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Shaji Kumar

Publications and source records attributed to Shaji Kumar.

At least 37 records · Page 2Linked to original sources
PubMed2005

SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma.

In this study we report that R-etodolac (SDX-101), at clinically relevant concentrations, induces potent cytotoxicity in drug-sensitive multiple myeloma (MM) cell lines, as well as in dexamethasone (MM.1R)-, doxorubicin (Dox40/RPMI8226)-, and bortezomib (DHL4)-resistant cell lines. Immunoblot analysis demonstrates that R-etodolac induces apoptosis characterized by caspase-8, -9, and -3 and PARP (poly-ADP [adenosine diphosphate]-ribose polymerase) cleavage and down-regulation of cyclin D1 expression. Subcytotoxic doses of R-etodolac up-regulate myeloid cell leukemia-1 proapoptotic variant (Mcl-1S), while enhancing dexamethasone (Dex)-induced caspase activation and apoptosis. The combination of R-etodolac with Dex results in a highly synergistic cytotoxic effect. R-etodolac also induces apoptosis against primary cells isolated from patients with MM refractory to chemotherapy. Although interleukin 6 (IL-6) and insulin-like growth factor-1 (IGF-1) abrogate Dex-induced MM cell cytotoxicity, neither IL-6 nor IGF-1 protects against R-etodolac-induced cytotoxicity in MM cells. R-etodolac also inhibits viability of MM cells adherent to bone marrow stromal cells (BMSCs), thereby overcoming a mechanism of drug resistance commonly observed with other conventional chemotherapeutic agents. Our data, therefore, indicate that R-etodolac circumvents drug resistance in MM cells at clinically relevant concentrations, targets Mcl-1, and can be synergistically combined with Dex.

Antineoplastic Agents↗
PubMed2005

Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo.

Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound that significantly inhibits production of interleukin 6 (IL-6) and inflammation in rat arthritis and autoimmune animal models. We here characterize the effect of atiprimod on human multiple myeloma (MM) cells. Azaspirane significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. IL-6, insulin-like growth factor 1 (IGF-1), or adherence of MM cells to bone marrow stromal cells (BMSCs) did not protect against atiprimod-induced apoptosis. Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by atiprimod. Azaspirane inhibits signal transducer activator of transcription 3 (STAT3) and a PI3-K (phosphatidylinositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERK1/2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorkappaBalpha (IkappaBalpha) and nuclear factor kappaB (NFkappaB) p65 phosphorylation triggered by tumor necrosis factor alpha (TNF-alpha). Of importance, azaspirane inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BMSCs triggered by MM cell binding and also inhibits angiogenesis on human umbilical vein cells (HUVECs). Finally, azaspirane demonstrates in vivo antitumor activity against human MM cell growth in severe combined immunodeficient (SCID) mice. These results, therefore, show that azaspirane both induces MM cell apoptosis and inhibits cytokine secretion in the BM milieu, providing the framework for clinical trials to improve patient outcome in MM.

Animals↗
PubMed2005

Successful treatment of scleromyxedema with autologous peripheral blood stem cell transplantation.

BACKGROUND: Scleromyxedema is a rare chronic fibromucinous disorder that can have devastating clinical manifestations, including sclerosis of the skin with progressive pharyngeal and upper airway involvement, resulting in high mortality due to respiratory complications. Herein we describe a novel therapeutic approach. Because autologous hematopoietic stem cell transplantation is effective in other plasma cell proliferative disorders, it may be effective in this setting. OBSERVATIONS: We retrospectively evaluated 6 patients who were offered high-dose chemotherapy with stem cell rescue as treatment for scleromyxedema. One heavily pretreated patient was unable to mobilize stem cells. The remaining 5 patients mobilized stem cells and underwent successful transplantation. There was no treatment-related mortality. Hematologic responses were seen in 4 patients, including 2 complete remissions and 2 partial remissions, and all 4 had improvement in extracutaneous manifestations. All 4 patients subsequently had relapse of the monoclonal protein, and 3 developed skin relapses at 14, 37, and 45 months. CONCLUSIONS: High-dose chemotherapy with stem cell rescue is feasible for patients with scleromyxedema and, although not curative, offers durable remission in most patients. This therapy should be considered before treatment with alkylating agents or other treatments that could adversely affect the ability to collect stem cells.

