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

The anti-diquat (DQ) monoclonal antibodies with high specificity were produced. An immunogen was synthesized by binding DQ to bovine serum albumin via a diazo-coupled intermediate. BALB/c mice were injected intraperitoneally once a month with 0.25 mg of the immunogen for 5 months. Their spleen cells were fused with P3U1 myeloma cells to get hybridoma clones secreting anti-DQ antibodies. Two anti-DQ monoclonal antibodies (ADM-1, ADM-2) were subtyped to be IgM and IgG3, respectively. A competitive ELISA was developed with ADM-2. More than 0.05 micrograms of DQ was measured without any interference from human serum. The ADM-2 showed high affinity for DQ and no cross-reactivities with paraquat and other analogues. DQ in sera of poisoning patients were successfully determined by the ELISA. On the other hand, the ADM-2 was applicable to the immunohistochemical demonstration of DQ distribution in experimental animals. An avidin-biotin-peroxidase complex method was used in this immunohistochemical study. DQ-intoxicated rats were killed at 3 h, 12 h, 24 h, 3 days and 7 days after intravenous administration of DQ (30 mg/kg). The macrophages containing DQ in the lung started to be observed at 12 h after injection and the number increased till 7 days. From 3 hours after injection, DQ was localized in the epithelial cells of the distal tubules and collection tubules, but not in the glomeruli in the kidney. In the heart, at every time from 3 h to 7 days after DQ administration, a few myocardial cells were positive with the immunohistochemical staining. The ADM-2 was expected to be available in practice of forensic and analytical toxicology.
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PMID:[Production of monoclonal antibody against diquat and its application for forensic medicine]. 181 Nov 7

In this article, the clinical effects of rH-TNF on various cancer patients and the mechanism of self-induction of defense against rH-TNF cytotoxicity in tumor cells and the counter measures against this are reviewed. 1) Clinical effects of rH-TNF Intratumoral administration of rH-TNF was performed in 7 patients and clinical efficacy (PR + MR) was observed in 3/7 (42.9%). Also a reduction of leukemia cells in peripheral blood was observed in all 4 leukemia patients following intravenous (i.v.) administration of rH-TNF. Furthermore, in 2 multiple myeloma patients, the myeloma protein and plasma cells in bone marrow were reduced by i.v. administration of rH-TNF. 2) Self-induction of defense against rH-TNF cytotoxicity Investigation of the effect of TNF on RNA and protein synthesis by tumorigenic and normal cell lines showed that their synthesis in tumor cells was increased at 12 h and peaked at 24 h of incubation with TNF, while that in normal diploid fibroblast (HEL) cells was apparently unaffected by the presence of TNF. Artificial inhibition of either RNA or protein synthesis by L-M cells, upon addition of Act D or CHI increased the cytotoxic effect of TNF, thus suggesting that the elevated RNA and protein synthesis is related not to the cytotoxic reaction itself but rather to a defense mechanism. Similar incubation of HEL cells with TNF in the presence of either inhibitor resulted in the occurrence of cytotoxicity not observed with TNF alone, thus suggesting the existence of a defense mechanism in normal, TNF-resistant cells which is absent or greatly weakened in tumor cells. 3) Combination therapy of rH-TNF with various anticancer drugs. A synergistic increase in the cytotoxic effects of rH-TNF and anti-cancer drugs was demonstrated in vitro The cytotoxicity of rH-TNF against L-M cells in combination with MMC, ADM, Ara-C, ACD, DM, CDDP, VCR and 5-FU was 4 to 347 times as high as that of rH-TNF alone. These results suggest that combination therapy including rH-TNF and anti-cancer drugs may be of value in the treatment of malignancy in human patients.
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PMID:[Anti-tumor effect of human recombinant TNF]. 329 72

