Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisphosphonates have been used for the treatment of hypercalcemia associated with malignancies and osteoporosis. It was previously reported that the mevalonate pathway is involved in nitrogen-containing bisphosphonate-induced apoptosis in osteoclasts and myeloma cells. The aim of this study was to determine the effects of two bisphosphonates, incadronate, and newly developed bisphosphonate YM529 on human myeloma cells, U266, RPMI-8226, and HS-Sultan. Both incadronate and YM529 induced S-phase cell cycle arrest and apoptosis in these myeloma cells. Treatment of the myeloma cells with cell-permeable substrates for mevalonate pathways, geranylgeraniol, and farnesol prevented bisphosphonate-mediated growth suppression. Checkpoint kinases, Chk1/2, and MAPK became phosphorylated after stimulation with bisphosphonates in the myeloma cells. Bisphosphonate-induced apoptosis was partially prevented by the pretreatment with MAPK inhibitor. These results demonstrate that incadronate and YM529 suppress the proliferation of myeloma cells through mevalonate pathway and MAPK pathway.
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PMID:Nitrogen-containing bisphosphonates induce S-phase cell cycle arrest and apoptosis of myeloma cells by activating MAPK pathway and inhibiting mevalonate pathway. 1274 32

The knowledge and training of nursing staff is essential for the safety and comfort of patients receiving i.v. therapies. The use of i.v. bisphosphonates as an adjunct to standard antineoplastic therapies in patients with advanced cancer is becoming widespread. Zoledronic acid and pamidronate (Zometa and Aredia, Novartis Pharmaceuticals Corporation, East Hanover, NJ) are nitrogen-containing bisphosphonates. Pamidronate has been the standard of care for patients with osteolytic bone lesions from breast cancer or multiple myeloma. However, zoledronic acid, which has demonstrated increased potency and a broad clinical utility, is emerging as the new standard of care. In addition to treating hypercalcemia of malignancy, zoledronic acid is approved for treating patients with bone metastases (osteolytic or osteoblastic) from a wide range of solid tumors, including breast, prostate, and lung cancers, or osteolytic bone lesions from multiple myeloma. Zoledronic acid (4 mg via a 15-minute infusion) has a safety profile comparable with pamidronate (90 mg via a two-hour infusion) and has demonstrated comparable or superior efficacy to that of pamidronate in every patient population tested. The shorter infusion time of zoledronic acid compared with that of pamidronate may provide added convenience, but safety guidelines should be followed for all i.v. bisphosphonate therapies. These guidelines and nursing care of patients receiving i.v. bisphosphonates are reviewed.
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PMID:Advances in supportive care of patients with cancer and bone metastases: nursing implications of zoledronic acid. 1292 73

X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin's disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.
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PMID:New therapy for leukemia, polycythemia, and lymphoma. 1301 1

Epsilon (epsilon) chain is one of the five classes of immunoglobulins that plays an important role in allergic diseases. Production of monoclonal antibodies by a single clonotype against different epitopes of epsilon chain have high priority in development of diagnostic kits. In this study, an attempt was made to produce monoclonal antibodies against human epsilon chain. Balb/c mice were immunized with semipurified epsilon chain and spleen cells were fused with Sp2/0 mouse myeloma cell line in the presence of poly ethylene glycol. Supernatant of hybridoma cells were screened for detection of antibody by Enzyme-linked Immuno Sorbent Assay (ELISA) method. Cloning of selective high absorbance wells were done with limiting dilution method. The suitable clones (monoclones) were selected by ELISA and confirmed by immunoblot. The subclasses of the chosen monoclonal antibodies were determined and the clones freezed and kept in liquid nitrogen. During this study three successful fusions were carried out, which resulted in over than 100 clones with high production of anti- epsilon chain. Twelve clones with the highest titers were selected for cloning. After limiting dilution more than 50 monoclonal antibodies were produced and the unsuitable one (C1F2) displayed higher absorbance in reaction with purified IgE, relatively high cross-reactivity with IgM, and the highest cross-reactivity with IgG. In Immunoblotting, presence of relatively high-density band in reaction with IgE was confirmed. The unsuitable monoclonal antibody was shown to be IgG1 subclass with kappa light chain. It seems that, this monoclonal antibody could not be successfully useful in diagnostic kits.
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PMID:Development of hybridoma cells producing monoclonal antibody against human epsilon (epsilon) chain. 1464 37

