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2.
Leukemia ; 29(10): 2039-49, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25975191

ABSTRACT

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Synergism , Membrane Glycoproteins/metabolism , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/metabolism , Adult , Aged , Aged, 80 and over , Animals , Antibodies, Monoclonal/administration & dosage , Antibody-Dependent Cell Cytotoxicity , Apoptosis/drug effects , Bone Marrow/drug effects , Bone Marrow/pathology , Cell Proliferation/drug effects , Cytotoxicity, Immunologic , DNA-Binding Proteins/physiology , Disease Models, Animal , Drug Resistance, Neoplasm/drug effects , Female , Flow Cytometry , Humans , Male , Mice , Middle Aged , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/pathology , Salvage Therapy , Tretinoin/administration & dosage , Tumor Cells, Cultured
3.
J Clin Immunol ; 34(6): 642-54, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24952009

ABSTRACT

BACKGROUND: Pulmonary disease is common in patients with common variable immunodeficiency disorders (CVID) and involves infections, chronic airway disease and interstitial lung disease. Chronic pulmonary disease is associated with excess morbidity and early mortality and therefore early detection and monitoring of progression is essential. METHODS AND PURPOSE: Thin slice CT scan and pulmonary function were used to determine the prevalence and spectrum of chronic (pre-clinical) pulmonary disease in adult CVID patients regardless of symptoms. CT Scans were scored for airway abnormalities (AD) and interstitial lung disease (ILD). Other CVID related complications and B and T lymphocyte subsets were analyzed to identify patients at risk for pulmonary disease. RESULTS: Significant pulmonary abnormalities were detected in 24 of the 47 patients (51%) consisting of AD in 30% and ILD in 34% of cases. In only 7 (29%) of these 24 patients pulmonary function test proved abnormal. The presence of AD was correlated to (recurrent) lower respiratory tract infections despite IgG therapy. The presence of ILD was correlated to autoimmune disease and a reduction in the numbers of CD4 + T cells, naïve CD4 + T cells, naïve CD8 + T cells and memory B cells and lower IgG through levels over time. CONCLUSION: Preclinical signs of AD and ILD are common in CVID patients despite Ig therapy and do not correlate to pulmonary function testing. Patients at risk for ILD might be identified by the presence of autoimmunity or a deranged T cell pattern. Larger studies are needed to confirm these findings and to determine thresholds for the T lymphocyte subsets.


Subject(s)
B-Lymphocytes/immunology , Common Variable Immunodeficiency/diagnosis , Lung/pathology , Pulmonary Disease, Chronic Obstructive/diagnosis , T-Lymphocytes/immunology , Adolescent , Adult , Child , Child, Preschool , Common Variable Immunodeficiency/immunology , Female , Follow-Up Studies , Humans , Immunologic Memory , Lung/diagnostic imaging , Male , Prevalence , Pulmonary Disease, Chronic Obstructive/immunology , Respiratory Function Tests , Tomography, X-Ray Computed , Young Adult
4.
Clin Immunol ; 133(1): 95-107, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19586803

ABSTRACT

Work in the past years has led to a refined phenotypical description of functionally distinct T- and B-cell subsets. Since both lymphocyte compartments are established and undergo dramatic changes during childhood, redefined pediatric reference values of both compartments are needed. In a cohort of 145 healthy children, aged 0-18 years, the relative and absolute numbers of the various T- and B-cell subsets were determined. In addition, we found that besides thymic output, naive (CD27(+)CD45RO(-)) T-cell proliferation contributed significantly to the establishment of the naive T-cell compartment. At birth, regulatory (CD25(+)CD127(-)CD4(+)) T cells (Tregs) mainly had a naive (CD27(+)CD45RO(-)) phenotype whereas 'memory or effector-like' (CD45RO(+)) Tregs accumulated slowly during childhood. Besides the CD27(+)IgM(+)IgD(+) memory B-cell population, the recently identified CD27(-)IgG(+) and CD27(-)IgA(+) memory B-cell populations were already present at birth. These data provide reference values of the T- and B-cell compartments during childhood for studies of immunological disorders or immune reconstitution in children.


