UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro inhibitory effect of all-trans retinoic acid (ATRA) on myeloma cell growth may be synergistically potentiated by the activity of dexamethasone (DEX) and alpha-interferon (IFN). We treated 10 patients with advanced, refractory multiple myeloma (MM) using a combination of ATRA (100 mg p.o., once a day for two weeks every month), DEX (40 mg i.v., for 4 days every 4 weeks) and IFN (3 MU s.c., three times a week). Eight patients completed at least three months of treatment and were evaluable for response. Two of them showed a partial response which persists after 15 to 17 months. Three patients experienced a stable plateau phase of 4 to +11 months, with a significant improvement in the performance status and bone pain. Progressive disease was seen in the remaining three patients. We conclude that the association of ATRA, DEX and IFN warrants further consideration in MM patients.
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PMID:All-trans retinoic acid in combination with alpha-interferon and dexamethasone for advanced multiple myeloma. 923 91

In this study, we show that both all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9-cis-RA) are potent inducers of tissue transglutaminase (TGase II), an enzyme involved in apoptosis, at the level of both enzyme activity and mRNA in the human myeloma cell line RPMI 8226. RPMI 8226 cells were shown to express mRNAs for all the retinoid receptors subtypes, ie, RARalpha, RARbeta, RARgamma, RXRalpha, RXRbeta, and RXRgamma. To identify which of these receptors are involved in regulating TGase II expression, several receptor-selective synthetic retinoids were used. Neither CD367, a very potent retinoid that selectively binds and activates receptors of the RAR family, nor CD2425, an RXR-selective agonist, induced TGase II when used alone. However, combination of CD367 and CD2425 resulted in nearly full induction of the enzyme. Moreover, when used in combination with atRA, CD367 partially inhibited the atRA-dependent induction of TGase II, whereas CD2425 enhanced it. The effects of Am 580, CD417, and CD437, three synthetic retinoids selective for the RARs subtypes RARalpha, RARbeta, and RARgamma, respectively, were also investigated. None of these compounds was able to induce TGase II when used alone; however, the combination of each of them with CD2425 resulted in strong induction of the enzyme activity, reaching 30% to 50% of the values obtained in the presence of retinoic acid and suggesting functional redundancy between the RAR subtypes. Finally, treatment with atRA or the combination of CD367 and CD2425, but not with CD367 or CD2425 alone, was also shown to trigger apoptosis in RPMI 8226 cells, with prominent accumulation of TGase II immunoreactivity in apoptotic cells. Taken together these data suggest that the induction of TGase II expression and apoptosis in the RPMI 8226 myeloma cell line required ligand-dependent activation of both the RAR and RXR receptors.
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PMID:Evidence for the involvement of both retinoic acid receptor- and retinoic X receptor-dependent signaling pathways in the induction of tissue transglutaminase and apoptosis in the human myeloma cell line RPMI 8226. 951 42

All-trans retinoic acid (ATRA) is a vitamin A derivative that induces the differentiation of myeloid leukemia cells in vitro and in vivo. Several investigators have recently reported that ATRA downregulates the production of interleukin-6 (IL-6) and the expression of IL-6 receptor (IL-6R) and also inhibits the proliferation of myeloma cells. It has also been reported that myeloma cells express Fas antigen, and in some of these cells apoptosis was induced by treatment with anti-Fas monoclonal antibody (mAb). In the present study, we demonstrated that ATRA increased Fas expression in the human myeloma cell line, U266B1. We observed that both apoptosis induction and growth inhibition were enhanced in cells exposed to a combination of anti-Fas mAb and ATRA compared with cells exposed to either treatment alone. We also examined whether ATRA modulated bcl-2, an anti-apoptosis protein, in U266B1 cells. Flow cytometry analysis revealed that the mean fluorescence intensity of bcl-2 protein was slightly decreased in cells treated with ATRA. These results indicate that in U266B1 cells, combined treatment with anti-Fas mAb and ATRA enhances the induction of apoptosis by modulating the expression of Fas and bcl-2 by ATRA.
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PMID:All-trans retinoic acid modulates Fas antigen expression and affects cell proliferation and apoptosis in combination with anti-Fas monoclonal antibody in the human myeloma cell line, U266B1. 962 Feb 83