Bone is a favorable microenvironment for tumor cell colonization because of abundant growth factors released during active bone resorption. Bisphosphonates can dramatically affect the ability of tumor cells to grow in bone by inhibiting osteoclast-mediated bone resorption and by depriving tumors of growth-promoting signals. Moreover, bisphosphonates have direct anti-tumor effects in vitro via induction of apoptosis. Zoledronic acid is a nitrogen-containing bisphosphonate that has demonstrated potent anti-tumor activity in vitro and in vivo. In vitro studies have provided important clues as to the molecular mechanisms by which zoledronic acid induces apoptosis of human breast cancer cell lines. Studies in multiple myeloma and breast cancer models have shed further light on the possible mechanisms underlying the in vivo anti-tumor effects of zoledronic acid. These studies have led to the development of novel strategies to target specific molecular pathways involved in osteoclast maturation and activity, tumor cell metastasis, and tumor growth and survival. The clinical application of these strategies may ultimately prevent bone metastasis.
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PMID:The anti-tumor potential of zoledronic acid. 1465 41

Nitrogen mustards (NMs) are useful chemotherapeutic agents in the treatment of lymphoma, leukemia, multiple myeloma, and ovarian carcinoma. The antitumor activity of NMs has been attributed to their ability to cross-link the twin strands of DNA. The resulting bifunctional lesions, if not repaired, can inhibit DNA replication and transcription, eventually leading to cell cycle arrest, apoptosis, and the inhibition of tumor growth. The predominant bifunctional DNA lesions of NM have been reported to involve the distal guanine bases in the opposite strands of 5'-GNC sequences. In the present work, the formation of guanine-adenine and adenine-adenine adducts of N,N-bis(2-chloroethyl)methylamine (mechlorethamine) in double-stranded DNA is demonstrated. Guanine-adenine cross-links of mechlorethamine were identified as N-(2-[N3-adenyl]ethyl)-N-(2-[N7-guanyl]ethyl)methylamine (N3A-N7G-EMA), N-(2-[N1-adenyl]ethyl)-N-(2-[N7-guanyl]ethyl)methylamine, and N-(2-[N(6)-adenyl]ethyl)-N-(2-[N7-guanyl]ethyl)methylamine. All three adducts were produced interstrand, while N3A-N7G-EMA was the dominant intrastrand G-A cross-link. The prevalent adenine-adenine mechlorethamine lesions have the structure of N,N-bis(2-[N3-adenyl]ethyl)methylamine (bis-N3A-EMA). DNA-derived lesions have the same HPLC retention times, UV spectra, and MS/MS fragmentation patterns as the authentic standards prepared independently. bis-N3A-EMA lesions were produced in a concentration-dependent manner in calf thymus DNA treated with increasing amounts of mechlorethamine. Furthermore, HPLC-ESI-MS/MS analysis was used to demonstrate the formation of analogous N3-N3 adenine lesions in DNA treated with aromatic nitrogen mustards, N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid and L-phenylalanine mustard. The presence of cross-linked adenine-adenine lesions may explain the enhanced cytotoxicity and mutagenicity of NMs in cells deficient in N3-alkyladenine glycosylase.
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PMID:Adenine-containing DNA-DNA cross-links of antitumor nitrogen mustards. 1525 21