Subject(s)
B-Lymphocyte Subsets/immunology , Immune System Diseases/blood , T-Lymphocyte Subsets/immunology , Adolescent , Child , Child, Preschool , Cohort Studies , Fetal Blood/immunology , Humans , Infant , Infant, Newborn , Lymphocyte Count , Reference Values
5.
Haematologica ; 92(12): e130-1, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18055977

ABSTRACT

In a prospective phase II study, we evaluated the combination of high dose simvastatin and VAD chemotherapy in patients with refractory or relapsed multiple myeloma. Although treatment was feasible with mild side effects, only 1 of 12 patients achieved a partial response. According to our predefined criteria this was insufficient to continue the study.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Drug Resistance, Neoplasm/drug effects , Multiple Myeloma/drug therapy , Simvastatin/administration & dosage , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clinical Trials, Phase I as Topic , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Multiple Myeloma/complications , Simvastatin/adverse effects , Vincristine/administration & dosage , Vincristine/adverse effects
6.
Leukemia ; 19(12): 2177-85, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16239913

ABSTRACT

Failure of myeloma cells to undergo apoptosis plays an important role in the accumulation of myeloma cells within the bone marrow (BM). Moreover, inhibition of drug-induced apoptosis has been indicated as a major contributor of drug resistance in myeloma. The BM microenvironment promotes survival and blocks the apoptotic effects of various cytotoxic agents through the production of cytokines as well as through direct physical interactions. Several antiapoptotic proteins and antiapoptotic signaling cascades have been identified that contribute to the antiapoptotic phenotype of the myeloma cell. In this review, we discuss mechanisms that result in enhanced survival and drug resistance of myeloma cells. Insight into these mechanisms is essential to make progress in the therapy of myeloma.


Subject(s)
Growth Substances/physiology , Multiple Myeloma/pathology , Signal Transduction , Apoptosis , Bone Marrow/metabolism , Bone Marrow/physiology , Drug Resistance, Neoplasm , Humans , Multiple Myeloma/metabolism
8.
Leukemia ; 18(6): 1078-84, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15085157

ABSTRACT

Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame. In this study, G3139 was delivered as a continuous intravenous infusion for 7 days at a fixed dose of 7 mg/kg/day in combination with VAD (vincristine, adriamycin, and dexamethasone) chemotherapy. In total, 10 heavily pretreated patients with refractory myeloma participated in this trial, including eight patients with VAD refractory disease. The combination of G3139 and VAD was feasible and well tolerated. Seven patients (70%) responded including four patients (40%) with a partial response and three patients (30%) with a minor response. Median progression-free survival was 6 months (range, 2-7+ months) and median overall survival has not been reached. G3139 downregulated Bcl-2 protein levels in peripheral blood circulating myeloma cells, B cells, T cells, and monocytes. These results indicate that G3139 may overcome classical resistance and restore sensitivity of myeloma tumor cells to VAD chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/therapeutic use , Doxorubicin/therapeutic use , Genetic Therapy , Multiple Myeloma/drug therapy , Oligonucleotides, Antisense/administration & dosage , Proto-Oncogene Proteins c-bcl-2/genetics , Vincristine/therapeutic use , Adult , Aged , Anemia/etiology , B-Lymphocytes , Blood Platelets , Drug Resistance, Neoplasm , Female , Genetic Therapy/adverse effects , Humans , Male , Middle Aged , Monocytes , Multiple Myeloma/pathology , T-Lymphocytes
9.
Leukemia ; 17(4): 764-74, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12682635

ABSTRACT

The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and anti-apoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.


