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Biomedical subjects

D Damiani

Publications and source records attributed to D Damiani.

At least 19 recordsLinked to original sources
PubMed1997

P-glycoprotein (PGP) and lung resistance-related protein (LRP) expression and function in leukaemic blast cells.

P-glycoprotein (PGP) lung resistance protein (LRP) and multidrug resistance associated protein (MRP) expressions and function were evaluated by flow cytometry in 65 leukaemic patients (38 acute non-lymphocytic leukaemias, eight acute lymphocytic leukaemias, 19 Ph-positive chronic myeloid leukaemias in blastic phase). By using the MRK-16, the LRP-56 and the MRPm6 MoAbs, 34% of the cases did not over-express any proteins (-); 24.5% over-expressed (+) only PGP, 11% only LRP, 1.5% only MRP, 24.5% both PGP and LRP, and 4.5% both PGP and MRP. The mean intracellular daunorubicin accumulation (IDA) and rhodamine 123 (Rh123) retention in the presence or absence of the reversal agent SDZ PSC 833 (PSC) of the PGP-/LRP-/MRP- cases were comparable to the ones observed in normal leucocytes. With respect to the non-over-expressing cases, the PGP-/LRP+/MRP- cases showed only an impaired IDA (mean 204 +/- 29; P < 0.001). The PGP+/ LRP+/MRP- cases had a defect both in IDA (mean 166 +/- 47, P < 0.001) and Rh123 retention (mean 0.42 +/- 0.14: P < 0.001), which were both corrected by PSC. All the PGP+/LRP+/MRP- cases had a defect in IDA (mean daunorubicin (DNR) accumulation 192 +/- 44; P < 0.001). However, only in 8/16 of them an evident defect in Rh123 retention was found. In conclusion, both PGP and LRP over-expression were common in leukaemia. An impaired IDA was found in all cases over-expressing PGP, LRP or both. The study of Rh123 retention could give incorrect information about the blast cells' ability to accumulate cytotoxic drugs in patients over-expressing both PGP and LRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Modulation of phosphoinositide turnover by chronic nicergoline in rat brain.

Basal and agonist-stimulated phosphoinositide (PI) turnover and inositol 1,4,5 -trisphospate (InsP3) content in rat brain were investigated after chronic nicergoline (SERMION) treatment. Oral administration of nicergoline (5 mg/kg b.i.d. for 7 weeks) enhanced the basal turnover of PI in the cerebral cortex compared to controls. This effect was paralleled by a significant rise of cortical InsP3 levels. No significant changes of noradrenaline- or carbachol-induced accumulation of [3H]-inositol-I-phophate ([3H]-InsP1) were found in cortices from nicergoline-treated rats. On the contrary, in the striatum nicergoline significantly potentiated the responsiveness of noradrenaline- and carbachol-stimulated PI turnover, leaving unchanged the basal production of [3H]-InsP1 and InsP3 levels. The results suggest that the interaction of nicergoline with PI transducing pathway might have relevance to the mechanisms of action of nicergoline.

Animals↗
PubMed1996

Primary systemic CD30 (Ki-1)-positive anaplastic large cell lymphoma of the adult: sequential intensive treatment with the F-MACHOP regimen (+/- radiotherapy) and autologous bone marrow transplantation.