The present AML protocol which only applies one anthracycline associated with arabinosyl-cytosine gives a first remission plateau of 65% and a 75% survival plateau at five years. Contrary to other teams, we do not apply the allogenic bone marrow graft at the first remission but at the second one. The new protocol comprises application of two anthracyclines, adriamycin and aclacinomycin, a possible autologous bone marrow graft at first remission upon reinforcement, a combination of methotrexate and thioguanine as maintenance chemotherapy and immunotherapy with bestatine. The two protocols respectively applied to the ALL good prognosis and reserved prognosis, give 85% global survival. The autologous bone marrow graft is added at first remission to B or T forms or voluminous CALLA + types. The advantage of CNS radiotherapy is compared with its disadvantages. Bestatine is employed in immunotherapy. The immunoprevention protocol applied to CML blastic crisis (vaccination with a pool of CB blasts) from the second year has prolonged survival of patients suffering from this affection and also treated by splenectomy and hydroxyurea. Allogeneic or autologous bone marrow graft is added to the protocol. The same protocol is applied to not very aggressive LLC and LNH (lymphocytic and centrofollicular with small cleaved nucleus cells) and includes maximum remission induced by chemotherapy followed by immunotherapy (by thymuline and then, if immunity disorders are not corrected, by zinc, then bestatine and finally tuftsin). A similar sequence was applied to the myeloma, comprising MLP-PDN-CPM chemotherapy to induce remission, combination of MLP-PDN and CPM and, if there is resistance, CLB, 6-TG, PDN and TNP. Interferon is appropriate with certain cytopenic forms. A protocol comprising VCR, ADM, PDN, CPM and TNP is applied to centrofollicular NHL with small non cleaved nucleus cells or large cells. As Hoerni and Jones have obtained significant benefits with BCG, its terminal application is compared with that of bestatine. Finally a less mutagenic protocol than MOPP and/or ABVD is proposed for Hodgkin's disease. In this protocol, two cycles alternate, and they combine: a) firstly VCR, PDN, THP-ADM and VPS, and b) secondly VLB, DXM, ACM and TNP with alternatively BLM and PPM between the cycles. This chemotherapy is followed by the same immunorestoration protocol as that applied to LLC and myeloma.
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PMID:[Protocols for the treatment of leukemia and lymphoma: toward escalation or toward reduction of degree?]. 638 Jun 5

For elderly patients with multiple myeloma (MM), conventional melphalan and prednisone (MP) therapy has been the treatment of choice; the vincristine, doxorubicin and dexamethasone (VAD) regimen is preferred for younger patients who also receive high-dose melphalan in combination with autologous or allogeneic bone marrow transplantation (BMT). Although survival time is similar in both the MP and VAD regimens, the continuous infusion of doxorubicin which the latter treatment entails constitutes a disadvantage along with the 4-day hospitalization required. Doxorubicin also induces cardiotoxicity, particularly in the elderly. A modified form of VAD therapy includes liposomal doxorubicin (Caelyx) (40 mg/m2 for 1 d) [corrected], oncovin (2 mg for 1 d) and dexamethasone 40 mg for 4 d per os. Doxorubicin encapsulated with liposomes has less cardiotoxicity, is more efficient and has fewer side effects than conventional doxorubicin, and it can be administered on an outpatient basis: dexamethasone can be given orally and vincristine in bolus infusion. In order to estimate its efficacy and tolerability, we administered this regimen to 12 patients (first-line treatment in 6 patients, salvage therapy in 6 patients). All patients exhibited good tolerance to liposomal doxorubicin with no severe side effects. Eight patients achieved complete hematological remission and three partial response. One patient died before completing the treatment. In conclusion, compared to other therapies, this modified VAD regimen containing liposomal doxorubicin can be more easily administered to MM patients, without severe side effects and with increased full remission rates, almost similar to those with the conventional VAD treatment.
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PMID:Administration of a modified chemotherapeutic regimen containing vincristine, liposomal doxorubicin and dexamethasone to multiple myeloma patients: preliminary data. 1096 72

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non-Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.
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PMID:Proteasome inhibition in hematologic malignancies. 1522 57

Encapsulation of doxorubicin in polyethylene glycol-coated liposomes (Doxil/Caelyx [PLD]), was developed to enhance the safety and efficacy of conventional doxorubicin. The liposomes alter pharmacologic and pharmacokinetic parameters of conventional doxorubicin so that drug delivery to the tumor is enhanced while toxicity normally associated with conventional doxorubicin is decreased. In animals and humans, pharmacokinetic advantages of PLD include an increased area under the plasma concentration-time curve, longer distribution half-life, smaller volume of distribution, and reduced clearance. In preclinical models, PLD produced remission and cure against many cancers including tumors of the breast, lung, ovaries, prostate, colon, bladder, and pancreas, as well as lymphoma, sarcoma, and myeloma. It was also found to be effective as adjuvant therapy. In addition, it was found to cross the blood-brain barrier and induce remission in tumors of the central nervous system. Increased potency over conventional doxorubicin was observed and, in contrast to conventional doxorubicin, PLD was equally effective against low- and high-growth fraction tumors. The combination of PLD with vincristine or trastuzumab resulted in additive effects and possible synergy. PLD appeared to overcome multidrug resistance, possibly as the result of increased intracellular concentrations and an interaction between the liposome and P-glycoprotein function. On the basis of pharmacokinetic and preclinical studies, PLD, either alone or as part of combination therapy, has potential applications to treat a variety of cancers.
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PMID:Pegylated liposomal doxorubicin: proof of principle using preclinical animal models and pharmacokinetic studies. 1571 36