Subject(s)
Hepatocyte Growth Factor/physiology , Multiple Myeloma/pathology , Neoplasm Proteins/physiology , Proto-Oncogene Proteins c-met/physiology , Aged , Apoptosis/physiology , Cell Division/physiology , Female , Humans , MAP Kinase Kinase 1 , MAP Kinase Signaling System , Male , Middle Aged , Mitogen-Activated Protein Kinase Kinases/physiology , Phosphatidylinositol 3-Kinases/physiology , Phosphorylation , Plasma Cells/metabolism , Plasma Cells/pathology , Protein Processing, Post-Translational , Protein Serine-Threonine Kinases/physiology , Signal Transduction/physiology , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/pathology , ras Proteins/physiology
10.
Clin Exp Immunol ; 131(2): 340-6, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12562398

ABSTRACT

Cytotoxic T cells play an important role in graft-versus-host-disease (GvHD) and graft-versus-leukaemia/myeloma, which may occur in patients treated with an allogeneic stem cell transplantation (ASCT). Here, we describe the selection of a myeloma reactive CD4+ cytotoxic T cell-line (CTL) and two CD4+ clones from this CTL. The CTL was generated from the blood from a patient with multiple myeloma (MM) with graft versus myeloma/GvHD, following an ASCT. The CTL was stimulated using irradiated peripheral blood mononuclear cells and EBV transformed B cells from the myeloma patient (EBVp), both of which were obtained prior to ASCT. Both the CTL and the two T cell clones specifically lysed EBVp and secreted IFN-gamma after coculture with EBVp and autologous myeloma tumour cells in a class II restricted fashion. These results show that myeloma tumour cells and autologous B cells present a common polymorphic peptide that functions as a target for graft derived cytotoxic T cells. Identification of these proteins will give insight into the relationship between graft versus myeloma (GvM) and GvHD and may provide immunotherapeutical targets in the treatment of MM.


Subject(s)
B-Lymphocytes/immunology , Graft vs Host Reaction/immunology , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/immunology , Plasma Cells/immunology , Antigens, Surface/analysis , CD4-Positive T-Lymphocytes/immunology , Cell Line , Cell Transformation, Viral , Herpesvirus 4, Human , Humans , Interferon-gamma/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged
11.
Leukemia ; 17(1): 211-9, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12529680

ABSTRACT

An antisense oligodeoxynucleotide (ODN) complementary to the first six codons of the Bcl-2 mRNA, G3139 (oblimersen sodium; Genasense), has been shown to downregulate Bcl-2 and produce responses in a variety of malignancies including drug-resistant lymphoma. Incubation of ex vivo purified plasma cells from patients with multiple myeloma (MM) with carboxyfluorescein (FAM)-labeled antisense ODNs resulted in a time- and dose-dependent uptake in the cytoplasm and nucleus. No major differences in uptake of Bcl-2 antisense ODNs were observed among patients' samples. Incubation of purified myeloma plasma cells with G3139, but not solvent or reverse polarity control ODNs, resulted in a reduction (>75%) of Bcl-2 mRNA levels after 2 and 4 days, as measured by Real-Time PCR. Treatment with G3139 led to a sequence-specific reduction of Bcl-2 protein levels within 4 days of exposure in 10 out of 11 clinical samples from patients with chemosensitive and multidrug-resistant disease, without significant reduction of alpha-Actin, Bax, Bcl-XL, or Mcl-1 proteins. This resulted in a significantly enhanced sensitivity of the myeloma tumor cells to dexamethasone or doxorubicin-induced apoptosis. G3139 can consistently enter myeloma cells, downregulate the expression of Bcl-2, and enhance the efficacy of myeloma therapy. These data support further clinical evaluation of G3139 therapy in multiple myeloma.


