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 increased risk of nonocular cancer seen consistently in studies of survivors of retinoblastoma may be caused in part by the presence of a retinoblastoma gene that also predisposes to other cancers. It has been claimed that this gene also increases the risk for cancer among unaffected relatives of genetic retinoblastoma probands. We report here a population-based study of the risk of nonocular cancer in parents and siblings of persons notified to the Danish Cancer Registry with retinoblastoma during 1943-84. No excess was observed among first degree relatives of 61 genetic retinoblastoma probands, whereas a slight (10%) excess was seen among the parents of 115 nongenetic probands. The latter was the result of significant excesses of malignant melanoma (4 observed, 0.4 expected), multiple myeloma (2 observed, 0.2 expected) and osteogenic sarcoma (1 observed, 0.03 expected). The observed risk pattern cannot be explained by the presence of the retinoblastoma gene.
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PMID:Risk of nonocular cancer in first-degree relatives of retinoblastoma patients. 239 44

Recently, the National Cancer Institute published a comprehensive monograph on multiple primary cancers in Connecticut and Denmark. This paper summarizes some of the observations made on the Connecticut population. Data compiled by the Connecticut Tumor Registry have extended our knowledge about the patterns of multiple primary cancers, especially among long-term survivors of cancer and among patients with relatively rare tumors about which little information currently exists. When compared with the general Connecticut population, cancer patients had a 31 percent (RR = 1.31) increased risk of developing a second cancer and a 23 percent (RR = 1.23) elevated risk of second cancer at a different site from the first. Common environmental exposures seemed responsible for the excess occurrence of many second cancers, particularly those related to cigarette smoking, alcohol consumption, or both. For example, persons with epithelial cancers of the lung, larynx, esophagus, buccal cavity, and pharynx were particularly prone to develop new cancers in the same or contiguous tissue throughout their lifetimes. Cancers of the colon, uterine corpus, breast, and ovary frequently occurred together, suggesting underlying hormonal or dietary influences. Only patients with prostate cancer were at significantly low risk for second cancer development; this might be an artifact of case finding, since advanced age at initial diagnosis was generally associated with an underascertainment of second cancers. Radiotherapy may have caused rectal and other cancer among patients with cancers of the female genital tract, and leukemia among patients with uterine corpus cancer. Chemotherapy with alkylating agents probably contributed to the excess of acute nonlymphocytic leukemia following multiple myeloma or cancers of the breast and ovary. Genetic susceptibility seemed to explain some tumor complexes, such as the multiple occurrences of cutaneous melanoma and the excess of bone cancer following retinoblastoma. Research into multiple cancer syndromes should enhance our understanding of carcinogenic factors and mechanisms and the development of strategies for cancer prevention and control.
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PMID:Multiple primary cancers in Connecticut, 1935-82. 354 9

The surface fixation method has been found to be a reliable procedure for detection of antibodies of retrogenetic origin in cancer serum and also for specific immunoglobulins stimulated by antigens sinthezized in malignant cells. An insoluble extract obtained from human placentas has been used for detection of retrogenectic antibodies and with soluble substances obtained from the urine of patients it has been possible to detect what seem to be specific antibodies in retinoblastoma, Hodgkin, sarcoma and carcinoma. However with a urine extract from leukemia patients the positive reactions occur with leukemia serum from leukemia as well as with the related lymphoma and myeloma. Circulating tumor associated antigens can be detected in mixtures of an anti-fetal serum with cancer serum, but cross-reactions have been found in similar tests with pregnant women's serum.
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PMID:A simple test for detection of specific and unspecific immunological reactions in cancer. 739 35

Increased P-glycoprotein expression has been shown to be the molecular cause of multidrug resistance in tumor cell lines. Sensitive immunohistochemical and molecular biologic techniques have been developed to detect P-glycoprotein/mdr1 mRNA expression in clinical samples of tumors. We have reviewed the tools now available for assessment of P-glycoprotein expression in the clinic, the current evidence for a relevant role of the protein in mediation of resistance to chemotherapy, and one strategy used to overcome therapeutic failures due to multidrug resistance. It is now recognized that low levels of increased P-glycoprotein/mdr1 mRNA can occur at diagnosis and during the course of treatment in some cases of acute myelogenous leukemia, non-Hodgkin's lymphoma, multiple myeloma, breast carcinoma, rhabdomyosarcoma and undifferentiated sarcoma of children, neuroblastoma, and retinoblastoma, and these relatively low levels of mdr1 overexpression appear to be associated with poor prognosis. In contrast, it has not been established whether a multidrug resistance mechanism is the rate-limiting factor in response to chemotherapy in carcinomas that arise from tissues normally expressing increased P-glycoprotein. Clinical trials have been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy-treated malignancies. Preliminary results suggest that chemosensitizers can modulate the effects of increased P-glycoprotein in low-expressing tumors for which effective multiagent chemotherapy is available. Further research is needed for more potent chemosensitizers or combinations of agents that can be used more effectively. The successful circumvention of chemotherapy failure by chemosensitizers will ultimately establish the clinical relevance of the P-glycoprotein efflux mechanism.
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PMID:Multidrug resistance. Clinical opportunities in diagnosis and circumvention. 791 5

