoietic progenitor cells. These results provide further knowledge for the improvement of ex vivo purification of human bone marrow from normal or leukemic T cells prior to allogeneic or autologous stem cell transplantation, respectively. Furthermore, since amantadine has long been employed safely in human therapy, its use in conjunction with immunotoxins might be exploited in vivo.

Amantadine↗
PubMed1987

Specific ex-vivo depletion of human bone marrow T lymphocytes by an anti-pan-T cell (CD5) ricin A-chain immunotoxin.

We studied optimal conditions for ex vivo elimination of mature T cells from human bone marrow by T101 immunotoxin (T101-IT) with criteria applicable to graft-versus-host disease (GVHD) prophylaxis prior to allogeneic marrow transplantation. T101-IT consisted of T101 anti-CD5 monoclonal antibody conjugated to purified ricin A-chain toxin. Marrow mononuclear cells isolated by Ficoll-Hypaque or by fractionation with soybean lectin (SBA- cells) were incubated with T101-IT at 37 degrees C with or without ammonium chloride and/or verapamil as potential enhancers of immunotoxin potency. As controls, competitive inhibition studies with unconjugated T101 or irrelevant IgG2a antibody were carried out. Residual T cells were quantified by limiting dilution in phytohemagglutinin (PHA)-interleukin 2 (IL-2) feeder-cell-containing microcultures and hematopoietic progenitors by CFU-GM assay. We demonstrated that T101-IT in the range of 1-100 nM does not affect early total cell viability; that its delayed cytotoxicity is T-cell-specific, greatly enhanced by ammonium chloride, and moderately by verapamil--which also is not synergistic with ammonium chloride; and that 10 nM X 3 fractionated doses (i.e., added at 0, 1.5, and 3 hr of incubation) in the presence of 10 mM ammonium chloride for 4 hr at pH 7.8 consistently induces 2 log T cell depletion. In addition, if the same T101-IT treatment is preceded by fractionation with soybean lectin (i.e., T101-IT treatment of SBA- marrow cells), 3 log T cell depletion is accomplished. We conclude that T101-IT is highly effective in eliminating T cells from donor grafts. However, data presented here indicate that T101-IT should be associated with additional methods, such as soybean lectin fractionation, to ensure more effective ex vivo T cell depletion and acute GVHD prevention.

Ammonium Chloride↗
PubMed1987

Myeloablation with diaziquone: in vitro assessment.

UNLABELLED: The promising antineoplastic agent diaziquone is associated with prolonged aplasia and rare instances of bone marrow necrosis, but only mild extramedullary toxicity. To explore the drug's potential as a myeloablative agent prior to bone marrow transplantation, we compared its effects on hematopoietic versus marrow stromal cells. After short-term (one to six hours) or prolonged (three to seven days) exposure to the drug, marrow was assayed for hematopoietic (CFU-Mix, BFU-E, CFU-GM) and stromal (CFU-F) colony-forming cells and studied in long-term marrow culture (LTMC). One- and three-hour treatments produced little cytotoxicity, even at 5000 ng/mL. After six-hour treatments with this dose, marrow was depleted of CFU-Mix, BFU-E, and CFU-GM, but produced CFU-GM in LTMCs, indicating an ongoing input of CFU-GM from a surviving pre-CFU-Mix population. In contrast, elimination of the latter may be inferred from the absence of CFU-GM in LTMCs exposed for three to seven days to diaziquone at only 150 ng/mL. Under these conditions, CFU-F recovery was 40% and adherent stromal layers in LTMCs were similar to untreated controls regarding rate of development and cellular composition. Our in vitro pre-CFU-Mix-ablative regimen correlates with clinical data that show prolonged but reversible myelosuppression at steady-state diaziquone plasma levels of 101 +/- 10 ng/mL (mean +/- standard error of mean) during 7-day constant infusions. IN CONCLUSION: hematopoietic cells are more sensitive than marrow stromal cells to the dose- and highly time-dependent cytotoxicity of diaziquone, a direct drug-induced noxious effect on the marrow microenvironment is an unlikely cause of the isolated episodes of marrow necrosis after the use of diaziquone in vivo, and prolonged infusion of diaziquone represents an attractive means for achieving myeloablation in selected clinical situations.

Aziridines↗
PubMed1985

Effects of in vitro purging with 4-hydroperoxycyclophosphamide on the hematopoietic and microenvironmental elements of human bone marrow.