Subject(s)
Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Oligonucleotides, Antisense/therapeutic use , Plasma Cells/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Thionucleotides/therapeutic use , Aged , Annexin A5/metabolism , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Apoptosis/drug effects , Blotting, Western , Bone Marrow/pathology , Dexamethasone/adverse effects , Dexamethasone/therapeutic use , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm , Female , Humans , Male , Middle Aged , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Myeloid Cell Leukemia Sequence 1 Protein , Neoplasm Proteins/metabolism , Oligonucleotides, Antisense/toxicity , Plasma Cells/drug effects , Plasma Cells/pathology , Polymerase Chain Reaction , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/metabolism , Vincristine/adverse effects , bcl-2-Associated X Protein , bcl-X Protein
12.
Leukemia ; 16(7): 1362-71, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12094262

ABSTRACT

Lovastatin is an irreversible inhibitor of HMG-CoA reductase and blocks the production of mevalonate, a critical compound in the production of cholesterol and isoprenoids. Isoprenylation of target proteins, like the GTP-binding protein Ras, is essential for their membrane localization and subsequent participation in intracellular signaling cascades. Lovastatin effectively decreased the viability of plasma cells from cell lines (n = 10) and myeloma patients' samples (n = 8) in a dose- and time-dependent way. Importantly, co-incubation of lovastatin with dexamethasone had a synergistic effect in inducing plasma cell cytotoxity. This effect was not the consequence of a change in the protein expression levels of Bcl-2 or Bax induced by lovastatin. The decrease in plasma cell viability was the result of induction of apoptosis and inhibition of proliferation. Mevalonate effectively reversed the cytotoxic and cytostatic effects of lovastatin in plasma cells. The cytotoxic activity of lovastatin was higher in Pgp expressing cell lines, but did not correlate with the multidrug resistance (MDR)-related proteins LRP, Bcl-2 and Bax. Lovastatin treatment resulted in a shift of Ras localization from the membrane to the cytosol that was reversed by mevalonate. The data presented in this paper warrant study of lovastatin alone or in combination with therapeutic drugs, in the treatment of myeloma patients.


Subject(s)
Anticholesteremic Agents/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Lovastatin/pharmacology , Plasmacytoma/drug therapy , Anticholesteremic Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Cell Division/drug effects , Down-Regulation/drug effects , Humans , Lovastatin/therapeutic use , Plasmacytoma/metabolism , Plasmacytoma/pathology , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Tumor Cells, Cultured , bcl-2-Associated X Protein
13.
Leukemia ; 16(1): 135-43, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11840273

ABSTRACT

Expression of CD44v9-containing isoforms (CD44v9) on myeloma plasma cells correlates with unfavorable prognosis, suggesting that CD44 variant molecules are involved in the disease process. In this study, the presence of CD44v on B cell lines from different stages of development was analyzed by flow cytometry and a role in adhesion to stromal cells from different tissues was evaluated in in vitro binding assays. CD44v3, v6 and v9 isoforms were exclusively expressed on plasma cell lines and CD44v9 expression correlated with IL-6-dependent plasma cell growth. Binding studies using CD44 isoform- specific reagents showed that CD44v6 and CD44v9 were involved in binding to bone marrow stromal cells, but not to in vitro synthesized ECM or hyaluronic acid. CD44v9-mediated plasma cell binding resulted in a significant induction of IL-6 secretion by bone marrow stromal cells. Large differences in quantitative plasma cell binding to stromal cells from different tissues were observed. These, however, could not be related to a differential use of CD44v in these binding processes. The role of CD44v9 in adhesion induced IL-6 secretion and its preferential expression on IL-6-dependent plasma cell lines may explain the previously observed correlation between CD44v9 expression and adverse prognosis in multiple myeloma.


Subject(s)
Antigens, Neoplasm/physiology , B-Lymphocytes/cytology , Bone Marrow Cells/cytology , Glycoproteins/physiology , Hyaluronan Receptors/physiology , Multiple Myeloma/pathology , Neoplastic Stem Cells/cytology , Plasma Cells/cytology , Protein Isoforms/physiology , Stromal Cells/cytology , Adult , Antibodies, Monoclonal/pharmacology , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , B-Lymphocytes/metabolism , Bone Marrow Cells/metabolism , Cell Adhesion , Child , Exons/genetics , Extracellular Matrix/metabolism , Glycoproteins/genetics , Glycoproteins/immunology , Humans , Hyaluronan Receptors/genetics , Hyaluronan Receptors/immunology , Hyaluronic Acid/metabolism , Interleukin-6/metabolism , Multiple Myeloma/mortality , Neoplastic Stem Cells/metabolism , Organ Specificity , Plasma Cells/metabolism , Prognosis , Protein Isoforms/genetics , Protein Isoforms/immunology , Recombinant Fusion Proteins/physiology , Stromal Cells/metabolism
14.
Leuk Res ; 25(12): 1051-7, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11684276

