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)

The effects of two cationic synthetic peptides, derived from the C-terminal region of Lys49 phospholipase A2 homologues from snake venoms, upon various murine tumor cell lines (B16 melanoma, EMT6 mammary carcinoma, S-180 sarcoma, P3X myeloma, tEnd endothelial cells) were evaluated. The peptides are 13-mers derived from Agkistrodon piscivorus piscivorus Lys49 PLA2 (p-AppK: KKYKAYFKLKCKK) and Bothrops asper Lys49 myotoxin II (pEM-2[D]: KKWRWWLKALAKK), respectively, in the latter case with slight modifications and with all-D amino acids. All tumor cells tested were susceptible to the lytic action of the peptides. The susceptibility of tumor cell lines was not higher than that of C2C12 skeletal muscle myoblasts, utilized as a non-transformed cell line control. However, in a murine model of subcutaneous solid tumor growth of EMT6 mammary carcinoma, the intraperitoneal administration of pEM-2[D] caused a tumor mass reduction of 36% (p<0.05), which was of similar magnitude to that achieved by the administration of paclitaxel, an antitumor drug in clinical use. Thus, the C-terminal peptides of Lys49 phospholipase A2 homologues present antitumor effects that might be of interest in developing therapeutic strategies against cancer.
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PMID:Antitumor effects of cationic synthetic peptides derived from Lys49 phospholipase A2 homologues of snake venoms. 1717 38

Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of bortezomib dosing. Here we describe the antitumor activity of PR-171, a novel epoxyketone-based irreversible proteasome inhibitor that is currently in clinical development. In comparison to bortezomib, PR-171 exhibits equal potency but greater selectivity for the chymotrypsin-like activity of the proteasome. In cell culture, PR-171 is more cytotoxic than bortezomib following brief treatments that mimic the in vivo pharmacokinetics of both molecules. Hematologic tumor cells exhibit the greatest sensitivity to brief exposure, whereas solid tumor cells and nontransformed cell types are less sensitive to such treatments. Cellular consequences of PR-171 treatment include the accumulation of proteasome substrates and induction of cell cycle arrest and/or apoptosis. Administration of PR-171 to animals results in the dose-dependent inhibition of the chymotrypsin-like proteasome activity in all tissues examined with the exception of the brain. PR-171 is well tolerated when administered for either 2 or 5 consecutive days at doses resulting in >80% proteasome inhibition in blood and most tissues. In human tumor xenograft models, PR-171 mediates an antitumor response that is both dose and schedule dependent. The antitumor efficacy of PR-171 delivered on 2 consecutive days is stronger than that of bortezomib administered on its clinical dosing schedule. These studies show the tolerability, efficacy, and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies using dose-intensive schedules.
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PMID:Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. 1761 98

The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q-myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated. The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein. Encouraging results with these thalidomide analogues brought forth synthesis and screening of additional novel thalidomide analogues in the N-substituted and tetrafluorinated classes, including CPS11 and CPS49. This review also discusses the patents and preclinical findings for these agents.
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PMID:Thalidomide analogues as anticancer drugs. 1797 53

Quinolines are a class of chemical compounds with emerging anti-cancer properties. Here, we tested the activity of series of quinolines and quinoline-like molecules for anti-cancer activity and identified a novel diquinoline, 1-methyl-2-[3-(1-methyl-1,2-dihydroquinolin-2-yliden)prop-1-enyl]quinolinium iodide (Q(2)). Q(2 )induced cell death in leukemia, myeloma, and solid tumor cell lines with LD50s in the low to submicromolar range. Moreover, Q(2) induced cell death in primary acute myeloid leukemia (AML) cells preferentially over normal hematopoietic cells. In a mouse model of leukemia, Q(2) delayed tumor growth. Mechanistically, Q(2) induced cell death through caspase independent mechanisms. By electron microscopy, Q(2) increased cytoplasmic vacuolization and mitochondrial swelling. Potentially consistent with the induction of autophagic cell death, Q(2) treatment led to a punctate distribution of LC3 and increased MDC staining. Thus, Q(2) is a novel quinolinium with preclinical activity in malignancies such as leukemia and myeloma and warrants further investigation.
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PMID:A novel diquinolonium displays preclinical anti-cancer activity and induces caspase-independent cell death. 1841 80

Multiple malignancies in the same patient are unusual. This is particularly true for patients with hematologic malignancies who have a concomitant solid tumor. We report the unexpectedly higher frequency of renal cell carcinoma (RCC) associated with plasma cell dyscrasias. We report 6 cases of RCC in our institutional database of 600 patients with plasma cell dyscrasias over the past 10 years. We discuss the possible mechanisms that predisposed these patients to a secondary malignancy.
Clin Lymphoma Myeloma 2008 Jun
PMID:Association between renal cell carcinoma and plasma cell dyscrasias: a case series of six patients. 1865 Jan 85

73-year-old woman complaining of bone pain and weight loss was suspected to have a malignant disease, and extensive laboratory investigations were carried out. She was diagnosed with multiple myeloma; however, because of the finding of extremely high serum levels of CA125 and CA15.3 and focal liver lesions, a concomitant solid tumor was suspected, which was then excluded with the appropriate tests, including an ultrasound-guided liver biopsy. While being diagnosed, the patient developed a rapidly evolving plasma cell leukemia with a simultaneous increase in CA125 and CA15.3. After treatment with cyclophosphamide and dexamethasone, the peripheral blood plasma cells disappeared and there was a dramatic decrease in the CA125 and CA15.3 tumor markers. High levels of the latter can be observed in patients with aggressive plasma cell dyscrasias, an observation that is crucial in order to avoid unnecessary tests that can result in treatment delay.
Clin Lymphoma Myeloma 2008 Oct
PMID:Increased serum tumor markers (CA125 and CA15.3) in primary plasma cell leukemia: a case report and review of the literature. 1885 88