Few series of adult patients with primary systemic CD30 (Ki-1)-positive anaplastic large cell lymphoma (ALCL) are reported in the literature; most of them have been treated with combination chemotherapy (CHT), with only an occasional patient being autotransplanted, mainly after relapsing. The remission rate ranges from 60% to 90%, but relapses are frequent (up to 60%) and precocious (mainly in the first 24 months). The aim of our study was to analyze the outcome of a series of adult patients affected by primary systemic ALCL that were treated at our institution with a sequential intensive therapeutic program including CHT, radiotherapy (RT), and autologous bone marrow transplantation (ABMT). Sixteen consecutive, unselected patients with ALCL were identified. All of them were treated with the 5-fluorouracil, methotrexate, cytosine arabinoside, cyclophosphamide, doxorubicin, vincristine, and prednisone (F-MACHOP) regimen; 9 of 16 (56.2%) reached a complete remission (CR). In six cases with residual mediastinal disease, involved-field RT was performed, allowing three additional patients to become free of disease. All 16 were then autotransplanted with bone marrow stem cells after conditioning with the cytosine arabinoside, etoposide, cyclophasphamide, and carmustine (BAVC) regimen. A present, 16 of 16 patients are alive and in CR. The actuarial overall survival is 100% at a median of 45.5 months, and the actuarial disease-free survival is 100% at a median of 33.5 months. These data suggest that ALCL can be successfully managed with a sequential intensive treatment (CHT +/- RT + ABMT) that prevents early relapses and projects these patients as long-term survivors.

Adolescent↗
PubMed1996

Screening for multidrug resistance in leukemia: cell reactivity to MRK-16 correlates with anthracycline retention and sensitivity of leukemic cells.

The biologic and clinical importance of the multidrug resistance (MDR) that is related with the overexpression of the P170 glycoprotein (Pgp) is widely recognized. However, a major issue that has not yet been solved is the definition of the degree of Pgp expression which is associated with a significant decrease of the sensitivity of the cells to chemotherapy. For this reason we studied the leukemic cells from 83 cases of acute leukemia. Leukemic cells were fixed in PLP and treated with saponine. Pgp expression was assayed by flow cytometry, using the anti Pgp monoclonal antibody MRK-16. Results were expressed both as the number of positive cells and by the intensity of the reaction as defined by the mean fluorescence index (MFI), i.e. the ratio between the mean fluorescence intensity of the MRK-16 incubated cells and of the IgG2a incubated cells. Thus, Pgp expression was compared with the results of two in vitro tests of cell sensitivity to anthracyclines, daunorubicin (DNR) cell retention and DNR cytotoxicity. We found that it was not the number of MRK-16 positive cells, but the degree of the reaction with MRK-16 (MFI) that significantly related to the anthracycline toxicity tests. Therefore, we propose that for clinical purposes a quick and cheap determination of Pgp-related MDR in leukemic cells may be obtained by measuring the MFI with MRK-16 in a standard flow cytometry assay and that the assay may indeed be sufficient to estimate Pgp expression as well as the influence of Pgp on cell sensitivity to anthracyclines.

Anthracyclines↗
PubMed1996

Molecular analysis of sex determination in sex-reversed and true hermaphroditism.

The SRY (sex region of Y) gene determines testis formation but not all cases of sex reversal in humans can be explained by alterations in this gene. We studied one 46,XY female, four 46,XX males, and nine true hermaphrodites (TH): three with an XY and six with an XX chromosomal constitution. The SRY gene was identified in the XX males and the TH with a Y chromosome but was not demonstrated in the XY female and the six XX TH. The Y-heterochromatin region was also identified in one 46,XX male, indicating a low grade mosaicism undetected by cytogenetics. The amplification of the amelogenin gene showed the presence of a 977-bp band that belongs to the short arm of chromosome X in all patients but the absence of a 780-bp band of the short arm of chromosome Y in three 46,XX males and in all the 46,XX TH. These studies demonstrate that the molecular study of sex-reversed patients and TH will help to understand the complex mechanisms of sex determination. The SRY gene is involved but other genes on the X chromosome and autosomes still remain to be studied.

Adolescent↗
PubMed1995

Modulation of hippocampal ACh release by chronic nicergoline treatment in freely moving young and aged rats.