Adult↗
PubMed2005

Drug insight: thalidomide as a treatment for multiple myeloma.

Multiple myeloma (MM)--a malignancy of the bone marrow--remains incurable by current therapies, and there is an urgent need for new drugs based on a better understanding of the underlying disease biology. MM is characterized by monoclonal plasma cells that accumulate in the bone marrow, which provides a microenvironment that promotes tumor cell growth and survival and protection against various therapeutic agents. The MM cell interacts with bone marrow stromal cells and endothelial cells, as well as osteoblasts and osteoclasts. Our understanding of the tumor microenvironment has already prompted the development of new agents that are aimed at disrupting the multiple facets of these interactions. It has also enabled the development of a comprehensive and rational approach to preclinical evaluation of new agents, facilitating the translation of in vitro studies to in vivo tumor models and, subsequently, to clinical trials. In this review, we describe the preclinical studies that led to the development of clinical trials of thalidomide and its immunomodulatory derivatives as therapeutic agents for MM. These drugs, alone or in combination, have shown impressive activity at all stages of the disease, and these demonstrations of clinical benefit have in turn validated our model systems for drug discovery in MM. Integration of data from clinical trials and laboratory studies will allow the design of future clinical trials that combine thalidomide and its derivatives with other drugs, ultimately leading to more effective therapies and better outcomes in patients with MM.

Animals↗
PubMed2005

Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application.

Thalidomide and immunomodulatory drugs (IMiDs), which target multiple myeloma (MM) cells and the bone marrow microenvironment, can overcome drug resistance. These agents also have immunomodulatory effects. Specifically, we have reported that thalidomide increased serum interleukin-2 (IL-2) levels and natural killer (NK) cell numbers in the peripheral blood of responding MM patients. In this study, we investigated the mechanisms whereby IMiDs augment NK cell cytotoxicity. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells cultured with IMiDs were examined in the presence or absence of anti-IL-2 antibody, ciclosporin A or depletion of CD56-positive cells. IMiDs-induced signalling pathways, triggering IL-2 transcription in T cells, were also delineated. IMiDs facilitated the nuclear translocation of nuclear factor of activated T cells-2 and activator protein-1 via activation of phosphoinositide-3 kinase signalling, with resultant IL-2 secretion. IMiDs enhanced both NK cell cytotoxicity and ADCC induced by triggering IL-2 production from T cells. These studies defined the mechanisms whereby IMiDs trigger NK cell-mediated tumour-cell lysis, further supporting their therapeutic use in MM.

Cell Line, Transformed↗
PubMed2005

Plasma cell labeling index.

Multiple myeloma is characterized by proliferation of monoclonal plasma cells (PCs), mostly in the bone marrow. The proliferative rate of the malignant plasma cell is an important determinant of the disease biology and can be measured as the percentage of PCs in the S-phase of the cell cycle. This percentage, or PC labeling index, can be measured using a slide-based immunofluorescence method using an antibody against 5-bromo-2'-deoxyuridine, which is actively incorporated by DNA of the dividing PCs. This technique, which can be performed using bone marrow or peripheral blood specimens, also utilizes concurrent cytoplasmic staining against immunoglobulin as well as kappa and lambda light chains. Employment of cytoplasmic immunoglobulin staining allows more specific identification of PCs as well as confirmation of the monoclonal nature of the PC population. The staining procedure, which can be done manually or using an automated stainer, as well as the process of reading and interpreting these slides is described in detail. The bone marrow peripheral blood labeling index is an important clinical test, providing valuable diagnostic and prognostic information.

Cell Cycle↗
PubMed2005

Thalidomide and dexamethasone: therapy for multiple myeloma.