Bortezomib has recently become the new treatment standard for relapsed or refractory multiple myeloma. We previously demonstrated that bortezomib also had a significant growth-inhibiting and apoptotic effect on squamous cell carcinoma of the head and neck (SCCHN) cells in vitro. Preclinical evidence has provided a rationale for combining bortezomib with dexamethasone in multiple myeloma, suggesting that the therapeutic effects of the two agents might be additive. These findings are in contrast with the results achieved in solid tumor models where the addition of dexamethasone reduced the efficacy of other antineoplastic drugs. In the present study, we investigated the effect of dexamethasone in combination with bortezomib in SCCHN cell lines for the first time. The antiproliferative effect of bortezomib alone or in combination with increasing concentrations of dexamethasone was investigated in four SCCHN cell lines. Cell growth inhibition and viability were measured quantitatively using WST and LDH assays. Bortezomib alone inhibited the growth of all four SCCHN cell lines significantly (p<0.047). The addition of dexamethasone leads to a clear tumor cell decline and showed a trend in enhancing the growth-inhibitory effect of bortezomib although the difference failed to reach statistical significance (p>0.05). Our first results show that dexamethasone increased the cytotoxic activity of bortezomib in most SCCHN cell lines investigated. These findings might be dependent on molecular factors such as the degree of tumor cell differentiation and proliferation rate. Therefore, further studies will be required to elucidate these molecular factors to substantiate our findings from a cancer biological point of view.
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PMID:Effects of combination treatment of bortezomib and dexamethasone in SCCHN cell lines depend on tumor cell specificity. 1894 23

Historically, most drugs developed for treatment of leukemias, lymphomas, and myeloma had already been studied in the solid tumor setting. Nearly 10 years ago, chronic myelogenous leukemia (CML) forever changed this paradigm. Imatinib showed that it was possible to nullify the pathognomic genetic lesion in a hematologic malignancy. Since the approval of imatinib for CML, a host of new drugs active in blood cancers have emerged. This article highlights some areas of innovative drug development in lymphoma where possible; it emphasizes the biologic basis for the approach, linking this essential biology to the biochemical pharmacology. The article focuses on the many new targets including Syk, Bcl-2, CD-40, and the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin pathway.
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PMID:New drugs for the treatment of lymphoma. 1895 49

Upon its 'reinvention', thalidomide was quickly applied to 'microenvironment-dependent' diseases such as multiple myeloma, yet its role in the solid tumor spectrum has not been validated. A report into recurrent prostate cancer by Figg et al. shows that thalidomide can reduce time to PSA progression in patients treated with androgen deprivation therapy.
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PMID:Prostate cancer: thalidomide for prostate cancer: is there progress? 1942 70

When the primary site is unknown in patients with spinal metastases, there can be problems in locating the site of tumor origin. Most previous reports on metastases of unknown origin have not been limited to the spine. The purpose of this study is to assess the usefulness of laboratory analysis, chest, abdominal and pelvic CT and CT-guided biopsy in patients with spinal metastases of unknown origin (SMUO). A retrospective review of the clinical histories of 27 patients with SMUO was done. A total of 43 patients with SMUO were seen at our institution between 2002 and 2007. Of the 43 patients, 27 who underwent all 3 tests (laboratory analysis including M protein and tumor markers, chest, abdominal and pelvic CT and CT-guided biopsy) were included in this study. We retrospectively assessed the diagnostic usefulness of those 3 tests in the 27 patients. In 27 patients, the final diagnosis was obtained in 26 patients. Myeloma was the most common malignancy followed by lung carcinoma. M protein was positive in all 7 patients with myeloma and negative in patients with other malignancies. The level of tumor markers was elevated in 16 of 17 patients with a solid tumor and in all 3 with lymphoma. CA15-3 was elevated in 4 of 27 patients, CA19-9 in 5 of 27 patients, CA125 in 2 of 27 patients, CEA in 6 of 27 patients, SCC in 2 of 27 patients, NSE in 7 of 27 patients, AFP in 1 of 27 patients, PIVKA-II in 1 of 27 patients, TPA in 6 of 27 patients, IAP in 3 of 12 patients, thyroglobulin in 2 of 27 patients, sIL-2R in 3 of 24 patients, and PSA in 5 of 17 male patients. Myeloma, lymphoma and prostate carcinoma had a marker with high sensitivity and specificity (M protein, sIL-2R and PSA). Eleven primary tumor sites (40.7%) were detected (6 lung, 1 prostate, 1 kidney, 1 thyroid, 1 liver, and 1 pancreas) by chest, abdominal and CT scanning. Biopsy led to determination of the final diagnosis in 12 (44.4%) of 27 patients (5 myelomas, 3 lymphomas, 2 prostate carcinomas, 1 renal-cell carcinoma, 1 thyroid carcinoma). In the remaining 15 patients, biopsy did not lead to determination of the final diagnosis, because the histological diagnosis was either an adenocarcinoma or an undifferentiated carcinoma, the tissue sample was not diagnostic. A laboratory analysis limited to specific tumor markers such as PSA and protein electrophoresis is considered to be useful in making a final diagnosis. Chest, abdominal and pelvic CT is considered to be useful for making a final diagnosis in solid tumors, but not for hematologic tumors. A CT-guided biopsy had a low determination rate in the final diagnosis in comparison to a laboratory analysis and CT scanning for solid tumors and it is not considered to be essential for the diagnosis of hematologic tumors.
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PMID:Diagnosis of a previously unidentified primary site in patients with spinal metastasis: diagnostic usefulness of laboratory analysis, CT scanning and CT-guided biopsy. 1953 81


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