ABSTRACT

To evaluate the role of CD44 variant isoforms (CD44v) in plasma cell dyscrasias, CD44v expression was analysed in bone marrow (BM) biopsies of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients, in biopsies of soft tissue infiltration by MM and in extramedullary plasmacytoma samples. Expression of CD44 isoforms containing the 3v, 4v, 6v or 10v domain was observed in 15, 7, 13 and 5% of 87 samples from 49 consecutive MM cases, but could not be detected in ten normal persons or 11 MGUS patients. In contrast, CD44v9 revealed a broader pattern of expression and was observed in plasma cells in three out of ten normal persons and in three out of 11 MGUS cases. In MM, CD44v9 was detected in 32 out of 87 samples (37%) of BM infiltrates and was associated with an advanced Durie and Salmon stage (P<0.03), a progressive disease (P<0.01) and an IgA subtype (P<0.01). Furthermore, CD44v9 expression was observed in three out of five cases of MM soft tissue infiltrates, was often upregulated during disease progression, was significantly correlated with a shorter overall survival (P<0.03) and emerged as an independent prognostic factor in multivariate analysis (stage: relative risk 1.36, P<0.02; CD44v9 expression: relative risk 1.45, P<0.04). These results substantiate the clinical relevance of CD44v domains in plasma cell disorders and establish CD44v9 as a new independent prognostic parameter in MM.


Subject(s)
Hyaluronan Receptors/analysis , Multiple Myeloma/mortality , Paraproteinemias/metabolism , Adult , Aged , Female , Humans , Hyaluronan Receptors/physiology , Male , Middle Aged , Multiple Myeloma/etiology , Multiple Myeloma/metabolism , Multivariate Analysis , Prognosis , Protein Isoforms , Risk Factors , Survival Rate
15.
Neth J Med ; 59(2): 50-6, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11476912

ABSTRACT

BACKGROUND: Multiple myeloma is an incurable disease and after several lines of chemotherapy, patients enter a phase in which no standard treatment options are available. The poor outlook of these patients requires mild, palliative therapy with low toxicity. Previously used regimens either require frequent hospital attendance, lack efficacy or have significant toxicity. METHODS: In the current study, daily low dose, oral cyclophosphamide (100 mg) and prednisone (10-20 mg; CP) were administered to patients with advanced myeloma. Forty-two patients with progressive disease after melphalan-based and VAD treatment were enrolled. RESULTS: Objective responses were observed in 29 of 42 (69%) patients. In responding patients, median overall survival and progression-free survival were 22.2 months and 15.0 months, respectively. In non-responders, median OS was 3.5 months only. Side-effects were limited. Cytopenia was the most frequent event (8/29) prompting dose reduction. CP had to be stopped permanently in four patients (two cytopenia, two infections). CONCLUSION: Orally administered, low dose continuous CP is a feasible, effective and well-tolerated regimen in the management of advanced multiple myeloma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Multiple Myeloma/drug therapy , Administration, Oral , Aged , Analysis of Variance , Cyclophosphamide/administration & dosage , Disease-Free Survival , Female , Humans , Male , Middle Aged , Multiple Myeloma/mortality , Netherlands/epidemiology , Prednisone/administration & dosage , Survival Rate
16.
Leuk Res ; 23(6): 539-48, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10374847