Peripheral blood CD14+ monocytes from multiple myeloma (MM) patients can be induced to differentiate into fully functional, mature, CD83+ dendritic cells (DCs) which are highly efficient in priming autologous T lymphocytes in response to the patient-specific tumor idiotype (Id). We have recently scaled up our manufacturing protocol for application in a phase I-II clinical trial of anti-Id vaccination with DCs in MM patients. Elegible patients received a series of by-monthly immunizations consisting of three subcutaneous and two intravenous injections of Id-keyhole limpet hemocyanin (KLH)-pulsed DCs (5 x -, 10 x -, 50 x 10(6) cells and 10 x -, 50 x 10(6) cells, respectively). To generate DCs, monocytes were labeled with clinical grade anti-CD14 conjugates and positively selected by immunomagnetic separation. Cells were then cultured, according to Good Manufacturing Practice guidelines, in FCS-free medium in cell culture bags, and differentiated to DCs with GM-CSF plus IL-4 followed by TNF-alpha or, more recently, by a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. Before maturation, Mo-DCs were pulsed with the autologous Id as whole protein or Id (VDJ)-derived HLA class I restricted peptides. Ten MM patients, who had been treated with two courses of high-dose chemotherapy with peripheral blood stem cell support, entered into the clinical study. CD14+ monocytes were enriched from 16.1+/-5.7% to 95.5+/-3.2% (recovery 67.9+/-15%, viability > 97%). After cell culture, phenotypic analysis showed that 89.6+/-6.6% of the cells were mature DCs. We obtained 2.89+/-1 x 10(8) DCs/leukapheresis which represented 24.5+/-9% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (31+/-10.9 of initial CD14+ cells) of DCs than TNF-alpha alone, secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic and autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of pre-loaded DCs. The recovery of thawed, viable DCs, was 78+/-10%. Thus, positive selection of CD14+ monocytes allows the generation of a uniform population of mature pre-loaded DCs which can be cryopreserved with no effects on phenotype and function and are suitable for clinical trials. Based on these results, a DCs-based phase II trial of anti-Id vaccination with VDJ-derived HLA class I-restricted peptides and KLH is underway for lymphoma patients.
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PMID:Generation of dendritic cells from positively selected CD14+ monocytes for anti-tumor immunotherapy. 1535 43

The intravertebral vacuum cleft sign (VCS) is an uncommon radiological sign, characterized by a radiolucent zone in the vertebral body. It is composed of 95% nitrogen and small amounts of oxygen and carbon dioxide. Post-traumatic ischemic necrosis could be its physiopathological mechanism, along with other pathologies like osteoporosis, corticosteroid therapy, diabetes, arteriosclerosis, alcoholism, multiple myeloma, bone metastasis and osteomyelitis. The broad diagnosis is made by antero-posterior X-ray, but computed tomography scan (CT scan) and magnetic resonance imaging (MRI) may help with the differential diagnosis. The aims of this paper are, on one hand, to communicate the clinical case of a 73-year-old osteoporotic woman with traumatic vertebral fractures who developed this sign in her radiological survey. On the other hand, its secondary aims are to review the medical literature about this sign and to show the clinical and radiological evolution after a percutaneous vertebroplasty.
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PMID:The vacuum cleft sign: an uncommon radiological sign. 1573 85

With recent advances in cancer management, patients with metastatic bone disease are likely to have a prolonged clinical course, with skeletal-related events such as pain, hypercalcemia, pathologic fractures, spinal cord and nerve compression. Bisphosphonate use has resulted in the reduction of skeletal-related complications for a number of tumors including breast, prostate and myeloma, and improvements in the quality of life for patients. There is now evidence that newer, highly potent, nitrogen-containing bisphosphonates reduce skeletal complications in patients with bone metastases from other solid tumors (including lung cancer). The early identification of patients at high risk for developing bone metastases may help curtail a complex and costly clinical problem--skeletal-related events. In this article, we review the different mechanisms of bisphosphonates and the potential role of newer-generation bisphosphonates, such as zoledronic acid, in the management of advanced, metastatic bone disease. We include a review of mechanistic studies and preclinical data. Additionally, the utility of evolving concepts such as bone markers and imaging of bone metastases are discussed.
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PMID:The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications. 1577 88

Bisphosphonates have demonstrated important clinical benefits for patients with malignant bone disease, metabolic bone diseases, such as Paget's disease, and postmenopausal osteoporosis. The introduction of nitrogen-containing bisphosphonates with high affinity for hydroxyapatite in bone represents an important advancement. These agents are now a standard of care for osteoporosis, Paget's disease, osteogenesis imperfecta, primary bone lesions from multiple myeloma and bone metastases from breast cancer. Moreover, the recent clinical development of zoledronic acid (4 mg by 15-minute intravenous infusion) has expanded the benefits of bisphosphonate therapy to patients with bone metastases from any solid tumour. Bisphosphonates are also being investigated at present for the prevention of bone loss resulting from cancer therapy. In addition, a variety of novel biologic agents, receptor activator of nuclear factor-kappaB (RANK) ligand antibodies, osteoprotegerin and cathepsin K inhibitors are being investigated at present for the treatment of malignant bone disease. The management of bone health is an important area of active research, and the armamentarium and role of bone-specific therapies continue to expand.
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PMID:New therapeutic agents for the treatment of bone diseases. 1595 12


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