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Biomedical subjects

D Morelli

Publications and source records attributed to D Morelli.

At least 37 records · Page 2Linked to original sources
PubMed1996

Tumor-necrosis-factor-induced fibroblast growth factor-1 acts as a survival factor in a transformed endothelial cell line.

Endothelial cells undergo apoptosis after withdrawal of growth factors, alterations in the extracellular matrix, or exposure to cytokines. Here we report that tumor necrosis factor (TNF)-alpha induces apoptosis of human endothelial cells derived from the umbilical vein in a dose-dependent fashion. Apoptosis is triggered through a pathway that is independent from the levels of Bcl-2. On the contrary, TNF stimulates the growth of spontaneously transformed human umbilical vein endothelial cells. This proliferative effect is mediated through the up-regulation of fibroblast growth factor-1 by TNF. The addition of specific fibroblast growth factor-1 antisense oligonucleotides inhibits TNF-induced fibroblast growth factor-1 expression, thus inhibiting the growth and triggering apoptosis of spontaneously transformed human umbilical vein endothelial cells.

Apoptosis↗
PubMed1996

Apoptosis of hair follicle cells during doxorubicin-induced alopecia in rats.

Alopecia is a common side effect of cancer chemotherapy, and to date, little progress has been made in alopecia prevention or treatment. The present studies were undertaken to topographically localize the site of injury in the hair follicle after doxorubicin (DXR) administration and to investigate the mechanism of DXR-induced alopecia. Tissue samples of head and proximal neck skin obtained from newborn rats treated with DXR were histologically examined by light and electron microscopy and stained by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. Light microscopy revealed pyknotic cells in the matrix and in the upper bulb and a decrease in the number of mitotic cells. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling analysis evidenced cells with nuclear staining indicative of apoptosis, as confirmed by ultrastructural analysis. Kinetics studies indicated that even a single DXR treatment induced apoptosis and a decrease in mitotically active cells. Our data show that DXR treatment induces injury in a cell subset localized in the hair matrix. The successful prevention of drug-induced alopecia in patients may depend on the selective protection of these cells of the hair follicle.

Alopecia↗
PubMed1996

Differential sensitivity to non-major histocompatibility complex-restricted recombinant interleukin 2-activated lymphocyte killing of human mammary epithelial MCF-10A cells overexpressing oncogenes or protein kinase A subunits.

The sensitivity of human tumor cells to activated lymphocytes is considered to play an essential role in the antitumor activity of recombinant interleukin-2 (rIL-2)-based immunotherapy. We have investigated the effects of several genes involved in the regulation of cell growth and transformation on the sensitivity of human mammary epithelial MCF-10A cells to non-MHC-restricted, rIL-2-activated lymphocytes. Therefore, the lysability of MCF-10A cells overexpressing activated oncogenes (Ha-ras, erbB-2, and a mutated p53), growth factors [transforming growth factor alpha (TGFalpha)], or cAMP-dependent protein kinase A subunits (RIalpha, RIIbeta, and Calpha) was evaluated comparatively at different effector:target ratios by a 51Cr release assay. Parental MCF-10A, MCF-10A p53-mutated, and MCF-10A RIIbeta cells showed an intermediate sensitivity. Lysability was increased significantly in MCF-10A Ha-ras, MCF-10A TGFalpha, and MCF-10A RIalpha cells, reduced in MCF-10A Calpha cells, and completely abrogated in MCF-10A erbB-2 cells. These differences could not be explained by simple changes in the cell surface expression of MHC class I and intercellular adhesion molecule-1 proteins or by secretion of TGFbeta. Treatment with TAb 250, a mouse anti-p185(erbB-2) monoclonal antibody, or down-regulation of p185(erbB-2) expression resulted in circumvention of MCF-10A erbB-2 cell resistance. We conclude that molecular changes at the single-gene level resulting in alterations of intracellular signaling and/or cell transformation modulate sensitivity of human mammary epithelial cells to non-MHC-restricted, rIL-2-induced cytotoxicity, regardless of MHC class I and/or intercellular adhesion molecule-1 expression or TGFbeta secretion. Furthermore, anti-p185(erbB-2) monoclonal antibodies may be useful as adjuncts to rIL-2 treatment in patients with erbB-2-overexpressing tumors.