Deletion of the retinoblastoma gene (Rb-1) was found in more than 50% (12/23) of patients with multiple myeloma (MM) by fluorescence in situ hybridization (FISH). Myeloma cells were highly purified from bone marrow aspirates by flow cytometry and analyzed using probes specific for the Rb-1 gene and the centromeric region of chromosomes 13 and 21. Routine cytogenetics revealed abnormal chromosome 13 in only 17% (4/23) of these patients. No correlation between Rb-1 deletion and tumor stage, immunoglobulin isotype, anemia, serum beta-2 microglobulin levels, patient age or the extent of prior therapy was found. However, the high incidence of Rb-1 deletion detected by FISH suggests a role of this tumor suppressor gene in the biology of MM. Although allelic loss of the Rb-1 gene is unlikely to be the only genetic change necessary for the development of MM, it may be a relatively early event in MM unrelated to chemotherapeutic intervention. Since the Rb-1 gene suppresses IL-6 production and secretion, Rb-1 deletion may result in deregulation of IL-6 expression and hence expansion of IL-6 dependent myeloma clones.
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PMID:Deletion of the retinoblastoma gene in multiple myeloma. 805 62

We looked for abnormalities of the retinoblastoma (RB-1) gene and of RB protein expression in 35 patients with multiple myeloma (MM). Mutations in exons 20 to 24 of the RB-1 gene (exons where mutations predominate in retinoblastoma and other solid tumors) were analyzed by single stranded conformation polymorphism (SSCP). RB-1 protein was studied in bone marrow plasma cells by immunocytochemistry (ABC peroxidase technique) with a specific monoclonal antibody. Southern blot analysis of RB-1 gene was also performed in 20 of the patients. Twenty two patients analyzed had advanced disease (stage III or, in one case, plasma cell leukemia) and cytogenetic analysis (performed in 31 cases) found monosomy 13 in 9 patients. No rearrangement of the RB-1 gene was found by Southern analysis. Absent or greatly reduced RB-1 protein level was found in plasma cells in 4 of the patients (11%), whereas normal levels were seen in the remaining cases. No point mutation in exons 20 to 24 and their flanking introns were found in any of the 35 patients. Three of the 4 patients with absent or reduced RB-1 protein expression had advanced MM (stage III: 2 cases; plasma cell leukemia: 1 case); all 4 patients were resistant to treatment (as compared to 7 of the 31 patients with normal RB-1 protein levels); only one of them was subsequently found to have monosomy 13 (as compared to 9 of the 28 other karyotyped patients). Our findings suggest that abnormalities of the RB-1 gene and its expression are rare in MM. Absent or reduced expression of RB-1 protein was not significantly correlated to monosomy 13 and was not associated with gross rearrangements of the RB-1 gene by Southern analysis or point mutations in exons 20 to 24 of the gene. Reduced expression of RB-1 protein may be associated with advanced disease and poor response to treatment, although larger numbers of patients will be required for more adequate conclusions.
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PMID:The retinoblastoma gene (RB-1) status in multiple myeloma: a report on 35 cases. 852 59

We have studied the retinoblastoma (RB-1) susceptibility gene status and pRB expression in 22 human myeloma cell lines (HMCL) and in 10 patients with advanced multiple myeloma (MM). Deletions of the RB-1 gene were observed in 81% (17/21) of the informative HMCL, regardless of their paracrine or autocrine interleukin-6 (IL-6) status. Among the deleted HMCL, only one (U266) had a biallelic deletion and lacked pRB expression. Monoallelic deletions had no consequence on the RB-1 gene activation and pRB expression. One patient of 10 presented the same biallclic deletion as U266 and six of 10 had monoallelic deletions. We conclude that monoallelic deletions of the RB-1 gene are frequent in HMCL and MM patients but have no consequence on gene activation and pRB expression.
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PMID:High incidence of deletions but infrequent inactivation of the retinoblastoma gene in human myeloma cells. 855 72