The effects of all trans retinoic acid (ATRA) on human myeloma cells growth were studied in vitro and in vivo using immunodeficient mice engrafted with malignant plasma cells. ATRA inhibited the in vitro proliferation of plasma cells originating from two patients with multiple myeloma whereas it had no effect on the in vivo growth of plasma cell grafts as assessed by the serial study of human Ig levels in mouse serum. Thus, the efficacy of ATRA for the treatment of human multiple myeloma remains to be ascertained.
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PMID:Differential in vitro and in vivo effects of all-trans retinoic acid on the growth of human myeloma cells. 971 66

Interleukin 6 (IL-6) is the most important known growth factor for multiple myeloma, and IL-6 signalling pathways are potential targets for therapy. We hypothesized that interfering with the IL-6 signalling pathway at more than one level would be more effective than a single block in inhibiting proliferation of myeloma cells. Accumulating data support the concept that glucocorticoids down-regulate IL-6, whereas retinoic acid derivatives (RA) down-regulate IL-6R in myeloma. We found that all-trans RA (ATRA), 13-cis-RA and 9-cis-RA each similarly inhibited growth of RPMI 8226 myeloma cells and that addition of dexamethasone (DEX) added to RA growth inhibition. The major effects of retinoids were to reduce the proliferative fraction and induce apoptosis whereas DEX increased the apoptotic fraction. When combined, apoptosis was enhanced. Effects of RA + DEX were also least able to be overcome by exogenous IL-6. RA decreased IL-6R levels and addition of DEX to RA delayed recovery of IL-6R levels compared with RA alone. Since RPMI 8226 cells have undetectable IL-6, we investigated U266B1 cells and found that RA and DEX decreased both IL-6 secretion and IL-6 RNA levels. Mechanistically, IL-6R down-regulation by RA was enhanced by DEX, whereas IL-6 protein and RNA levels were reduced by DEX and by RA. In summary, combinations of RA + DEX were not only more effective in inhibiting myeloma cells growth by the dual mechanisms of decreasing proliferative fraction and increasing apoptotic fraction, but were also less able to be overcome by IL-6.
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PMID:Dexamethasone plus retinoids decrease IL-6/IL-6 receptor and induce apoptosis in myeloma cells. 973 62

In contrast to cytotoxic agents inducing rapid cell death, biological agents such as hormones, vitamins (e.g., retinoids), cytokines, and antireceptor antibodies act slowly and may alter ratios between cell growth and programmed cell death (apoptosis). We showed previously that anti-interleukin 6 (IL-6) and antitransferrin (Tf) receptor antibodies inhibited in vitro growth and induced death of myeloma cells. Retinoids also inhibit in vitro growth of human cancer cells and decrease IL-6 receptor display and autosecretion by some myeloma cells. Retinoids may also antagonize in vitro growth-promoting effects of iron and transferrin. To develop a novel strategy for treating myeloma, we examined antiproliferative and cytotoxic effects of retinoids in combination with anti-Tf or anti-IL-6 receptor antibodies. Myeloma cell lines were cultured with retinoids with or without anti-growth factor receptor monoclonal antibodies. Both all-trans retinoic acid (ATRA) and 13-cis-retinoic acid showed variable, dose-dependent inhibition of myeloma cell line growth. ATRA also induced significant down-regulation of myeloma IL-6 receptors and inhibited IL-6 autosecretion by myeloma cells. Antiproliferative effects of ATRA were increased by coculture with anti-Tf but not anti-IL-6 receptor antibodies. Colony-forming assays showed that antiproliferative effects of anti-Tf receptor antibodies were largely reversible, but 1 microM ATRA was cytotoxic to myeloma cells. To assess apoptosis, a flow cytometry assay detecting DNA damage was used. Using previously studied cell line models, flow cytometry detected programmed cell death induced by transforming growth factor beta1 in leukemia cells and by anti-growth factor receptor antibody treatment of IL-6-dependent myeloma cells, treatments which caused only modest increases in the percentage of cells undergoing morphological apoptosis and increased internucleosomal DNA degradation. Flow cytometry analysis of ATRA and anti-Tf antibody-treated myeloma cells also showed evidence for apoptosis induced by ATRA, but not with anti-Tf receptor antibodies. These changes were apparent several days before detection of internucleosomal DNA degradation on agarose gels in 8226 cells but were not detected at any time in U266 cells, which underwent cell death but showed no DNA damage using flow cytometry or degradation on agarose gels. Retinoids merit further study as possible maintenance or chemoprevention therapies for clonal plasma cell disorders and for treating paraneoplastic disorders such as Castleman's disease. Flow cytometry rapidly detects apoptosis induced by biological agents and may be useful for in vitro screening of novel biological therapies.
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PMID:Effects of all-trans retinoic acid and antireceptor antibodies on growth and programmed cell death of human myeloma cells. 981 67