ABSTRACT

The clinical utility of anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) for treatment of multiple myeloma (MM) is limited by the occurrence of multidrug resistance (MDR). Highly lipophilic anthracyclines like idarubicin (IDA) might circumvent MDR and thereby enhance chemotherapeutic efficacy. To determine the efficacy of IDA in myeloma cells, the pharmacokinetics and cytotoxicity of IDA and its major metabolite idarubicinol (IDAol) were compared with those of DNR, DOX, and doxorubicinol (DOXol) in the cell line RPMI 8226-S and two MDR sublines (8226-R7 and 8226-Dox40) that overexpress the drug transporter P-glycoprotein (Pgp). Cytotoxicity assays using MTT (viability) or annexin V (apoptosis) showed a 10-50-fold higher potency of IDA compared with DNR or DOX in the MDR variant cell lines. The difference in cytotoxicity was lower in the sensitive parental cell line (3-fold). These results are explained by a better intracellular uptake of IDA compared to DNR in resistant 8226 cell lines. The Pgp-inhibitor verapamil affected IDA uptake only in the most resistant cell line 8226-Dox40. This indicates that IDA is less sensitive than DNR to transport-mediated MDR. IDAol was at least 32-fold more cytotoxic than DOXol, and more susceptible to Pgp transport than IDA. These studies demonstrate that the efficacy of IDA in MDR MM cell lines is superior to that of DOX or DNR, and that IDA may become an important drug in the treatment of MM, especially in refractory disease.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents/therapeutic use , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Idarubicin/therapeutic use , Multiple Myeloma/drug therapy , Daunorubicin/therapeutic use , Doxorubicin/therapeutic use , Tumor Cells, Cultured , Verapamil/therapeutic use
17.
Bone Marrow Transplant ; 23(2): 195-7, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10197809

ABSTRACT

We describe a patient with recurrent relapses after allogeneic BMT for multiple myeloma who repeatedly went into CR after donor leukocyte infusions (DLI). The first bone marrow relapse, 24 months after allogeneic BMT, was treated successfully with the infusion of 1.2 x 10(8) donor T cells. The second extramedullary relapse, 18 months later with a pleural mass and midthoracic spine process, responded again to DLI, however, only after three courses were given, each with escalating doses of T cells. The pleural mass was treated successfully with radiation therapy after the second DLI but reappeared 3 months later and responded again to the final DLI course with 5 x 10(8) T cells/kg. Nevertheless, graft-versus-host disease (GVHD) did not occur. Retrospective analysis of minimal residual disease in bone marrow aspirates during CR periods using a sensitive quantitative tumor-specific PCR showed that BM tumor cell infiltration persisted. The possible clinical implications of this case report, like maintenance DLI and the aim for molecular remissions, are discussed.


Subject(s)
Bone Marrow Transplantation , Leukocyte Transfusion , Multiple Myeloma/therapy , Humans , Infusions, Intravenous , Male , Middle Aged , Remission Induction , Retrospective Studies
18.
Leukemia ; 12(11): 1821-8, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9823960

ABSTRACT

CD44 variant isoforms (CD44v) have been shown to be important factors in adverse prognosis in hematological malignancies. To investigate whether CD44 expression is associated with malignant transformation in multiple myeloma, RNA and protein expression of CD44 standard (CD44s) and CD44v4, v6, v9, v10 containing isoforms was compared on bone marrow plasma cells from normal individuals and myeloma patients at different stages of disease. CD44s protein expression is strongly decreased on myeloma plasma cells and non-malignant B cells in affected bone marrow of myeloma patients, while no differences in CD44s expression were found between blood B cells from normal individuals and myeloma patients. CD44v isoforms were expressed on plasma cells in the majority of normal and myeloma samples analyzed. CD44v9 and v10 containing isoforms were differentially expressed on bone marrow plasma cells from normal individuals (predominantly CD44v9+v10+) and myeloma patients with stable (predominantly CD44v9-v10+) or progressive (predominantly CD44v9+v10- disease. Normal and myeloma plasma cells contained CD44 mRNA transcripts consisting of multiple CD44v exons. In addition, CD44v9 positive myeloma cells carried large CD44 transcripts. These results imply that detection of CD44v isoforms may be a valuable diagnostic tool for monitoring myeloma disease progression and response to treatment.


