The European Organization for Research and Treatment of Cancer (EORTC) 58951 study (1703 patients) investigated a prednisolone/dexamethasone ratio of 10 (prednisolone 60 mg/m2 and dexamethasone 6 mg/m2; table 1)

The European Organization for Research and Treatment of Cancer (EORTC) 58951 study (1703 patients) investigated a prednisolone/dexamethasone ratio of 10 (prednisolone 60 mg/m2 and dexamethasone 6 mg/m2; table 1).44 The study arms did not differ significantly in the complete remission rate (both 98.4%) or the 5-year event-free survival estimate (82.4% for prednisolone vs. the dose ratio of the two drugs that exerted equivalent cytotoxicity ranged widely among individual samples. Selection of the type and dosage of glucocorticoid should be based on the risk of relapse, the treatment phase, and the concomitant chemotherapeutic drugs. and glucocorticoid resistance is an adverse prognostic factor in ALL, and several mechanisms have been reported.1 Glucocorticoid exposure induces up-regulation of the glucocorticoid receptor in ALL cells and approximately half of the 51 responsive genes identified have been functionally linked to 3 major pathways: cell proliferation and survival (MAPK pathways), NF-B signaling and glucose metabolism.11, 12 Glucocorticoid resistance has been associated with up-regulation of genes involved in glucose metabolism and increased glucose consumption.11, 13, 14 Glucocorticoids also release Ca2+ from the endoplasmic reticulum into the cytosol; the resulting mitochondrial Ca2+ increase induces cytochrome c release and triggers apoptosis. Elevated expression of calcium-binding proteins S100A8 and S100A9 and of the anti-apoptotic BCL-2 protein family member MCL-1 inhibited free cytosolic Ca2+ and mitochondrial Ca2+ signals, respectively, causing glucocorticoid resistance.15C17 Traditionally, prednisone has been the glucocorticoid most commonly used in ALL therapy; it is typically given for 4 consecutive weeks in combination with vincristine, an anthracycline, asparaginase, and intrathecal chemotherapy. Dexamethasone, another glucocorticoid, is used increasingly in recent years to treat ALL. These two glucocorticoids are synthetic analogs of cortisol that differ molecularly in several important aspects (figure 2).18C21 Dexamethasone differs from prednisolone (active metabolite of prednisone) only by a fluorine atom in the 9 position of ring B and a methyl group in the C 16 position of ring D. The 9 fluorine slows the metabolism of dexamethasone, thereby extending its plasma half-life (200 min vs. 60 min for prednisolone) and biological half-life (36C54 h vs. 24C36 h).19, 21 The C 16 methyl group minimizes dexamethasones sodium-retention effect. Prednisone is considered to have half the mineral corticoid activity of cortisol, while dexamethasone is thought to have little or none.21 Open in a separate window Figure 2 Chemical structures of cortisol and of the synthetic glucocorticoids prednisone, prednisolone, and dexamethasone. Bioequivalence studies of dexamethasone and prednisone have often yielded Rabbit polyclonal to PON2 discordant results. Generally, 1 mg of dexamethasone has been considered equivalent to 5 to 10 mg of prednisone in reducing inflammation.20C22 However, this assumption has not been experimentally confirmed. Here we review the use of prednisone and dexamethasone in ALL, weighing evidence from in vitro studies, preclinical models, and clinical studies; compare the drugs benefits and adverse effects; and discuss their optimal uses. In vitro cytotoxicity of prednisolone and dexamethasone The cytotoxicity of prednisolone and dexamethasone to ALL cells was initially compared in samples from 133 pediatric patients with untreated ALL by using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in cell suspension cultures.23 The cytotoxicity of dexamethasone was considerably greater than that of prednisolone and was much greater than that predicted by the relative anti-inflammatory effects of the drugs. The median LC50 (concentration producing 50% cytotoxicity) values of prednisolone and dexamethasone were 3.5 M and 0.2 M, respectively, and the median ratio of the prednisolone and dexamethasone LC50 values was 16.2. Interestingly, the ratio ranged widely (from 0.7 to 500) in samples from individual patients. Ito et al.24 compared the in vitro cytotoxicity of prednisolone and dexamethasone in leukemia cells grown on bone marrowCderived stromal layers. The stromal cells create a microenvironment similar to that of bone marrow in vivo, preventing apoptosis of leukemic lymphoblasts and allowing their proliferation.25 In 28 B-lineage ALL samples tested, prednisolone and dexamethasone had median LC50 values of 43.5 nM and 7.5 nM, respectively. The median dexamethasone-to-prednisolone ratio was 1:5.5 for both the LC50 and LC90 values. This ratio was considerably lower than that determined by the MTT assay but was similar to the percentage of the medicines estimated anti-inflammatory activity and to their standard dose percentage. Again, individual samples showed a wide range in the dexamethasone-to-prednisolone LC50 (1:1.0 to 1 1:24.4) and LC90 (1:1.1 to 1 1:25.5) ratios. It is not obvious why dexamethasone is definitely more cytotoxic to leukemia cells than prednisolone. Lippman et al.26 identified a highly specific glucocorticoid receptor in preparations of cytosol from glucocorticoid-sensitive ALL cells. Several studies showed the dexamethasone receptor complex is more stable than the prednisolone receptor complex27 and that the glucocorticoid receptor of leukemia cells offers higher affinity for dexamethasone than for prednisolone.26, 28 However, other studies showed that glucocorticoid receptor offers similar affinity for prednisolone and dexamethasone.18 In addition, both in vitro cytotoxicity studies explained above found a broad range in.The better results in T-ALL patients who received dexamethasone during remission-induction in the ALL 2000 BFM/AIEOP study would justify its early use with this group of patients (table 2).42 In the ongoing St. Consequently, the relative effectiveness of prednisone and dexamethasone is definitely dose dependent and must be cautiously weighed against toxicity. Moreover, although dexamethasone generally exhibited higher activity against ALL cells in vitro, the dose percentage of the two medicines that exerted equal cytotoxicity ranged widely among individual samples. Selection of the type and dose of glucocorticoid should be based on the risk of relapse, the treatment phase, and the concomitant chemotherapeutic medicines. and glucocorticoid resistance is an adverse prognostic factor in ALL, and several mechanisms have been reported.1 Glucocorticoid exposure induces up-regulation of the glucocorticoid receptor in ALL cells and approximately half of the 51 responsive genes recognized have been functionally linked to 3 major pathways: cell proliferation and survival (MAPK pathways), NF-B signaling and glucose rate of metabolism.11, 12 Glucocorticoid resistance has been associated with up-regulation of genes involved in glucose rate of metabolism and increased glucose usage.11, 13, 14 Glucocorticoids also launch Ca2+ from your endoplasmic reticulum into the cytosol; the producing mitochondrial Ca2+ increase induces cytochrome c launch and causes apoptosis. Elevated manifestation of calcium-binding proteins S100A8 and S100A9 and of the anti-apoptotic BCL-2 protein family member MCL-1 inhibited free cytosolic Ca2+ and mitochondrial Ca2+ signals, respectively, causing glucocorticoid resistance.15C17 Traditionally, prednisone has been the glucocorticoid most commonly used in ALL therapy; it is typically given for 4 consecutive weeks in combination with vincristine, an anthracycline, asparaginase, and intrathecal chemotherapy. Dexamethasone, another glucocorticoid, is used increasingly in recent years to treat ALL. These two glucocorticoids are synthetic analogs of cortisol that differ molecularly in several important elements (number 2).18C21 Dexamethasone differs from prednisolone (active metabolite of prednisone) only by a fluorine atom in the 9 position of ring B and a methyl group in the C 16 position of ring D. The 9 fluorine slows the rate of metabolism of dexamethasone, therefore extending its plasma half-life (200 min vs. 60 min for prednisolone) and biological half-life (36C54 h vs. 24C36 h).19, 21 The C 16 methyl group minimizes dexamethasones sodium-retention effect. Prednisone is considered to have