The effects of nicergoline on basal and K(+)-stimulated release of ACh in the hippocampus of 3- and 19-month old rats has been studied by microdialysis. A significant decrease of basal ACh release (59%) was found in aged vehicle treated rats in comparison to young rats. High-K+ (100 mM) in the perfusate strongly increased the release of ACh by up to 6-fold over the baseline of both young and aged rats. Chronic oral administration of nicergoline to aged rats (5 mg/kg b.i.d. for 6 weeks) significantly reversed (93%) the age-related decrease of basal release of ACh, leaving the increase due to K+ depolarization unchanged. In young animals, nicergoline did not affect the basal output of ACh, but enhanced the K(+)-evoked release of ACh by 39%. Results from this study demonstrate that nicergoline treatment increases the ability of hippocampal cholinergic terminals to release ACh, and suggest that this drug can reset the cholinergic impairement associated with aging.

Acetylcholine↗
PubMed1995

The presence of lymphoid-associated antigens in adult acute myeloid leukemia is devoid of prognostic relevance.

The immunophenotype of 110 adult patients with diagnosis of acute myeloblastic leukemia (AML) was analyzed using a wide panel of monoclonal antibodies (mAbs). Leukemic blasts were tested by applying direct immunofluorescence analysis and dual-fluorescence staining, and two groups of patients were identified: 56/110 (51%) expressing only myeloid antigens (My/AML) and 54/110 (49%) expressing both myeloid and lymphoid antigens (Ly/AML). CD13 and CD33 were expressed in almost all FAB subtypes, whereas CD14, frequently expressed in M4 and M5 subtypes (70%), was rarely expressed in M0 + M1 cases (9%). On the contrary, CD34, expressed in 77% of M0 + M1 cases, was practically absent in M3 and M5 subtypes (6% and 7%, respectively). CD2 and CD7 antigens were found in 34% and 42% of patients respectively, whereas B cell-associated antigens, such as CD10 and CD19, were found in 31% and 18% of patients. Cytogenetic abnormalities characteristically present in AML patients were also analyzed and, except for t(8;21) which was found in both groups of patients, the other abnormalities were frequently found in cases coexpressing lymphoid-associated antigens. Finally, the complete remission (CR) rate, survival and event-free survival were analyzed according to the presence of lymphoid markers and also of some specific antigens such as CD7 and CD34. The only prognostic difference was represented by CD34+ patients who showed a reduction in the CR rate compared with CD34- patients (65% versus 82%) (p = 0.05) which became more evident when the mean intensity of fluorescence was considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

P170 glycoprotein expression and impaired anthracycline retention in chronic myeloid leukaemia.

Chronic myeloid leukaemia (CML) is a well known model of a disease refractory to chemotherapy, including anthracyclines and other drugs that are believed to be pumped out of the cells by a 170 Kd transmembrane glycoprotein (P170). In 35 cases of Ph+ CML we investigated the reactivity of leukaemic cells to a P170-directed monoclonal antibody (MRK-16), by means of flow cytometry. P170 overexpression was found in 4/14 (29%) chronic phase CML cases and in 16/23 (70%) accelerated and blastic phase CML cases (P = 0.01). The same cells were assayed for their ability to retain Daunorubicin and Idarubicin after 2-hours in vitro incubation with 1000 ng/ml of either drug. It was found that anthracycline cell concentration was negatively related with the degree of the reactivity to MRK-16. In accelerated and blastic phase, CML cells simultaneously expressed P170 and the stem cell related marker, CD34. These data confirm that Ph+ leukaemic cells overexpress P170, show that P170 overexpression is functionally relevant, and suggest that P170-related multidrug resistance may be an important factor for chemotherapy failure in Ph+ CML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

MDR-related P170-glycoprotein modulates cytotoxic activity of homoharringtonine.