Multiple myeloma is a plasma cell malignancy that remains incurable with current treatment approaches including high-dose therapy and autologous stem cell transplantation. Thalidomide represents a major advance in the treatment of this disorder, having demonstrated significant activity in all phases of the disease. Thalidomide exerts its antimyeloma effect through multiple mechanisms including antiangiogenesis, immunomodulation and induction of apoptosis in tumor cells, as well as its effect on the tumor microenvironment. Corticosteroids have formed the mainstay of myeloma therapy for decades along with the alkylating agents and have demonstrated synergy when used in combination with thalidomide. The combination of thalidomide and dexamethasone has demonstrated remarkable activity in the treatment of both newly diagnosed as well as relapsed myeloma, and has become an important addition to the armamentarium of myeloma therapies. Overall responses of approximately 70% have been seen with this combination in patients with newly diagnosed myeloma. The combination is associated with an increased risk of deep vein thrombosis necessitating routine prophylactic anticoagulation. Other drugs have been added to this combination that also result in improved response rates. Currently, this combination is used in newly diagnosed patients as an induction therapy prior to stem cell transplant, for those who fail to achieve adequate response to dexamethasone alone or in whom a relatively rapid response is desired based on clinical presentation. Thalidomide analogs with a better safety profile are currently undergoing evaluation in the clinic.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma.

Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.

Antineoplastic Agents↗
PubMed2004

VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis.

Interleukin-6 (IL-6) triggers multiple myeloma (MM) cell proliferation and protects against apoptosis by up-regulating myeloid cell leukemia 1 (Mcl-1). Vascular endothelial growth factor (VEGF) induces modest proliferation of MM cells and induces IL-6 secretion in a paracrine loop involving MM cells and bone marrow stromal cells. Using murine embryonic fibroblast cell lines as a model (Mcl-1(wt/wt) and Mcl-1(Delta/null) MEFs), we here demonstrate that deletion of Mcl-1 reduces fetal bovine serum (FBS)-, VEGF-, and IL-6-induced proliferation. We also show that VEGF up-regulates Mcl-1 expression in a time- and dose-dependent manner in 3 human MM cell lines and MM patient cells. Importantly, we demonstrate that the pan-VEGF inhibitor, GW654652, inhibits VEGF-induced up-regulation of Mcl-1 and, as with Mcl-1 siRNA, is associated with decreased proliferation and induction of apoptosis. Finally, we show that VEGF protects MM patient cells against FBS starvation-induced apoptosis. Our studies therefore demonstrate that VEGF-induced MM cell proliferation and survival are mediated via Mcl-1, providing the preclinical framework for novel therapeutics targeting Mcl-1 and/or VEGF to improve patient outcome in MM.

Animals↗
PubMed2004

Thalidomid: current role in the treatment of non-plasma cell malignancies.

Thalidomide, initially introduced as a sedative, was withdrawn from the market in the early 1960s after it was found to be a teratogen. However, it later found use as an investigational agent in the treatment of erythema nodosum leprosum, oral ulcers, graft versus host disease, and wasting associated with the human immunodeficiency syndrome. Its antiangiogenic properties were recognized in the early 1990s during a period where the importance of angiogenesis became increasingly apparent as a critical step in the in the proliferation and spread of malignant neoplasms. This led to the evaluation of thalidomide as an antiangiogenic agent in the treatment of several cancers. Thalidomide has already become part of standard therapy for the treatment of patients with relapsed and refractory multiple myeloma. It has also been found to have varying degree of benefit in various other malignancies. Although more clinical trials are needed, Kaposi' s sarcoma and myelofibrosis represent other malignancies in which thalidomide has already demonstrated promising activity. The mechanism of action of thalidomide in cancer is still unclear, but do appear to be mediated by several other mechanisms in addition to its anti-angiogenic properties. This article reviews the current status of thalidomide for the treatment of non-plasma-cell malignancies.

Angiogenesis Inhibitors↗
PubMed2004

Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression.