All-trans retinoic acid (ATRA) has been shown to inhibit in vitro growth of multiple myeloma (MM) cells, and this effect can be further potentiated by the addition of Dexamethasone (DEX). We here extended this study by testing the activity of 9-cis retinoic acid (9-cis RA) and 13-cis retinoic acid (13-cis RA), both alone and in combination with DEX, in two MM cell lines, U266 and RPMI 8226. Furthermore, we aimed at investigating the mechanisms involved in the interactions of retinoids and DEX in this setting. 9-cis RA appeared to be the most active agent in U266 cell line (IC50 = 1.2 mumol/l vs 10.5 and 9.8 mumol/l obtained with ATRA and 13-cis RA, respectively) while, in RPMI 8226 cell line, 9-cis RA and 13-cis RA were almost equally cytotoxic (IC50 = 1 and 0.8 mumol/l) and ATRA was less effective. Co-incubation with DEX resulted in a synergistic cytotoxic activity in both the cell lines except for the combinations DEX + 9-cis RA in U266 cell line and DEX + 13-cis RA in RPMI 8226 cell line, where the effect was merely additive. A synergistic cytotoxic effect of retinoids and DEX was also observed on fresh MM cells obtained from 7 patients. Both retinoids and DEX are known to be inducers of apoptosis; we verified that the combined inhibitory activity of retinoids and DEX could be attributed to an increased induction of apoptosis. This effect may be mediated by a reduced intracellular expression of BCL-2 protein, which indeed observed after prolonged in vitro treatment with retinoids. It has been described recently that an enhanced expression of BCL-2 protein can contribute to the occurrence of early chemoresistance; the downregulation of BCL-2 protein induced by retinoids could thus be exploited, by means of novel chemotherapy plus retinoids combinations, in order to improve the efficacy of conventional chemotherapy in MM.
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PMID:In vitro treatment with retinoids decreases bcl-2 protein expression and enhances dexamethasone-induced cytotoxicity and apoptosis in multiple myeloma cells. 1008 90

All-trans retinoic acid (ATRA) has previously been shown to inhibit the growth of OPM-2 human myeloma cells. The growth inhibition was postulated to result from a transcriptional downregulation of interleukin-6 receptor alpha (IL-6Ralpha) with IL-6Rbeta (gp130) unaffected. To formally test this hypothesis, an expression vector designed for constitutive IL-6Ralpha expression was constructed and used for transfection of OPM-2 cells. Six stable transfectants were cloned. The expression of IL-6Ralpha was shown by immunofluorescence with anti-IL-6Ralpha antibody and 125I-IL-6 binding. In five of six transfectant clones, cellular IL-6Ralpha was 1.5- to 6-fold higher than the parental cells, with the ligand binding affinity unchanged. While ATRA reduced IL-6Ralpha expression in the parental OPM-2 cells, it enhanced its expression in these five transfectants. The clonogenic growth of these transfectants, however, remained strongly inhibited by ATRA. Further analysis, comparing the parental OPM-2 cells and a representative transfectant, clone C5, showed that IL-6 caused rapid tyrosine phosphorylation of gp130 in both OPM-2 and C5 clones. Pretreatment with ATRA greatly reduced IL-6-induced gp130 phosphorylation in OPM-2 cells, reflecting a reduction in cellular IL-6Ralpha. In contrast, IL-6-induced gp130 phosphorylation was not reduced by ATRA pretreatment in C5 cells, indicating that the expressed IL-6Ralpha was functional. Similar to OPM-2 cells, C5 cells were sensitive to growth inhibition by dexamethasone, which was entirely reversed by exogenous IL-6, suggesting that the IL-6 postreceptor signal transduction remained intact. ATRA was further shown to upregulate p21(WAF1) expression and cause dephosphorylation of the retinoblastoma protein (pRB) in both OPM-2 and C5 cells. Exogenous IL-6 also failed to reverse these effects of ATRA. Thus, the growth inhibitory activity of ATRA is not mediated through cellular IL-6Ralpha downregulation and is likely to result from a direct upregulation of p21(WAF1) and consequent dephosphorylation of pRB.
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PMID:Growth inhibition of a human myeloma cell line by all-trans retinoic acid is not mediated through downregulation of interleukin-6 receptors but through upregulation of p21(WAF1). 1038 20