UNLABELLED: We describe the effects of 4-hydroperoxycyclophosphamide (4-HC) on the hematopoietic and stromal elements of human bone marrow. Marrow cells were exposed to 4-HC and then assayed for mixed (CFU-Mix), erythroid (BFU-E), granulomonocytic (CFU-GM), and marrow fibroblast (CFU-F) colony-forming cells and studied in the long-term marrow culture (LTMC) system. The inhibition of colony formation by 4-HC was dose and cell-concentration dependent. The cell most sensitive to 4-HC was CFU-Mix (ID50 31 mumol/L) followed by BFU-E (ID50 41 mumol/L), CFU-GM (ID50 89 mumol/L), and CFU-F (ID50 235 mumol/L). In LTMC, a dose-related inhibition of CFU-GM production was noted. Marrows treated with 300 mumol/L 4-HC were completely depleted of CFU-GM but were able to generate these progenitors in LTMC. Marrow stromal progenitors giving rise to stromal layers in LTMC, although less sensitive to 4-HC cytotoxicity, were damaged by 4-HC also in a dose-related manner. Marrows treated with 4-HC up to 300 mumol/L, gave rise to stromal layers composed of fibroblasts, endothelial cells, adipocytes, and macrophages. Cocultivation experiments with freshly isolated autologous hematopoietic cells showed that stromal layers derived from 4-HC-treated marrows were capable of sustaining the long-term production of CFU-GM as well as controls. IN CONCLUSION: (1) Hematopoietic progenitors cells, CFU-Mix, BFU-E, and CFU-GM, are highly sensitive to 4-HC, whereas marrow stromal progenitor cells are relatively resistant. (2) Marrows treated with 300 mumol/L 4-HC that are depleted of CFU-Mix, BFU-E, and CFU-GM can generate CFU-GM in LTMC, suggesting that most primitive hematopoietic stem cells (not represented by CFU-Mix) are spared by 4-HC up to this dose. (3) Consequently, the above colony assays are not suitable tools for predicting pluripotent stem cell survival after 4-HC treatment in vitro.

Bone Marrow↗
PubMed1982

Cell-mediated immunity in children with chronic cholestasis.

Cell-mediated immune response was evaluated in 14 children with long-lasting intra- or extrahepatic cholestasis. Cell-mediated immunity was clearly depressed in children with intrahepatic cholestasis while children with extrahepatic biliary obstruction had a more modest and variable degree of impairment. This finding may be related to the longer duration of cholestasis and the higher total bile acid level in the intrahepatic compared to the extrahepatic group. In particular, in children with Byler disease, long-lasting, severe intrahepatic cholestasis was associated with depressed cell-mediated immunity and recurrent severe infections.

Adolescent↗
PubMed1982

Colostral T lymphocytes detected by intracytoplasmic and membrane markers.

Colostral lymphocytes were studied using two established T-cell markers: intracytoplasmic alpha-naphtyl-acetate esterase (ANAE) staining and membrane receptors for sheep erythrocytes (E rosettes). ANAE staining allowed counting and identification of T-cell subsets independently of the status of membrane structures and receptors frequently altered in colostral cells. The fact that a sizeable number of colostral lymphocytes had the same phenotype as the majority of mature circulating peripheral blood lymphocytes supports the hypothesis that colostral lymphocytes may play a role in protecting neonates against infections, in transferring immune information to the newborn, or in modulating the immune response via release of soluble factors. A considerable percentage of colostral T lymphocytes are ANAE-negative. This phenotype is similar to that observed among thymocytes.

Carboxylic Ester Hydrolases↗
PubMed1981

Receptors for peanut agglutinin on a high percentage of human cord-blood lymphocytes: phenotype characterization of peanut-positive cells.

The results of this study show that a high percentage of human cord-blood lymphocytes bears receptors for peanut agglutinin. Determination of the presence of other lymphocyte markers (E rosettes, membrane immunoglobulins, alpha-naphthyl-acetate esterase, Ia antigens) in the peanut-positive cells indicated that they include both T and B cells. The peanut receptor, also expressed by blast cells of most acute, but not chronic, leukemias, seems to be a marker of immaturity for both T- and B-lymphocyte subsets in man as it is in the mouse.

Aging↗
PubMed1981

Multiple serum inhibitors of lectin-induced lymphocyte proliferation in nephrotic syndrome.

Inhibitory activity on PHA- and Con A-induced lymphocyte proliferation was observed in the serum of 29 patients with nephrotic syndrome (NS); this inhibitory activity was present both in steroid-sensitive nephrotic syndrome (SSNS; 18 patients) and in NS due to other glomerulopathies (11 patients). In order to characterize the inhibitory activity, peripheral blood lymphocytes from normal donors were stimulated with various concentrations of Con A in culture medium supplemented with: (1) 20% SSNS serum, (2) various concentrations (1, 5 and 20%) of either SSNS serum or normal human serum (NHS) and (3) 20% of a serum prepared by mixing different proportions of SSNS and NHS. The results suggest that the inhibitory activity is due to at least two different factors: (a) inhibitor(s) acting competitively with the lectin Con A, and (b) inhibitor(s) neutralized by factor(s) present in NHS. A disturbance in the normal equilibrium between inhibiting and enhancing factors which results in overall inhibition might well be a consequence of the marked alteration in serum proteins characteristic of NS.