Animals↗
PubMed1995

A monoclonal antibody extends the half-life of an anti-HIV oligodeoxynucleotide and targets it to CD4+ cells.

An approach was sought to increase the half-life and target cell specificity of antisense oligodeoxynucleotides (oligos). A monoclonal antibody (MAb) was derived from mice immunised with an oligo complementary to a region (1-20) of the HIV genome. This MAb exerts a protective effect on the oligo from the degradation induced by plasma exonucleases in vitro and in vivo. Moreover the anti-oligo MAb dissociates from the oligo in the presence of its complementary sequence to allow hybridization of the two complementary strands. To direct the oligo to CD4+ cells the anti-oligo MAb was cross-linked to an anti-CD4 MAb. The heteroaggregate determines a 5-fold increase in the cellular membrane binding of the oligo to CD4+ lymphocytes. These findings suggest a new approach to enhancing the therapeutic action and the target specificity of antisense oligodeoxynucleotides useful for the selective inhibition of HIV replication in vivo.

Animals↗
PubMed1995

The differential response to interferon gamma by normal and transformed endothelial cells.

Interferon gamma, a multifunctional cytokine secreted by activated T lymphocytes and NK cells, induces normal endothelial cell apoptosis which is inhibited by the activation of protein kinase C. Interestingly, interferon exerts a dual effect on transformed endothelial cell proliferation: at low concentrations it stimulates their growth, while at high concentrations it exerts an inhibitory effect. The different response of normal and transformed endothelial cells correlates with the levels of interferon receptor: when expressed at high levels--such as in normal cells--interferon promotes apoptosis; on the contrary, when cells possess a low number of receptors--such as transformed cells--the cytokine promotes cell growth. Since interferon induces it own receptor, we anticipate that transformed cells exposed to high doses of interferon may upregulate the receptor and, consequently, respond to the cytokine with a reduction in cell viability.

Apoptosis↗
PubMed1994

Modulation of drug-induced cytotoxicity by a bispecific monoclonal antibody that recognizes the epidermal growth factor receptor and doxorubicin.

A hybrid hybridoma secreting a bispecific hybrid mAb (bsmAb), which recognizes both the epidermal growth factor receptor (EGF-R) and the drug doxorubicin, was produced by somatic hybridization of two hybridomas. The bsmAb obtained was able to retarget doxorubicin cytotoxicity in vitro specifically on EGF-R-positive cells exerting at the same time an antidotal effect on cells that did not overexpress the EGF-R. Distribution studies in mice indicate that the bsmAb selectively delivers the drug to tumour cells and modifies doxorubicin biodistribution with a statistically significant decrease of drug concentration in the intestine, which is the main target of early anthracycline toxicity. In keeping with this finding is the remarkable antidotal activity exerted by bsmAb in mice treated with doxorubicin, which is proved by retardation in loss of body weight and mortality. The effectiveness on tumour growth of the mAb followed by the administration of doxorubicin appears to be equal to that of the drug alone; however, the bsmAb exerts a remarkable antidotal activity.

Animals↗
PubMed1994

Effect of a bifunctional monoclonal antibody directed against a tumor marker and doxorubicin on the growth of epidermoid vulvar carcinoma grafted in athymic mice.