We compared the angiogenic potential of bone marrow plasma and the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors on plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma (NMM). Cytokine and cytokine-receptor expression was studied by bone marrow immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (RT-PCR) on sorted plasma cells, and quantitative Western blot analysis. Bone marrow angiogenic potential was studied using a human in vitro angiogenesis assay. The expression levels of VEGF, bFGF, and their receptors were similar among MGUS, SMM, and NMM. Sixty-one percent of NMM samples stimulated angiogenesis in the in vitro angiogenesis assay compared with SMM (0%) and MGUS (7%) (P <.001). Importantly, 63% of MGUS samples inhibited angiogenesis compared with SMM (43%) and NMM (4%) (P <.001). The inhibitory activity was heat stable, not overcome by the addition of VEGF, and corresponded to a molecular weight below 10 kd by size-exclusion chromatography. Our results suggest that increasing angiogenesis from MGUS to NMM is, at least in part, explained by increasing tumor burden rather than increased expression of VEGF/bFGF by individual plasma cells. The active inhibition of angiogenesis in MGUS is lost with progression, and the angiogenic switch from MGUS to NMM may involve a loss of inhibitory activity.

Bone Marrow↗
PubMed2004

Cell proliferation of myeloma plasma cells: comparison of the blood and marrow compartments.

The plasma cell labeling Index (PCLI), a measure of marrow plasma cells in S phase of the cell cycle, provides a good estimate of the proliferative capacity of the malignant clonal plasma cells. Multiple studies have also demonstrated its prognostic value in multiple myeloma (MM). Clonal plasma cells have been demonstrated in the peripheral blood of patients with multiple myeloma. The labeling index of these circulating cells can also be determined by a method similar to that employed for marrow plasma cells. The goal of this study was to compare the proliferation kinetics of plasma cells in the marrow to that in the circulation. The PCLI was estimated on peripheral blood (PBLI) and bone marrow aspirates (BMLI) using a slide-based bromodeoxyuridine (BrdU) immunofluorescence microscopy technique. One hundred seventeen patients who had simultaneous estimation of the PBLI and BMLI and who had > or =90% of the blood cIg+ cells identified as monoclonal plasma cells were studied. The PBLI was generally lower than the BMLI (median difference 0.4) and correlated with the BMLI (rho = 0.491, P < 0.0001). Twenty-seven patients with PBLI higher than BMLI had a poorer prognosis, with median survival of 2 months from the time of the labeling index determination, compared to 12 months for the remaining 90 patients (P = 0.01). Myeloma plasma cells circulating in the peripheral blood are capable of proliferation, albeit at a slower rate compared to those in the marrow. These differences reflect a more favorable microenvironment in the marrow likely resulting from the differences in the cytokine levels and supporting stromal cells in the marrow.

Adult↗
PubMed2003

Expression of CD52 on plasma cells in plasma cell proliferative disorders.

Multiple myeloma (MM) and primary systemic amyloidosis (AL) remain incurable disorders, and new treatments targeted to the malignant plasma cells are needed. Alemtuzumab is a humanized monoclonal antibody to CD52 and has activity in chronic lymphocytic leukemia. We examined the CD52 expression on CD45+ and CD45- plasma cell populations to evaluate the potential for using alemtuzumab for these disorders. Bone marrows from 61 patients (29 AL, 23 MM, and 9 MGUS [monoclonal gammopathies of undetermined significance]) were studied using 3-color (CD38/45/52) flow cytometry. Among those with MGUS, MM, and AL, 67%, 52%, and 35%, respectively, were positive for CD52 expression. The CD52 expression was predominantly confined to the clonal CD38+/CD45+ plasma cell fraction with median expression of 68%, 88%, and 82% in MGUS, MM, and AL, respectively, compared with 18%, 6%, and 9% among the CD45- plasma cell population. Clinical trials are warranted in these diseases to learn the therapeutic benefit of anti-CD52 immunotherapy.

Alemtuzumab↗
PubMed2003

Acquired von Willebrand's syndrome: a single institution experience.