half the mineral corticoid activity of cortisol, while dexamethasone is definitely thought to have little or none.21 Open in a separate window Number 2 Chemical structures of cortisol and of the synthetic glucocorticoids prednisone, prednisolone, and dexamethasone. Bioequivalence studies of dexamethasone and prednisone have often yielded discordant results. Generally, 1 mg of dexamethasone has been considered equivalent to 5 to 10 mg of prednisone in reducing swelling.20C22 However, this assumption has not been experimentally confirmed. Here we review the use of prednisone and dexamethasone in ALL, weighing evidence from in vitro studies, preclinical models, and clinical studies; compare the medicines benefits and adverse effects; and discuss their ideal uses. In vitro cytotoxicity of prednisolone and dexamethasone The cytotoxicity of prednisolone and dexamethasone to ALL cells was initially compared in samples from 133 pediatric individuals with untreated ALL by using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in cell suspension ethnicities.23 The cytotoxicity of dexamethasone was considerably greater than that of prednisolone and was much greater than that expected from the relative anti-inflammatory effects of the medicines. The median LC50 (concentration generating 50% cytotoxicity) ideals of prednisolone and dexamethasone were 3.5 M and 0.2 M, respectively, and the median percentage of the prednisolone and dexamethasone LC50 ideals was 16.2. Interestingly, the percentage ranged widely (from 0.7 to 500) in samples from individual individuals. Ito et al.24 compared the in vitro cytotoxicity of prednisolone and dexamethasone in leukemia cells grown on bone marrowCderived stromal layers. The stromal cells develop a microenvironment related to that of bone marrow in vivo, preventing apoptosis of leukemic lymphoblasts and allowing their proliferation.25 In 28 B-lineage ALL samples tested, prednisolone and dexamethasone experienced median LC50 values of 43.5 nM and 7.5 nM, respectively. The median dexamethasone-to-prednisolone ratio was 1:5.5 for both the LC50 and LC90 values. This ratio was considerably lower than that determined by the MTT assay but was similar to the ratio of the drugs estimated anti-inflammatory activity and to their standard dose ratio. Again, individual samples showed a wide range in the dexamethasone-to-prednisolone LC50 (1:1.0 to 1 1:24.4) and LC90 (1:1.1 to 1 1:25.5) ratios. It is not obvious why dexamethasone is usually more cytotoxic to leukemia cells than prednisolone. Lippman et al.26 identified a highly specific glucocorticoid receptor in preparations of cytosol from glucocorticoid-sensitive ALL cells. Several studies showed that this.The relative toxicity of prednisone and dexamethasone has not been fully elucidated in patients with ALL, but toxicity has more often been associated with dexamethasone in published studies (table 1). vitro, the dose ratio of the two drugs that exerted comparative cytotoxicity ranged widely among individual samples. Selection of the type and dosage of glucocorticoid should be based on the risk of relapse, the treatment phase, and the concomitant chemotherapeutic drugs. and glucocorticoid resistance is an adverse prognostic factor in ALL, and several mechanisms have been reported.1 Glucocorticoid exposure induces up-regulation of the glucocorticoid receptor in ALL cells and approximately half of the 51 responsive genes recognized have been functionally linked to 3 major pathways: cell proliferation and survival (MAPK pathways), NF-B signaling and glucose metabolism.11, 12 Glucocorticoid resistance has been associated with up-regulation of genes involved in glucose metabolism and increased glucose consumption.11, 13, 14 Glucocorticoids also release Ca2+ from your endoplasmic reticulum into the cytosol; the producing mitochondrial Ca2+ increase induces cytochrome c release and triggers apoptosis. Elevated expression of calcium-binding proteins S100A8 and S100A9 and of the anti-apoptotic BCL-2 protein family member MCL-1 inhibited free cytosolic Ca2+ and mitochondrial Ca2+ signals, respectively, causing glucocorticoid resistance.15C17 Traditionally, prednisone has been the glucocorticoid most commonly used in ALL therapy; it