Subject(s)
Bone Marrow Cells/immunology , Hyaluronan Receptors/immunology , Multiple Myeloma/immunology , Plasma Cells/immunology , Exons , Flow Cytometry , Humans , Hyaluronan Receptors/genetics , Multiple Myeloma/pathology , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction
19.
J Infect Dis ; 178(5): 1279-87, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9780247

ABSTRACT

The relationship between T cell activation and human immunodeficiency virus type 1 (HIV-1) replication was studied in HIV-infected subjects, 20 with and 10 without anti-HIV treatment. Expression of Ki-67 proliferation-associated antigen was increased in CD4+ and CD8+ T cells and correlated with HLA-DR. In subjects without anti-HIV treatment, the plasma HIV-1 RNA level correlated with HLA-DR in CD4+ T cells, with Ki-67 in CD8+ T cells, and with expression of CD38 in both T cell subsets. A proportion of treated subjects had increased T cell activation despite 4 months of highly active antiretroviral treatment (HAART). In subjects receiving HAART, a high percentage of HLA-DR+ CD4+ T cells was associated with signs of opportunistic infections. This work supports the concept that, in the natural course of HIV-1 infection, HIV replication itself leads to general T cell activation and that opportunistic infections generate additional CD4+ T cell activation and HIV replication.


Subject(s)
Antigens, CD , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , HIV Antigens/analysis , HIV Infections/immunology , HIV-1/growth & development , RNA, Viral/blood , Virus Replication/immunology , ADP-ribosyl Cyclase , ADP-ribosyl Cyclase 1 , Adult , Antigens, Differentiation/analysis , Biomarkers , HIV Infections/virology , Humans , Ki-67 Antigen/analysis , Lymphocyte Activation , Membrane Glycoproteins , Middle Aged , NAD+ Nucleosidase/analysis , beta 2-Microglobulin/analysis
20.
Blood ; 91(3): 1029-36, 1998 Feb 01.
Article in English | MEDLINE | ID: mdl-9446666

ABSTRACT

This study was undertaken to assess the significance of lung-resistance related protein (LRP) expression in plasma cells from untreated multiple myeloma (MM) patients and to determine whether LRP was associated with a poor response and survival in patients treated with different dose regimens of melphalan. Seventy untreated patients received conventional oral dose melphalan (0.25 mg/kg, day 1 to 4) combined with prednisone (MP) or intravenous intermediate-IDM; 70 mg/m2) or high- (140 mg/m2) dose Melphalan (HDM). LRP expression was assessed with immunocytochemistry using the LRP-56 monoclonal antibody. LRP expression was found in 47% of patients. In the MP treated patients, LRP expression was a significant prognostic factor regarding response induction (P < .05), event free survival (P < .003), and overall survival (P < .001). In the intensified dose melphalan treated patients LRP did not have a prognostic value. The response rates of LRP-positive patients to MP and IDM/HDM were 18% versus 81%, respectively (P < .0001). We conclude that LRP is frequently expressed in untreated MM patients and is an independent predictor for response and survival in patients treated with MP. Pretreatment assessment of LRP identifies a subpopulation of patients with a poor probability of response to conventional dose melphalan. Dose intensification of melphalan is likely to overcome LRP-mediated resistance.


Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Melphalan/administration & dosage , Multiple Myeloma/drug therapy , Neoplasm Proteins/analysis , Vault Ribonucleoprotein Particles , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Cells/chemistry , Disease-Free Survival , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Humans , Male , Melphalan/therapeutic use , Middle Aged , Multiple Myeloma/metabolism , Plasma Cells/chemistry , Prednisone/administration & dosage , Prednisone/therapeutic use , Prognosis , Remission Induction , Survival Rate , Treatment Outcome
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