Retinoic acid resistance in acute promyelocytic leukemia. APL cellular elements in acquired ATRA resistance. In vitro ATRA sensitivity testing. Although fresh APL cells do not replicate effectively during short- term culture, their response to ATRA, nevertheless, follows a concentration- and time- dependent maturation sequence similar to that of exponentially proliferating, ATRA- responsive cells from leukemia cell lines, such as HL- 6. NB4. 3. 3,3. 8,1. Also, although the in vitro culture environment, typically including 1. RPMI 1. 64. 0 or Iscove's modified Dulbecco's medium (IMDM), presumably markedly differs from the environment of APL cells in vivo, the in vitro maturation response, properly studied, usually correlates well with clinical response to ATRA therapy. As described above, variations in the sensitivity of ATRA- naive APL cells under non- saturating ATRA conditions (0. M for 3 days) is positively correlated with DFS but not with the incidence of near- universal CR. At the time of first relapse from previous ATRA therapy, whether or not given in combination with chemotherapy, there was a variable loss of APL cell sensitivity to ATRA- induced APL cell maturation in vitro in the great majority of cases. In some of these cases, the loss of ATRA sensitivity was detectable as reduced APL cell terminal differentiation even at high ATRA exposure conditions, eg 1 M ATRA . After two or more relapses, APL cell sensitivity to ATRA- induced maturation in vitro is typically reduced and is associated with clinical ATRA resistance (Table 2). These observations re- emphasize that ATRA sensitivity/resistance of APL cells is relative, that it reflects a continuum of intrinsic APL cellular variations with a bearing on the efficacy of ATRA therapy and that at some level cellular ATRA resistance shares cross- resistance with chemotherapeutic agents and/or with intrinsic cellular alterations involved with progression of the leukemic process. Mechanisms that may limit ATRA access to the cell nucleus. The terminal differentiation response of APL cells depends primarily on the delivery of sufficient ATRA to nuclear receptors (PML- RAR and RAR) to modulate the transcriptional activity of requisite genes. Therefore, relative ATRA resistance can develop in two fundamental ways: by limiting the access of ATRA to nuclear receptor sites or by aberrations in the nuclear transcription machinery, including RA receptors and downstream co- factors required to produce activation of appropriate target genes. Breakout - Topic:Stock market - Online Encyclopedia - What is what? Everything you always wanted to know. The Resistance – Torture Tactics Full Album leak Free Download link MP3 ZIP RAR. Artist: The Resistance. Break - Resistance (2010). Download Links: Break. Enter the code above *. RAR - You command the fleet at Wolf 359. It was released as the lead single from the band's fifth studio album, The Resistance, on September 7. Muse's fifth studio album, The Resistance, was released on September 14 th 2009. Like previous Muse albums it draws from a wide range of genres and influences. Retinoic acid resistance in acute promyelocytic. Primary resistance of PML-RAR. Characterization of acute promyelocytic leukemia cases with PML-RAR break. Break - Resistance 2010 Form. Calyx & Teebee 02. Breakout Forex Strategies is an index of trading system based on breakout trading method. ATRA access to nuclear transcription sites may be impeded by essentially four different mechanisms, as detailed below. Decreased effective APL cell ATRA uptake: Information about the net uptake of ATRA by fresh APL cells is available from two investigative groups. In a study of ATRA- naive APL cells from nine patients, the first group found a nearly 1. ATRA between low (n = 3; median 2. ATRA uptake cases. This corresponded to differences in in vitro sensitivity of APL cells from the low or high uptake subgroups to ATRA- induced maturation, . Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6. Drug Resistance; Exons; Female; Humans. Although the relevance of such in vitro observations to ATRA resistance that develops under clinical conditions is uncertain, they are a reminder that it is not known whether the major site of ATRA activity in vivo is on APL cells in the blood or in the bone marrow and extramedullary sites where the cells may be bathed in low- protein interstitial fluid that could have a marked effect on ATRA potency. Effective cellular uptake of pharmacological agents is determined by the balance of influx and efflux rates. There is no precedent for increased extrusion of unconjugated lipophilic ligands for nuclear receptors, like ATRA, that enter cells by passive diffusion across the cell membrane. Nevertheless, it has been queried whether increased expression of members of the ATP- binding transmembrane transporter gene superfamily that can produce multidrug resistance (MDR) might have an effect on ATRA uptake. The relevance of this query is enhanced by the fact that most clinical protocols involve the co- administration of ATRA with an anthracycline and/or cytarabine, both of which can induce MDR in AML. It is well- recognized that APL cells express no or much lower levels of P- glycoprotein (PGP), the prototype MDR gene, than other myeloid leukemia cells. However, the data in relapse APL are somewhat controversial, based on small case numbers. In an early study, 2/2 relapse ATRA- resistant cases were reported to express low levels of PGP, and the PGP inhibitor verapamil significantly