We investigated the effects of all-trans retinoic acid (RA) and dexamethasone (Dex) on the in vitro growth of the human myeloma cell line RPMI 8226. RA inhibited RPMI 8226 cell growth by both antiproliferative effect and induction of apoptosis. Typical morphological and biochemical characteristics of apoptosis including chromatin condensation, apoptotic bodies formation and internucleosomal DNA cleavage were detected after 4 days of treatment with 1 microM RA. In situ TUNEL assay demonstrated that DNA cleavage preceded chromatin condensation. The expression of tissue transglutaminase (tTG), an enzyme proposed to play a role in apoptosis was induced with RA, as shown by both enzymatic assay and in situ immunofluorescence detection. Dex, when used alone, had no effect on cell growth and apoptosis. When combined to RA, Dex did not interfere with the RA-dependent inhibition of cell proliferation, but unexpectedly inhibited both quantitatively and qualitatively several morphological and biochemical features of the apoptosis induced by RA. Dex did not affect RA-induced DNA breaks formation but impeded the progression of chromatin condensation and the formation of apoptotic bodies. Interestingly, Dex also inhibited the RA-dependent induction of tTG. RU486, a glucocorticoid antagonist, counteracted all Dex effects. Taken together these data demonstrate that key cytoplasmic and nuclear events occurring during apoptosis are differentially regulated by RA and Dex in myeloma cell line RPMI 8226.
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PMID:Induction of apoptosis by all-trans retinoic acid in the human myeloma cell line RPMI 8226 and negative regulation of some of its typical morphological features by dexamethasone. 1038 37

All-trans retinoic acid (ATRA) is currently widely used in the therapy of acute promyelocytic leukemia and is being tested in vitro and in vivo on several other malignancies. Previously ATRA has been shown to inhibit the growth in vitro, of established human myeloma cell lines as well as cultured primary myeloma cells from patients. ATRA acts by down-regulating IL-6-receptor-alpha or gp130 on the surface of the myeloma cells. However, despite its in vitro effects on myeloma cells, ATRA therapy on advanced stage multiple myeloma (MM) patients has so far largely been ineffective. In current studies, we have assessed the efficacy of ATRA therapy against primary murine plasma cell tumors, which are an animal model for human MM. These tumors are induced at about 50% incidence in pristane-primed BALB/c mice by injection of v-raf/v-myc- containing retroviruses and are IL-6 dependent. Using this animal model, we assessed the effect of ATRA as a therapeutic agent against primary tumors at two early time points in disease development. ATRA was administered in liposomal vesicles (ATRAGEN), since liposomal-ATRA has been shown to circumvent clearance mechanisms by hepatic microsomes, which normally occur with free ATRA. In addition, ATRAGEN was previously shown to be less toxic in mice than free ATRA. ATRAGEN was administered beginning on day 25 or day 45 after virus injection and continued twice weekly for 8-11 weeks. ATRAGEN administration begun at either time point did not alter the incidence or the latency of plasma cell tumors compared with control animals. These results suggest that ATRA may not be an effective sole therapy against early MM.
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PMID:Assessment of all-trans retinoic acid (ATRA) efficacy as a single agent in primary lymphoid neoplasia. 1045 60

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