Adolescent↗
PubMedDate not supplied

Rapid and complete hemopoietic reconstitution following combined transplantation of autologous blood and bone marrow cells. A changing role for high dose chemo-radiotherapy?

The role of high dose chemo-radiotherapy with autologous bone marrow transplantation in the treatment of neoplasia remains to be clearly defined. Because of the iatrogenic morbidity, mortality and high cost of the supportive care required during the post-transplantation period of prolonged marrow aplasia, intensive therapy remains a sophisticated procedure lacking proper evaluation in clinical trials. We report here that when autologous bone marrow cells are supplemented with a small number of peripheral blood nucleated cells collected after prior myelosuppressive chemotherapy, complete hematological recovery is so prompt that myeloid toxicity appears no longer the major limiting factor of high-dose chemo-radiotherapy. The increased therapeutic index made possible by the procedure will allow us to address the issue of whether intensive cytoreductive therapy can be useful as initial treatment of selected tumors with curative intent.

Adolescent↗
PubMedDate not supplied

Mobilization of peripheral blood progenitor cells for autografting: chemotherapy and G-CSF or GM-CSF.

The mobilization of haematopoietic progenitor cells is a multifactorial process, still poorly understood at the molecular level. Mobilized haematopoietic progenitors, as defined by the expression of CD34 cell surface molecule, comprise heterogeneous subpopulations of cells committed to different haematopoietic lineages. Haematopoietic progenitors may be mobilized by chemotherapy alone, haematopoietic growth factors alone, or by chemotherapy plus haematopoietic growth factors. The choice of a mobilization regimen that allows an optimal yield of progenitors with a minimum number of leukaphereses should incorporate, in most patients, a disease-specific chemotherapeutic agent(s) plus a haematopoietic growth factor, to be continued until completion of harvest.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Pathophysiology, clinical manifestations and supportive care of metastatic brain cancer.

Brain metastases (BrM) are tumours that originate in tissues outside the central nervous system and spread secondarily to involve mainly the brain. The management of patients with cerebral metastases is complex, costly, and in some instances controversial. Furthermore, even in patients with widespread systemic cancer, the symptoms of the disease are often controllable while the symptoms of the BrM may be disabling. The treatment of BrM is one of the few areas of neuro-oncology where real progress has been made in the last twenty years. Moreover, the costs of managing this disease are rising, as therapies become more intensive and the number of patients with BrM increases. Modern neuroradiological imaging techniques, which are able to discover BrM earlier in the course of systemic cancer, and the greater efficacy of specific treatments, which lengthens survival, have increased the prevalence. The aggressive treatment of BrM may add some benefits to the patient, but its excessive cost leads to the necessity for accurate cost-effectiveness analysis. The latter begins with a complete understanding of the disease: its diagnosis, natural history and results of various modalities of treatment. While the development of BrM usually indicates a poor prognosis for the patient, advances in supportive care have made it possible to reverse most of the neurological symptoms and to give patients a meaningful extension of useful life.

Brain Neoplasms↗
PubMedDate not supplied

Controversies in the management of brain metastases: the role of chemotherapy.

The role of chemotherapy (CT) for brain metastases (BrM) is still controversial. Limited life expectancy and presence of the blood-brain barrier (BBB) have been considered as contraindications for relatively aggressive therapies, such as CT. Nevertheless, more recent studies emphasise the possibility that in addition to historical nitrosoureas, also platinum derivatives, etoposide, teniposide, gemcitabine, irinotecan, topotecan and temozolomide can pass the BBB as they are active against selected BrM. Interaction of cytotoxic agents with other drugs may represent a problem in the treatment of BrM. By far, the most important factor conditioning the response to cytotoxic agents is the chemosensitivity of different tumours. CT proved to be effective in patients with BrM from lung cancer, mainly small cell lung cancer, breast cancer, choriocarcinoma and germ cell tumours. In these malignancies the responses to CT are similar to those observed in other metastatic sites. This observation, confirmed by many studies, contrasts with the theory, emphasised in the past, of the brain as a sanctuary. In fact BBB may be important in protecting normal brain tissue and micrometastases from CT, but not when BrM are symptomatic and clinically evident. The clue to the treatment of chemosensitive tumours is to assess the most active drugs and combinations. Cisplatin and etoposide was confirmed to be the treatment of choice in many situations (BrM from lung and also from breast cancer). Newer drugs are now on study: topotecan and temozolomide seem to be particularly promising (alone or in association with other drugs) in the treatment of various BrM (also from melanoma) and could represent an alternative to more widely-used drugs or as second-line treatments.

Antineoplastic Combined Chemotherapy Protocols↗