Interleukin-6 (IL-6), a product of bone marrow stromal cells (BMSCs), is a growth factor for multiple myeloma (MM) cells. Transforming growth factor-beta1 (TGF-beta1) is also produced by BMSCs and can regulate IL-6 secretion by several tissues, including BMSCs. The present study was designed to characterize in vitro tumor growth regulation by TGF-beta1 in MM. Sorted CD38+CD45RA- MM cells secreted significantly more TGF-beta1 (8.2 +/- 2.0 ng/mL) than peripheral blood mononuclear cells (P < .001), splenic B cells (P < .001), and CD40 ligand (CD40L) pretreated B cells (P < .05). TGF-beta1 secretion by MM-BMMCs (3.8 +/- 0.9 ng/mL) was significantly greater than by N-BMMCs (1.2 +/- 0.1 ng/mL, P < .001). MM-BMSCs also secreted significantly more TGF-beta1 (6.6 +/- 2.5 ng/mL, n = 11) than N-BMSCs (4.4 +/- 0.6 ng/mL, P < .02, n = 10) and N-BMSC lines (3.9 +/- 0.2 ng/mL, P < .02, n = 6). TGF-beta1 secretion was correlated with IL-6 secretion in MM-BMSCs. Anti-TGF-beta1 monoclonal antibody both blocked IL-6 secretion by BMSCs and inhibited the increments in IL-6 secretion by BMSCs induced by MM cell adhesion. Moreover, exogenous TGF-beta1 upregulated IL-6 secretion by MM-BMSCs, normal BMSCs, and CD38+ CD45RA- MM cells, as well as tumor cell proliferation. This is in contrast to the inhibitory effect of TGF-beta1 on proliferation and Ig secretion of normal splenic B cells. Finally, retinoblastoma proteins (pRB) are constitutively phosphorylated in MM cells; TGF-beta1 either did not alter or increased pRB phosphorylation. pRB are dephosphorylated in splenic B cells and phosphorylated in CD40L triggered B cells in contrast to its effects on MM cells, TGF-beta1 decreased phosphorylation of pRB in CD40L treated B cells. These results suggest that TGF-beta1 is produced in MM by both tumor cells and BMSCs, with related tumore cell growth. Moreover, MM cell growth may be enhanced by resistance of tumor cells to the inhibitory effects of TGF-beta1 on normal B-cell proliferation and Ig secretion.
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PMID:Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells. 863 41

Interleukin-6 (IL-6) mediates autocrine and paracrine growth of multiple myeloma (MM) cells and inhibits tumor cell apoptosis. Abnormalities of retinoblastoma protein (pRB) and mutations of RB gene have been reported in up to 70% of MM patients and 80% of MM-derived cell lines. Because dephosphorylated (activated) pRB blocks transition from G1 to S phase of the cell cycle whereas phosphorylated (inactivated) pRB releases this growth arrest, we characterized the role of pRB in IL-6-mediated MM cell growth. Both phosphorylated and dephosphorylated pRB were expressed in all serum-starved MM patient cells and MM-derived cell lines, but pRB was predominantly in its phosphorylated form. In MM cells that proliferated in response to IL-6, exogenous IL-6 downregulated dephosphorylated pRB and decreased dephosphorylated pRB-E2F complexes. Importantly, culture of MM cells with RB antisense, but not RB sense, oligonucleotide (ODN) triggered IL-6 secretion and proliferation in MM cells; however, proliferation was only partially inhibited by neutralizing anti-IL-6 monoclonal antibody (MoAb). In contrast to MM cells, normal splenic B cells express dephosphorylated pRB. Although CD40 ligand (CD40L) triggers a shift from dephosphorylated to phosphorylated pRB and proliferation of B cells, the addition of exogenous IL-6 to CD40L-treated B cells does not alter either pRB or proliferation, as observed in MM cells. These results suggest that phosphorylated pRB is constitutively expressed in MM cells and that IL-6 further shifts pRB from its dephosphorylated to its phosphorylated form, thereby promoting MM cell growth via two mechanisms; by decreasing the amount of E2F bound by dephosphorylated pRB due to reduced dephosphorylated pRB, thereby releasing growth arrest; and by upregulating IL-6 secretion by MM cells and related IL-6-mediated autocrine tumor cell growth.
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PMID:Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. 882 42

Genetic mechanisms leading to the development of multiple myeloma (MM) remain poorly understood. Given the frequency of chromosome 13 deletion in MM and the localization in 13q14 of the retinoblastoma susceptibility gene RB-1, an involvement of RB-1 in MM pathogenesis has been proposed. Moreover, interleukin-6 (IL-6) has been shown to be the main growth factor for MM in vitro and in vivo. The product of the RB-1 gene (pRB) can down-regulate IL-6 gene expression. Absence of pRB may then induce an autocrine IL-6 expression in myeloma cells and contribute to the autonomous growth of MM. As assessed in this review, heterozygous deletion of RB-1 is very common in MM but does not alter gene transcription and protein expression. Nevertheless, homozygous deletion of RB-1 has been identified in some MM patients with advanced disease and in the IL-6-autocrine human myeloma cell line U266. Thus, even if inactivation of RB-1 appears to be only a rare and late oncogenic event in MM and is not likely to represent the main mechanism involved in IL-6 up-regulation in MM, definitive assessment of the actual role played by RB-1 in MM pathogenesis still needs further investigation particularly the examination of pRB function.
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PMID:The retinoblastoma susceptibility gene RB-1 in multiple myeloma. 915 53


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