Biomedical subjects

D Damiani

Publications and source records attributed to D Damiani.

115 records · Page 7Linked to original sources

PubMedDate not supplied

Expression of multidrug resistance gene (MDR-1) in human normal leukocytes.

BACKGROUND: The mdr-1 gene, which codes for a 170-kd transmembrane glycoprotein (P170), is frequently overexpressed in multidrug resistant (MDR) tumor cell lines and in spontaneous tumors, including leukemia and lymphoma. However, it is also constitutively expressed as a normal gene in normal tissues. METHODS: We used human mdr-1 cDNA and three anti-P170 monoclonal antibodies (MoAbs: MRK-16, C-219 and JSB-1) to investigate the normal peripheral blood leukocyte content of mdr-1 specific mRNA and of P170 through immunocytochemistry and flow cytometry. RESULTS: We did not find any increase in mdr-1-specific mRNA, while small amounts of P170 were easily detectable in about two thirds of the lymphocytes and monocytes and in about one third of the granulocytes. The level of P170 expression in leukocytes was similar to that found in non-MDR tumor cell lines. CONCLUSIONS: mdr-1 is constitutively expressed in human normal leukocytes at levels that cannot significantly affect drug resistance. Accordingly, low-level mdr-1 expression in leukemic cells should not be considered a label of pleiotropic drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Plasma cell P170 expression and response to treatment in multiple myeloma.

BACKGROUND: Vincristine and anthracyclines are first-line agents for the treatment of multiple myeloma (MM). P170-related multidrug resistance (MDR) may influence the response to these drugs. MATERIALS AND METHODS: P170 expression of bone marrow plasma cells was assayed by immunocytochemistry (alkaline phosphatase anti-alkaline phosphatase technique) with the MRK-16 monoclonal antibody. A case was considered positive if one per cent or more of plasma cells stained as strongly as positive controls. RESULTS: Six of 17 (35%) cases in relapse and 18/72 (25%) at diagnosis were MDR positive. MDR positivity was not found in micromolecular MM and was significantly associated with the serum beta 2-microglobulin level. Response to treatments including dexamethasone, vincristine and doxorubicin, or idarubicin, or mitoxantrone was independent of MDR positivity (50% in positive cases vs. 56% in negative ones). CONCLUSIONS: The detection of P170 in bone marrow plasma cells with the currently available methodology is not likely to predict response to treatments that include vincristine, anthracyclines or mitoxantrone. Further studies are required to evaluate the relevance of P170-related MDR to the development of MM therapy.

Adult↗

PubMedDate not supplied

Overcoming PGP-related multidrug resistance. The cyclosporine derivative SDZ PSC 833 can abolish the resistance to methoxy-morpholynil-doxorubicin.

BACKGROUND: The results obtained so far in studies designed to neutralize P glycoprotein (PGP)-related multidrug resistance (MDR) by using MDR reversal agents, have not yet fulfilled the promise of the experiments which were performed in vitro. In order to improve PGP-related MDR neutralization, we tested in vitro the activity of the cyclosporine derivative SDZ PSC 833 (PSC) together with doxorubicin (DOX) and with two new DOX derivatives named 4' iodo 4' deoxy-doxorubicin (IODODOX) and methoxy-morpholynil-doxorubicin (MMDOX, FCE 23762) using four different human cell lines and their multi-drug resistant variants. METHODS: Anthracycline toxicity was evaluated by using the MTT method after a 7-day culture with continuous exposure to the antitumor drugs with or without the addition of PSC. RESULTS: PSC significantly downmodulated the toxicity of all three anthracyclines in all the four cell systems. However, despite the great increase caused by PSC in the toxicity of DOX and a more modest effect on the toxicity of the two DOX derivatives, this MDR reversal agent could only completely block the PGP mediated MMDOX resistance whereas DOX refractoriness was only decreased. CONCLUSIONS: The combination of MMDOX or IODODOX with PSC 1.6 microM is more efficient than the combination of DOX plus PSC for the full reversion of PGP-mediated drug resistance. Careful clinical studies are required to evaluate if these associations can also effectively and safely neutralize MDR in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

The F-MACHOP regimen in the treatment of aggressive non-Hodgkin's lymphomas: a single center experience in 72 patients.

BACKGROUND: Since July 1991 we have employed the F-MACHOP regimen for the treatment of aggressive non-Hodgkin's lymphomas (NHL). The aim of the present study was to evaluate the response rate and the toxicity of this chemotherapy program. PATIENTS AND METHODS: Seventy-two consecutive patients entered the study and were treated with the F-MACHOP regimen for 6 planned courses, given every 21 days. G- or GM-CSF were administered whenever required. RESULTS: Sixty-six patients (92%) obtained a response: 38 (53%) a complete remission (CR) and 28 (39%) a partial remission (PR); 4 (6%) proved to be resistant and 2 (3%) died of chemotherapy-related toxicity. Fifty-seven patients with a good performance status were subsequently selected to undergo autologous stem cell transplantation (ASCT). During chemotherapy, grade III-IV neutropenia was observed in 59% of the patients; a significant drop in hemoglobin levels was detected, with blood transfusions being required in 21% of the cases; platelet counts were unaffected. The main extrahematological toxic events were: alopecia (100% of the patients), osteoarthromyalgias (58%), grade I-II neuropathy (53%) and grade I-II hepatic toxicity (43%). CONCLUSIONS: Our study confirms the efficacy of the F-MACHOP regimen in obtaining a high rate of response (CR + PR) in most aggressive NHL cases, with an acceptable toxicity and a low rate of toxic deaths. This regimen enables the majority of patients to be selected for ASCT as consolidation therapy without significant toxicity.