Even though the first monoclonal antibodies (MAbs) directed against tumor cells were produced 15 yr ago, the therapeutic application of immunoconjugates is still at the beginning. This is principally because of the enormous work that is required for the development of completely new therapeutic tools. An alternative could be to only use MAbs to improve conventional treatment such as chemotherapy. To this aim, a MAb directed against doxorubicin (DXR) was produced. DXR is an anthracycline antibiotic of which the clinical usefulness in cancer chemotherapy is limited by serious side effects, such as cardiomyopathy, bone marrow depression, and gastrointestinal tract mucositis. This toxicity was found to be reduced by treatment with the antidrug MAb, as shown by reduction in body weight loss and mortality of experimental mice. To improve the DXR therapeutic index, a bifunctional hybrid MAb (DOXER2), capable of simultaneously recognizing DXR and the epidermal growth factor (EGF) receptor, was produced. This reagent was found in vitro to increase the drug toxicity on the epidermoid carcinoma cell line A431, which overexpresses the EGF-R and, at the same time, to reduce DXR cytotoxicity on EGF-R negative cells. The effect of DOXER2 on the DXR biodistribution in vivo was also investigated. In mice previously injected ip with the DOXER2, the uptake of the drug, in comparison to the control group, was found to be reduced in the intestine and in myocardial tissue, and significantly increased in the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Protection against doxorubicin-induced alopecia in rats by liposome-entrapped monoclonal antibodies.

Alopecia is a common side effect of several anti-cancer drugs, including doxorubicin. Based on our recent observation that a monoclonal antibody (MAD11) directed against this anthracycline inhibits the systemic toxic effect of the drug in mice, we investigated the possibility that MAD11 administered topically might protect against doxorubicin-induced alopecia. In 31 of 45 young rats treated intraperitoneally with doxorubicin, alopecia was completely prevented by topical treatment of the skin with liposome-incorporated anti-doxorubicin monoclonal antibody. This type of treatment might find relevance in preventing anthracycline-induced alopecia in cancer patients. Our findings also provide the first demonstration that liposome-entrapped monoclonal antibodies are capable of penetrating the stratum corneum of the skin without losing their function.

Alopecia↗
PubMed1994

Relevance of antibody valency in EGF receptor modulation.

Binding characteristics of a monovalent bispecific monoclonal antibody (bsMoAb), which recognizes both epidermal growth factor receptor (EGF-R) and drug doxorubicin (DXR) were compared with those of the parental bivalent MoAb directed against the EGF-R binding site. Scatchard analysis indicated that both MoAbs bound to EGF-R-overexpressing A431 cells with the same affinity. In tracer amounts, both MoAbs also displayed the same capacity to be internalized after binding to the cell surface. However, when the MoAbs were used at saturating concentrations, down-modulation of the receptor was greater with the bivalent MoAb. The bivalent MoAb also inhibited proliferation of A431 cells both in vitro and in vivo whereas the bsMoAb was inhibitory only in vivo. These data suggest that MoAb bivalency is required for EGF-R down-modulation and in vitro cell growth inhibition.

Animals↗
PubMed1993

Purification of interleukin-2 antibodies from healthy individuals.

By covalent binding of recombinant interleukin-2 (rIL-2) to Sepharose, it was possible to immunopurify specific human anti-IL-2 antibodies from a pool of immunoglobulins obtained from healthy subjects. Since low quantities of the ligand released by the matrix could interfere with the evaluation of the biological activity of anti-IL-2 antibodies, the antibody preparation was subjected to pepsin digestion which is known to destroy the IL-2 molecule. Purified human anti-IL-2 antibodies were found to be mostly IgG1 and able to neutralize IL-2 induced peripheral blood lymphocytes (PBL) proliferation in vitro. The availability of purified anti-IL-2 antibodies, obtained from healthy individuals, able to modulate IL-2 activity, could be important in several therapeutic approaches.

Blotting, Western↗
PubMed1993

The detection and biological activity of human antibodies to IL-2 in normal donors.