Homoharringtonine (HHT) is a new drug with antileukemic activity which is currently tested for treatment of acute and chronic leukemias, either alone or in combination with other agents. Since HHT showed a low efficacy in refractory and relapsed acute leukemia and in the blastic phase of chronic myeloid leukemia (CML) which are frequently characterized by an overexpresion of the multidrug resistance (MDR)-related P170-glycoprotein, we postulated a relationship between the poor antileukemic effect of HHT in these leukemias and the expression of P170-glycoprotein. For this reason, sensitive (LOVO109 and CEM) and MDR (LOVO DX and CEM VLB) cell lines were exposed to HHT with or without some MDR modifiers, namely, Cyclosporine A (CyA), the Cyclosporine derivative SDZ PSC 833 (PSC), and the D-isomer of Verapamil (DVRP). It was found that MDR cells were about 15 times more resistant to HHT than non-MDR cells, and that resistance to HHT was significantly decreased by all the MDR modifiers that were tested. This in vitro study showed that HHT belongs to the category of MDR-related drugs, like anthracyclines, vinca alkaloids, epipodophylline derivatives, and taxol.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Visualization of PGP 9.5 immunoreactive nerve terminals in the mouse snout epidermis.

Intraepidermal free nerve endings were investigated in the mouse snout skin by means of an immunohistochemical procedure using a rabbit antiserum against protein gene product 9.5 (PGP 9.5). Immunoperoxidase reactivity was detected in different subtypes of intraepidermal nerves and cells. The great majority of axons observed in the stratified epithelium were varicose; a small percentage was either smooth (non-varicose) or irregularly shaped. Intraepidermal nerves ended at different levels within the epidermis, often with a terminal knob-like swelling. Various patterns of intraepidermal innervation could be distinguished. Most fibres entering the epidermis originated from large bundles running a horizontal course below the dermo-epidermal junction. Such fibres ascended vertically through the stratified epithelium in a "candelabrum-like" fashion, without emitting collaterals. Other fibres branched profusely and ended in complex intraepidermal neural networks. Less frequently, intraepidermal fibres terminated with large irregularly shaped expansions of different morphologies. Some of these were the intraepidermal continuations of axons within Meissner's corpuscles. Some fibres appeared to come into contact with PGP 9.5-immunoreactive cells (which closely resembled Merkel cells) located in the stratum basale. Rare suprabasal dendritic cells (Langerhans cells?) also became visible.

Animals↗
PubMed1994

Evaluation of the clinical relevance of the anionic glutathione-s-transferase (GST pi) and multidrug resistance (mdr-1) gene coexpression in leukemias and lymphomas.

By using RNA slot-blot technique, the frequency and the degree of GST pi and mdr-1 gene coexpression were investigated in 23 AML patients, 9 ALL, 9 CLL and 11 cases of NHL in an attempt to study their clinical and prognostic relevance. GST pi and mdr-1 levels were expressed as arbitrary units (U) with respect to the negative controls (U = 0), MCF7 and HL60 sensitive cell lines, and the positive controls (U = 10), MCF7/DOXO and HL60/DNR resistant cell lines. The concomitant GST pi/mdr-1 gene overexpression showed a negative prognostic value in the set of newly diagnosed AML pts (10 cases), furthermore higher GST pi and mdr-1 mRNA levels were averagely detected in the relapsed/resistant ALL pts (4 cases), and in CLL (7 cases) and NHL (8 cases) heavily pretreated patients who were unresponsive to chemotherapy and with a disease progression. These preliminary data show that two different mechanisms of drug resistance can be coexpressed at the same time in those leukemias and lymphomas with a clinically unfavourable course.

Adult↗
PubMed1993

D-verapamil downmodulates P170-associated resistance to doxorubicin, daunorubicin and idarubicin.

Verapamil (VRP) is an effective modulator of P170-associated multidrug resistance (MDR), but its clinical application is limited by cardiovascular side-effects. The D-isomer of VRP (D-VRP) is 10 times less active than the racemic mixture on the cardiovascular system, but retains a MDR modulating activity. Daunorubicin (DNR) and doxorubicin (DX) are two anthracyclines whose cytotoxicity is strongly related with the expression of P170, while their respective lipophylic derivatives idarubicin (IDA) and iododoxorubicin (IDX) are less P170-dependent. We studied the effect of D-VRP on intracellular retention and on the cytotoxicity of these four anthracyclines in two MDR cell systems (LOVO and CEM) by flow cytometry and by a microcultured tetrazolium colorimetric assay (MTT). We found that in MDR cells D-VRP increased intracellular anthracycline concentration and increased the cytotoxicity of DNR, IDA and DX but not of IDX. The effect of D-VRP was dose-related, but it was already consistent at D-VRP concentrations that can be readily maintained in vivo (2-3 microM). These data suggest that at a clinically tolerable concentration D-VRP can downmodulate the resistance to DNR and DX and can restore full sensitivity to IDA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

A comparative analysis of the sensitivity of multidrug resistant (MDR) and non-MDR cells to different anthracycline derivatives.