restored the ability of ATRA to induce terminal differentiation. However, in two subsequent reports with five. PGP. Two other members of the MDR family lung resistance- related protein (LRP) and multidrug resistance- associated protein (MRP1) were also not increased after relapse from combined ATRA/anthracycline therapy. After 2 relapses, however, 3/4 cases had a two to three- fold increase in PGP,1. APL cases with multiple relapses from chemotherapy but without prior ATRA exposure are frequently ATRA resistant (Table 2). The possible role of multidrug resistance in ATRA resistance has been studied further in ATRA- responsive cell line models. ATRA- resistant HL- 6. PGP m. RNA and to have increased maturation in response to ATRA when used in combination with the PGP inhibitor verapamil. Furthermore, targeted destruction of these PGP (MDR1) transcripts, using a specific ribozyme, partially restored ATRA sensitivity. In contrast to these findings, however, it was reported that stable transduction of the MDR1 gene into NB4 cells did not affect either the effective uptake of ATRA in the presence or absence of the specific PGP inhibitor PSC8. ATRA. 1. 10,1. 11. In sum, the results suggest that variations in ATRA uptake are a minor element in ATRA resistance, although, given the observation that relatively minor variations in APL cell ATRA sensitivity can be associated with differences in long- term outcome,3. ATRA resistance after multiple relapses from chemotherapy, although the most pertinent cell line model does not provide support for this possibility. Increased cytoplasmic sequestration: Cytoplasmic sequestration of ATRA was proposed as a major contributor to acquired ATRA resistance in APL related to the finding of markedly increased CRABP expression in the APL cells of four relapse cases with decreased sensitivity to ATRA- induced differentiation. Similar increases were observed in predominantly normal bone marrow cells after ATRA treatment, and it was established by a gel electrophoretic method that the cytoplasmic ATRA binding activity was CRABP- II, not CRABP- I. As previously mentioned, this hypothesis seemed logical, since the CRABP- II gene promoter contains a RARE, which, in response to pharmacological ATRA concentrations, could lead to increased CRABP- II production, providing a protective feed- back loop by which the incoming ATRA could be increasingly sequestered in the cytoplasm. However, in a larger screening study of 3. APL patients designed to assess the clinical associations of CRABP- II levels, it was unexpectedly found that CRABP- II was constitutively expressed in ATRA- naive cells, that its level did not significantly differ in bone marrow aspirate cells from patients following ATRA or chemotherapy induction treatment, that there was no increase in CRABP- II in relapse APL cells, and that there was no correlation between CRABP- II level and sensitivity to ATRA- induced maturation in vitro. As also previously mentioned, these results seem more consistent with the subsequent findings that CRABP- II functions as a positive rather than a negative regulator of ATRA activity by acting as a shuttle for the delivery of ATRA to nuclear transcription sites and as a co- activator of RAR. These developments raise the possibility, contrary to prior thinking, that decreased rather than increased expression or activity of CRABP- II may be associated with ATRA resistance in APL cells, which requires investigation. No alternative molecule to supplant CRABP- II as a vehicle of cytoplasmic sequestration has been suggested. Worth mentioning, perhaps, is that HL- 6. ATRA resistance develop marked alterations of cell membrane glycoproteins and glycolipids that, if also present in ATRA- resistant APL cells, might possibly affect the cellular disposition and activity of ATRA (reviewed in Ref. Increased cytoplasmic ATRA catabolism: Intracellular ATRA catabolism occurs primarily by oxidation, involving microsomal membrane- bound P4. The hypothesis that increased APL cellular metabolism is likely a factor in acquired ATRA resistance, apparently rests entirely on observations that ATRA can upregulate P4. ATRA catabolism in ATRA- resistant APL cells. In two studies of ATRA catabolism in ATRA- sensitive NB4 cells, rather different results were reported. In one, ATRA was slowly metabolized over several days without the observation of oxidative polar metabolites in either the cells or culture medium. In the other, the rate of ATRA catabolism is not stated but was associated with the generation of several polar metabolites in mixed extracts of cells and medium. Possibly, these differences could be related to serum differences between the two studies, a suggestion based on a study of HL- 6. In the presence of serum, ATRA catabolism in HL- 6. ATRA was rapidly catabolized (t. ATRA. Compared to the parental line, an ATRA- resistant subline showed no difference in the presence of serum but approximately four- fold more rapid catabolism in serum- free conditions. Whether this increased catabolism is a cause of the ATRA resistance, however, is questionable, since the parental and ATRA- resistant subline were each 1. ATRA- induced differentiation in serum- free medium than in serum- containing medium. These HL- 6. 0 cell observations are consistent with those in other types of cultured cells (breast cancer cells) in which ATRA sensitivity to growth inhibition is positively correlated with catabolic rate.
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