Antibodies to interleukin-2 (IL-2) have been reported in the sera of patients under therapies involving this cytokine and in the sera of patients infected with human immunodeficiency virus (HIV). Our study proves that auto-antibodies to IL-2 are present also, at a lower titre, in healthy individuals. These antibodies were affinity purified and studied for their capability to interfere with the in vitro biological activity of IL-2. Data obtained show that human anti-IL-2 antibodies can interfere with lymphocyte proliferation both in the lymphokine activated killer (LAK) cell assay and in the mixed lymphocyte reaction (MLR). However, the kinetics of inhibition by anti-IL-2 antibodies differs from LAK cell assay to MLR as the former are always inhibited in a time-independent manner, and the latter only by adding antibodies at the outset of culture. The neutralizing activity observed in vitro suggests that such antibodies play a part in the elaborate cytokine network by which the immune system regulates the amplitude and duration of its response.

Autoantibodies↗
PubMed1993

The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage.

A molecule that is immunologically related to the c-erbB-2 oncogene product (p185HER2/neu) was detected in the conditioned culture medium from neu-overexpressing tumor cell lines and in sera of advanced-stage breast carcinoma patients. Using a sensitive (in the range of 0.5 ng ml-1) double-determinant radioimmunoassay (DDIRMA) with two monoclonal antibodies (MAbs) directed against the neu extracellular domain (ECD), soluble oncoproteins were detected in supernatants from several neu-positive tumor cell lines, independent of the levels of membrane p185HER2 expression. The molecule detected did not react with a MAb directed against an intracytoplasmic epitope of the p185HER2. Western blot analysis of the concentrated supernatant revealed a protein of approximately 110 kDa molecular mass, which closely matches the predicted size of the glycosylated p185HER2 ECD. Immunoprecipitation of culture supernatant from cell surface-radioiodinated cells confirmed the 110 kDa molecular mass of the glycosylated shed protein, which migrated to 86 kDa after deglycosylation. Proteolytic cleavage of the p185HER2 molecule was demonstrated in release assays carried out with protease inhibitors. The combined use of leupeptin and EDTA completely inhibited release of the molecule. Analysis of sera from breast carcinoma patients and healthy donors by DDIRMA revealed the presence of soluble neu in 15% of pathologic sera but none of the normal sera. A good correlation was found between neu-overexpression in the primary tumor and the soluble marker in serum of patients with advanced disease; sera of early-stage patients were always negative, independent of neu-overexpression in the tumor. These results suggest the usefulness of soluble neu as an indicator of tumor aggressiveness but not as a diagnostic marker of breast cancer.

Biomarkers, Tumor↗
PubMed1993

Protection by N-acetylcysteine against pulmonary endothelial cell damage induced by oxidant injury.

The protective effect of N-acetylcysteine (NAC) against oxidant lung injury was investigated in a model of acute immunological alveolitis in the rat. Intrapulmonary immune complex deposition into rat lungs, induced by intratracheal infusion of immunoglobulin G (IgG) anti-bovine serum albumin (BSA) antibodies and intravenous injection of the antigen, caused lung damage associated with a marked decrease in [14C]5-hydroxytryptamine ([14C]5HT) uptake capacity, taken as a biochemical marker of endothelial cell function. The oral administration of a single dose of NAC (2 mmol.kg-1) 60 min before antigen/antibody (Ag/Ab) treatment was effective in preventing pulmonary endothelial cell [14C]5HT uptake loss induced by immune complex deposition. The mechanisms involved in this lung protective action of NAC were investigated by studying the antioxidant activity of NAC on hypoxanthine/xanthine oxidase-induced lung damage in vitro, and the effectiveness of the drug as lung glutathione (reduced form) (GSH) precursor in diethylmaleate-depleted rats. The results obtained provide further evidence on the ability of NAC to reduce the susceptibility of lung tissue to free radical-induced damage, by potentiating the antioxidant defence systems.

Acetylcysteine↗
PubMed1992

An anti-doxorubicin monoclonal antibody modulates kinetic and dynamic characteristics of the drug.