Because of the fact that tumor cell sensitivity to cytotoxic agents may play a major role in cancer treatment, and several anthracyclines are widely used for first-line treatment of leukemia, lymphoma and other tumors, and since the overexpression of the mdr-1 gene-coded 170 Kd glycoprotein (P170) decreases cell sensitivity to anthracyclines, we investigated the relationship between P170 overexpression and the cytotoxicity of two classic anthracyclines (Daunorubicin or DNR and Doxorubicin or DX) and two lipophilic anthracycline derivatives (Idarubicin or IDA and Iododoxorubicin or IDX). For these purposes, we used multidrug resistant (MDR) and non-MDR tumor and leukemia cell lines and the MTT-microcultured tetrazolium colorimetric assay. We showed that mdr-1 gene overexpression was strongly associated with the development of a high level of resistance to DNR and DX, but not to the derivatives IDA and IDX. These data suggest that more lipophilic anthracycline derivatives may also be active in MDR cell systems.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Serotoninergic fibres form dense synaptic contacts with Purkinje cells in the mouse cerebellar cortex--an immunohistochemical study.

The distribution of serotonin immunoreactivity in the mouse cerebellar cortex was studied using the indirect antibody peroxidase-antiperoxidase (PAP) technique of Sternberger (1979) on epoxy embedded semithin sections. The great majority of serotonin-positive afferents distribute throughout the Purkinje cell layer and form dense synaptic contacts with the somata of the Purkinje neurons. Only a sparse immunostaining of serotoninergic fibres could be detected at the granular cell and molecular layers. The microanatomical organization of the serotoninergic projections to the mouse cerebellar cortex is quite different from that observed in other animal species. These findings suggest that in the mouse cerebellar cortex, the Purkinje cell population represents the main target for serotoninergic afferents. Our histochemical data provide morphological support for a series of electrophysiological observations which indicate serotonin as a potential modulatory neurotransmitter for Purkinje cell firing activity.

Animals↗
PubMed1992

Overexpression of multidrug resistance-associated p170-glycoprotein in acute non-lymphocytic leukemia.

Resistance to several cytotoxic agents, including anthracyclines, vinca alkaloids and epipodophylline derivatives (multidrug resistance, or MDR) can develop in tumor cells by overexpression of a 170-kd glycoprotein (p170) which is an essential component of a membrane transport system leading to increased drug efflux and decreased intracellular drug concentration. By means of a p170-directed monoclonal antibody (MRK-16) and immunocytochemistry (alkaline phosphatase anti-alkaline phosphatase technique), we investigated the expression of p170 in marrow blast cells of 59 cases (38 at diagnosis and 21 in relapse) of acute-non-lymphocytic leukemia (ANLL). The proportion of strongly MDR-positive cells was higher in relapse that at diagnosis (median 15.5% vs 1.5%). Out of 31 patients who were evaluable for the results of first remission induction, failure of first-line treatment (including Daunorubicin, standard-dose and high-dose Arabinosyl Cytosine, and sometimes also Mitoxantrone) occurred in 8/22 MDR-positive cases and in 1/9 MDR-negative ones (p = 0.21). Failure of first-line treatment was always associated with a progressive increase of p170 expression. Total failures (no remission plus early relapse) were more frequent (p = 0.001) among MDR-positive cases (16/22) than among the others (2/9). These data show that MDR is very frequent in ANLL also at diagnosis and suggest that MDR can contribute to early failure of standard treatment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