Acquired von Willebrand's disease or syndrome (AVWS) is a rare bleeding disorder distinguished from congenital von Willebrand's disease by age at presentation and absence of personal and family history of bleeding disorders. We report on 22 patients with AVWS seen over 25 years. Mean age at diagnosis was 61.3 years (range 38-86 years); most patients had a spontaneous or a post-operative hemorrhage at presentation. Gastrointestinal bleeding and epistaxis were the most common spontaneous symptoms. Bleeding time was prolonged in most patients, associated with marked reductions in plasma von Willebrand factor antigen and ristocetin cofactor activity. Plasma VWF multimer distribution was normal (type 1 pattern) in 5 patients, indeterminate (no multimers detectable) in 6 patients (type 3 pattern), and abnormal (decreased higher-molecular-weight multimers, type 2 pattern) in 11 patients. None of 17 patients tested had an inhibitor of ristocetin cofactor activity. An underlying malignant or benign hematologic disease was found in 18 patients, and 1 patient had Crohn's disease. Desmopressin was effective in only half the patients so treated, but all patients responded to treatment with VWF-containing concentrates. Resolution of AVWS occurred with therapy of lymphoma (1 patient) and chronic lymphocytic leukemia (1 patient). Sixteen patients were alive at last follow-up; no deaths were related to bleeding. AVWS may be more prevalent than has been appreciated; we estimate up to 0.04%. Awareness of the existence of AVWS is essential for diagnosis and appropriate management. Therapy of associated diseases may improve the bleeding disorder.

Adult↗
PubMed2003

An oncolytic measles virus engineered to enter cells through the CD20 antigen.

We have earlier shown that attenuated measles virus (MV) has therapeutic potential as a replicating oncolytic virus in models of non-Hodgkin's lymphoma (NHL). In the current study, we investigated whether we could obtain replicating MVs capable of entering CD20(+) target cells through an interaction between a single-chain (scFv) anti-CD20 antibody and the CD20 antigen, a target of considerable clinical relevance in NHL. We replaced the H envelope glycoprotein of MV by an H-scFv anti-CD20 fusion protein with and without a protease-cleavable linker. Biochemical analysis of purified virions confirmed that the modified H proteins were incorporated into the viral particles with efficiency similar to unmodified H. Experiments employing CHO cells and CHO cells expressing human CD20 indicated that the MVH alpha CD20 viruses were able to replicate well in CHOCD20 but not CHO cells. MVH alpha CD20 or a nonmodified control MV were administered systemically to immunodeficient mice bearing bilateral human tumor xenografts, one side with and the other side without CD20 expression. Growth of CD20(+) tumors was retarded by MVH alpha CD20 as compared with the control virus. The viruses had equivalent effects on the CD20(-) tumors. Thus we have demonstrated that the entry of a replicating oncolytic virus can be mediated through an interaction between a highly clinically relevant single-chain antibody and its target antigen, and we have shown that this interaction enhances in vivo oncolytic activity.

Amino Acid Sequence↗
PubMed2003

Bone marrow angiogenesis and circulating plasma cells in multiple myeloma.

Bone marrow (BM) angiogenesis is increased in multiple myeloma (MM) and has prognostic significance. The presence of circulating plasma cells (PCs) in MM is associated with a poorer prognosis. We examined BM biopsies obtained at diagnosis of MM for angiogenesis, and correlated the microvessel density (MVD) with the presence of circulating PCs. There was a positive correlation between the absolute number of circulating PCs and the mean MVD. This relationship was independent of the disease activity and of the PC burden in the marrow. The increased angiogenesis may promote plasma cell proliferation and enable PC migration into the circulation.

Bone Marrow↗
PubMed2003

Plasma levels of tumour necrosis factor alpha and interleukin-6 predict progression-free survival following thalidomide therapy in patients with previously untreated multiple myeloma.

We studied marrow angiogenesis and plasma levels of angiogenic cytokines in 38 patients receiving thalidomide therapy for previously untreated myeloma. The effect of therapy and the relationship of cytokine levels to myeloma cell proliferation, bone marrow microvessel density and progression-free survival (PFS) were studied. High pretreatment tumour necrosis factor-alpha (TNFalpha) levels (> 11 pg/ml) and increased interleukin (IL)-6 of > 2 pg/ml predicted for poorer PFS (TNFalpha, 48% versus 74% at 2 years, P = 0.01; IL-6, 24% versus 70% at 2 years, P = 0.01). None of the other parameters predicted response or PFS, and no significant changes in cytokine levels occurred with therapy.

Adult↗