A monoclonal antibody (MAb) directed against doxorubicin (DXR), denominated MAD II, was found to exert an antidotal action by modulating the kinetic and dynamic characteristics of the drug. In vitro, MAD II has been found to reduce the cytotoxicity of DXR and the drug uptake on spleen lymphocytes more efficiently than on tumor cells (P388 leukemia cells). In vivo, the anti-DXR MAb modified the drug distribution; the drug uptake was found to be reduced in the intestine and myocardial tissues and increased in the tumor, liver and spleen. In mice treated with DXR, the administration of anti-DXR MAb exerted an antidotal activity which was proved by the reduction in body-weight loss and mortality. In contrast, the therapeutic efficacy of the drug in P388-tumor-bearing mice was not influenced by the anti-DXR MAb.

Animals↗
PubMed1992

Sample medication dispensing in a residency practice.

BACKGROUND: The distribution of sample medications to physicians by pharmaceutical manufacturers has been regulated by Congress and extensively critiqued in the medical literature. Manufacturers distributed 2.4 billion samples in 1988, yet there are no published reports on the clinical use of sample medications. METHODS: A 4-week descriptive study was conducted that catalogued the contents of a sample medication collection in a family practice residency model office, calculated the value of the sample collection (average wholesale price [AWP]), and monitored dispensing of medication samples. RESULTS: The collection initially contained 5546 samples with an AWP of $19,273. A total of 1012 samples worth $4154 was withdrawn from the collection during the study period. Patients received 548 of the sample packages in 105 dispensements ($2583), physicians or their families received 169 samples in 44 dispensements ($603), others received 26 samples in 6 dispensements ($152), and the destination of 269 samples ($816) was unknown. When a prescription was written at the time that a sample was dispensed, it was almost always for the same brand-name medication. CONCLUSIONS: Although a majority of medications dispensed were given to patients, approximately one third of the value of the medications withdrawn either went to physicians and their families or had an unknown destination. The high association of sample dispensing and simultaneous prescribing of the same brand-name drug supports the contention that sampling influences physician-prescribing habits. Further research should define how the availability of free sample medications affects physician-prescribing practices.

Adult↗
PubMed1988

Monoclonal antibodies against doxorubicin.

Hybridomas which secrete monoclonal antibodies (MAbs) reacting with doxorubicin (DXR), a widely used anthracycline cytotoxic antibiotic, have been obtained by fusing NSO/P3 mouse myeloma cells with spleen cells from BALB/c mice immunized with DXR-BSA conjugate. The best producer among the several clones obtained was expanded and the secreted MAb (MAD2) purified and characterized. MAD2 cross-reacts to varying degrees with anthracycline compounds such as some DXR analogues and derivatives, but does not recognize anthracene and anthraquinone structures, with the exception of weakly reacting Mitoxantrone. MAD2 and the panel of MAbs which are at present being purified may become a tool for studying the relevance of different domains of the anthracyclin molecule in terms of biologic activity.

Animals↗
PubMed1988

[Elements for an analysis of psychosocial indicators and psychological intervention in heart transplantation].

It is now accepted that cardiac transplantation is a viable therapeutic alternative for patients with end-stage heart disease. The most recent data offer a favourable short and medium term prognosis. Retrospective studies suggest that transplantation is associated with a good quality of life and tolerance of the side effects of the medication. Even if cardiac transplantation does not appear to be associated with serious psychological morbidity, it is important to assess the recipient's anxiety, depression, body image and his subjective quality of life, including satisfaction with his family and marital life, to prevent postoperative psychologic distress and enhance the patient's coping abilities. The family is the patient's chief buffer against stress but it is also under stress and needs to be aided through this process. The psychosocial themes that appear prominently at the different stages of the transplant process are somewhat predictable. These can be used to help the patient and family anticipate stress and deal with these issues in a way that enhances mastery of a difficult situation. The heart transplant team faces difficult ethical issues regarding patient selection and informed consent. Public input on these issues is needed, especially since more patients elect to receive heart transplants and the donor supply is likely to remain the same, thereby making donor hearts less available to those who could derive benefit from them.

Family↗