Patients with multiple myeloma (MM) typically respond to initial chemotherapy, but almost all patients relapse with a median survival of approximately 5 years. Combining vincristine and conventional doxorubicin with oral dexamethasone (VAD) or reduced-dose dexamethasone (VAd) provides rapid response in many patients, but its use is limited by toxicity concerns and the inconvenience of continuous infusions in each cycle. Use of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) and vincristine intravenous injection with oral dexamethasone (DVD) or reduced-dose dexamethasone (DVd) is safe and effective for the management of newly diagnosed or relapsed/refractory MM. Controlled trials showed that DVD/DVd is at least as effective as VAD/VAd for the treatment of MM, but DVd is associated with less neutropenia and alopecia in addition to requiring fewer days in the hospital or clinic for drug administration. DVd therapy has also been reported to be associated with an antiangiogenic effect not observed with VAD. Another liposomal anthracycline, liposomal daunorubicin (DaunoXome [DNX]), has been investigated in MM and preliminary data suggest that it is safe and effective, but studies comparing it with other regimens have not been reported. Early results from ongoing trials suggest that adding thalidomide, bortezomib, or other immune modulators to PLD-based chemotherapy may improve efficacy.
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PMID:Role of liposomal anthracyclines in the treatment of multiple myeloma. 1571 41

The aim of this prospective, multicenter, phase II study was to investigate the combination of pegylated liposomal doxorubicin (Caelyx) 40 mg/m2 on day 1 every 28 days, dexamethasone 40 mg p.o. on days 1-4 and 9-12 and thalidomide 100 mg daily in 50 patients with advanced multiple myeloma. Twenty-six percent of patients achieved a complete response, 6% a near complete response, 6% a very good partial response, 38% a partial response, 16% a minor response and 8% progressed, for an overall response rate of 92%. The median event-free survival was 17 months and the median overall survival was not reached. Grade 3 non-hematologic toxicity occurred in 12% of patients, thromboembolic disease in 12% and severe infection in 16%. The combination of pegylated liposomal doxorubicin, dexamethasone an thalidomide is safe and very effective in advanced multiple myeloma.
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PMID:Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study. 1643 83

Pegylated liposomal doxorubicin (Doxil, Caelyx) is associated with less frequent neutropenia, alopecia and cardiotoxicity than conventional doxorubicin and has an improved pharmacokinetic profile, allowing for intravenous administration over 1 hour. In the US and EU (as well as a number of other countries), pegylated liposomal doxorubicin is approved for use in combination with the proteasome inhibitor bortezomib for the treatment of patients with relapsed or refractory multiple myeloma. Results of the primary efficacy analysis of a large phase III trial in bortezomib-naive patients with relapsed or refractory multiple myeloma demonstrated that the combination of pegylated liposomal doxorubicin plus bortezomib significantly prolonged the time to progression (TTP) compared with bortezomib alone. In addition, pegylated liposomal doxorubicin plus bortezomib significantly increased TTP in most subgroup analyses, including in patients with or without previous anthracycline exposure. A number of secondary outcomes, including progression-free survival and overall survival at 15 months, were also improved with the combination compared with bortezomib alone in the overall study population. Pegylated liposomal doxorubicin plus bortezomib was associated with a higher incidence of grade 3 or 4 adverse events than bortezomib alone, which was mainly attributed to an increase in myelosuppression and gastrointestinal events with the combination. These events were predictable and often managed by dosage modifications and supportive therapy. The addition of pegylated liposomal doxorubicin to bortezomib treatment did not increase the incidence of cardiotoxicity or peripheral neuropathy, but did induce hand-foot syndrome in a proportion of patients. Pegylated liposomal doxorubicin plus bortezomib is now established as an additional standard of care in the treatment of patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
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PMID:Pegylated liposomal Doxorubicin: a review of its use in the treatment of relapsed or refractory multiple myeloma. 1901 77

Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.
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PMID:Induction of angiogenesis by normal and malignant plasma cells. 1929 35


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