Adolescent↗

PubMedDate not supplied

Effect of fludarabine and arabinosylcytosine on multidrug resistant cells.

BACKGROUND AND OBJECTIVE: Anthracyclines are first-line drugs in the treatment of acute leukemia, but the sensitivity of leukemic cells to anthracyclines can be downmodulated by multidrug resistance (MDR) transport proteins like Pgp. Pgp overexpression is negatively related to treatment response. Alternative drugs may be required to overcome the MDR problem. METHODS: Arabinosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoro-adenine monophosphate (fludarabine, F-ara) were tested alone and in combination in four pairs of leukemia and tumor non-MDR and MDR cell lines. Toxicity was assayed by growth inhibition with the microcultured MTT assay. RESULTS: MDR cells were more sensitive than or as sensitive as non-MDR cells to ara-C and to F-ara alone. The resistance index to ara-C was decreased upon pre-exposure of the MDR cells to low-dose F-ara (10 ng/mL), showing that the combination of ara-C and F-ara was more active on MDR cells than on non-MDR parental ones. INTERPRETATION AND CONCLUSIONS: Neither sensitivity to ara-C nor sensitivity to F-ara was influenced by Pgp overexpression. These data provide a rationale for more extensive and more intensive testing of combinations of ara-C and F-ara in Pgp-mediated MDR acute leukemia. In relapsed/resistant and in secondary acute leukemias, increasing the dose of ara-C and combining ara-C with F-ara might be more rewarding than administering anthracyclines or other Pgp-processable compounds.

Antineoplastic Agents↗

PubMedDate not supplied

Retrospective analysis of 23 cases with peripheral T-cell lymphoma, unspecified: clinical characteristics and outcome.

BACKGROUND AND OBJECTIVE: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of post-thymic malignancies relatively uncommon in the Western world and their prognosis and therapeutic approach are still not well defined. The aim of this study was to retrospectively analyze the clinical, hematological and histological features at diagnosis, the relevance of the International Prognostic Index and the outcome of a group of 23 patients affected by peripheral T-cell lymphoma, unspecified (PTCL-U), according to the Revised European-American Classification of Lymphoid Neoplasms (REAL), observed between September 1985 and April 1995 at our Institution. METHODS: Patients were separated into different prognostic groups according to Ann Arbor stage, cell size and International Prognostic Index. All patients had been treated with multiagent combination chemotherapy, mainly CHOP (9 cases) and F-MACHOP (9 cases), and were evaluable for response. The treatment was intensified with allogeneic bone marrow transplantation (BMT) in 1 patient and with autologous BMT in 4 patients. RESULTS: Median age was 55 (range 18-77) years and 70% of the patients were males. Four patients were in stage II (17%), 5 in stage III (22%) and 14 in stage IV (61%). Patient risk was classified according to the International Prognostic Index as follows: 8 cases (35%) low risk, 2 cases (9%) low-intermediate, 8 cases (35%) high-intermediate, 5 cases (21%) high. Median follow-up time was 20 months (range 2-132). Median progression-free survival (PFS) and overall survival (OS) for all the patients studied were 10 and 34 months, respectively. Stage IV was associated with a poorer response rate and a shorter PFS (median 6 months) and OS (median 32 months). No statistical correlation was found between cell size and overall response (complete + partial remission), PFS (p = 0.38) or OS (p = 0.59), although a better trend was observed for the large cell group. A less favorable outcome was observed in patients in the high-intermediate + high risk groups, where median PFS and OS were 7 and 24 months, respectively, than in patients in the low + low-intermediate risk groups. No difference in response or outcome was detected between patients treated with the CHOP and the F-MACHOP regimens, while all 5 patients given high-dose chemotherapy and BMT are alive and in CR. INTERPRETATION AND CONCLUSIONS: Our experience shows that PTCL-U are rare lymphomas frequently having an aggressive presentation. The response to conventional polychemotherapeutic regimens like CHOP or F-MACHOP is generally poor, especially in those cases with advanced stage and a high-intermediate or high International Prognostic Index. The observation that all five patients who were treated with bone marrow transplantation are alive and in complete remission suggests using this strategy, particularly in young patients with a poor International Prognostic Index.

Adolescent↗

PubMedDate not supplied

Bone marrow transplantation in a patient with chronic myeloid leukemia and achondroplasia.

A 25-year-old female with achondroplastic dwarfism, diagnosed when she was six months old, was diagnosed with chronic myeloid leukemia (CML) in chronic phase with 9;22 translocation, A2B3 gene rearrangement and a Sokal index of 0.5. A recombinant interferon-alpha 2A treatment was started in October '94, which obtained a hematological, but not a karyotypic, response at the 6th and 12th month. In August '94, the patient was submitted to allogeneic bone marrow transplantation (alloBMT) from a 36-year-old matched sibling. The procedure was well tolerated. Disease-free survival (DFS) and overall survival (OS) were 21 and 39 months, respectively. We have not found any reported cases of achondroplastic patients submitted to alloBMT in the literature or in the IBMT Registry.

Achondroplasia↗