is typically given for 4 consecutive weeks in combination with vincristine, an anthracycline, asparaginase, and intrathecal chemotherapy. Dexamethasone, another glucocorticoid, is used increasingly in recent years to treat ALL. These two glucocorticoids are synthetic analogs of cortisol that differ molecularly in several important aspects (physique 2).18C21 Dexamethasone differs from prednisolone (active metabolite of prednisone) only by a fluorine atom in the 9 position of ring B and a methyl group in the C 16 position of ring D. The 9 fluorine slows the metabolism of dexamethasone, thereby extending its plasma half-life (200 min vs. 60 min for prednisolone) and biological half-life (36C54 h vs. 24C36 h).19, 21 The C 16 methyl group minimizes dexamethasones sodium-retention effect. Prednisone is considered to have half the mineral corticoid activity Tulobuterol of cortisol, while dexamethasone is usually thought to have little or none.21 Open in a separate window Determine 2 Chemical structures of cortisol Tulobuterol and of the synthetic glucocorticoids prednisone, prednisolone, and dexamethasone. Bioequivalence studies of dexamethasone and prednisone have often yielded discordant results. Generally, 1 mg of dexamethasone has been considered equivalent to 5 to 10 mg of prednisone in reducing inflammation.20C22 However, this assumption has not been experimentally confirmed. Here we review the use of prednisone and dexamethasone in ALL, weighing evidence from in vitro studies, preclinical models, and clinical studies; compare the drugs benefits and adverse effects; and discuss their optimal uses. In vitro cytotoxicity of prednisolone and dexamethasone The cytotoxicity of prednisolone and dexamethasone to ALL cells was initially compared in samples from 133 pediatric patients with untreated ALL by using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in cell suspension cultures.23 The cytotoxicity of dexamethasone was considerably greater than that of prednisolone and was much greater than that predicted by the relative anti-inflammatory effects of the drugs. The median LC50 (concentration generating 50% cytotoxicity) values of prednisolone and dexamethasone were 3.5 M and 0.2 M, respectively, and the median ratio of the prednisolone and dexamethasone LC50 values was 16.2. Interestingly, the ratio ranged widely (from 0.7 to 500) in samples from individual patients. Ito et al.24 compared the in vitro cytotoxicity of prednisolone and dexamethasone Tulobuterol in leukemia cells grown on bone marrowCderived stromal layers. The stromal cells produce a microenvironment comparable to that of bone marrow in vivo, preventing apoptosis of leukemic lymphoblasts and allowing their proliferation.25 In 28 B-lineage ALL samples tested, prednisolone and dexamethasone experienced median LC50 values of 43.5 nM and 7.5 nM, respectively. The median dexamethasone-to-prednisolone ratio was 1:5.5 for both the LC50 and LC90 values. This ratio was considerably lower than that determined by the MTT assay but was similar to the percentage from the medicines approximated anti-inflammatory activity also to their regular.60 min for prednisolone) and biological half-life (36C54 h vs. stage, as well as the concomitant chemotherapeutic medicines. and glucocorticoid level of resistance is an undesirable prognostic element in ALL, and many mechanisms have already been reported.1 Glucocorticoid exposure induces up-regulation from the glucocorticoid receptor in every cells and about 50 % from the 51 responsive genes determined have already been functionally associated with 3 main pathways: cell proliferation and survival (MAPK pathways), NF-B signaling and glucose rate of metabolism.11, 12 Glucocorticoid level of resistance continues to be connected with up-regulation of genes involved with glucose rate of metabolism and increased blood sugar usage.11, 13, 14 Glucocorticoids also launch Ca2+ through the endoplasmic reticulum in to the cytosol; the ensuing mitochondrial Ca2+ boost induces cytochrome c launch and causes apoptosis. Elevated manifestation of calcium-binding protein S100A8 and S100A9 and of the anti-apoptotic BCL-2 proteins relative MCL-1 inhibited free of charge cytosolic Ca2+ and mitochondrial Ca2+ indicators, respectively, leading to glucocorticoid level of resistance.15C17 Traditionally, prednisone continues to be the glucocorticoid mostly found in ALL therapy; it really is typically provided for 4 consecutive weeks in conjunction with vincristine, an anthracycline, asparaginase, and intrathecal chemotherapy. Dexamethasone, another glucocorticoid, can be used increasingly lately to take care of ALL. Both of these glucocorticoids are artificial analogs of cortisol that differ molecularly in a number of important elements (shape 2).18C21 Dexamethasone differs from prednisolone (active metabolite of prednisone) only with a fluorine atom in the 9 position of band B and a methyl group in the C 16 position of band D. The 9 fluorine slows the rate of metabolism of dexamethasone, therefore increasing its plasma half-life (200 min vs. 60 min for prednisolone) and natural half-life (36C54 h vs. 24C36 h).19, 21 The C 16 methyl group minimizes dexamethasones sodium-retention effect. Prednisone is known as to possess half the nutrient corticoid activity of cortisol, while dexamethasone can be thought to possess little or non-e.21 Open up in another window Shape 2 Chemical substance structures of cortisol and of the man made glucocorticoids prednisone, prednisolone, and dexamethasone. Bioequivalence research of dexamethasone and prednisone possess frequently yielded discordant outcomes. Generally, 1 mg of dexamethasone continues to be considered equal to 5 to 10 mg of prednisone in reducing swelling.20C22 However, this assumption is not experimentally confirmed. Right here we review the usage of prednisone and dexamethasone in every, weighing proof from in vitro research, preclinical versions, and clinical research; compare the medicines benefits and undesireable effects; and discuss their ideal uses. In vitro cytotoxicity of prednisolone and dexamethasone The cytotoxicity of prednisolone and dexamethasone to all or any cells was compared in examples from 133 pediatric individuals with untreated Simply by using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in cell suspension system ethnicities.23 The cytotoxicity of dexamethasone was considerably higher than that of prednisolone and was much higher than that expected from the relative anti-inflammatory ramifications of the medicines. The median LC50 (focus creating 50% cytotoxicity) ideals of prednisolone and dexamethasone had been 3.5 M and 0.2 M, respectively, as well as the median percentage from the prednisolone Tulobuterol and dexamethasone LC50 ideals was 16.2. Oddly enough, the percentage ranged broadly (from 0.7 to 500) in examples from individual individuals. Ito et al.24 compared the in vitro cytotoxicity of prednisolone and dexamethasone in leukemia cells grown on bone tissue marrowCderived stromal levels. The stromal cells make a microenvironment identical compared to that of bone tissue marrow in vivo, avoiding apoptosis of leukemic lymphoblasts and permitting their proliferation.25 In 28 B-lineage ALL samples tested, prednisolone and dexamethasone got median LC50 values of 43.5 nM and 7.5 nM, respectively. The median dexamethasone-to-prednisolone percentage was 1:5.5 for both LC50 and LC90 ideals. This percentage was considerably less than that dependant on the MTT assay but was like the percentage from the medications approximated anti-inflammatory activity also to their typical dose proportion. Again, individual examples showed a variety in the dexamethasone-to-prednisolone LC50 (1:1.0 to at least one 1:24.4) and LC90 (1:1.1 to at least one 1:25.5) ratios. It isn’t apparent why dexamethasone is normally even more cytotoxic to leukemia cells than prednisolone. Lippman et al.26 identified an extremely particular glucocorticoid receptor in preparations of cytosol from glucocorticoid-sensitive ALL cells. Many research showed which the dexamethasone receptor complicated is more steady compared to the prednisolone receptor complicated27 which the glucocorticoid receptor of leukemia cells provides better affinity for dexamethasone than for prednisolone.26, 28 However, other research showed that glucocorticoid receptor provides similar affinity for prednisolone and dexamethasone.18 Furthermore, both in vitro cytotoxicity research defined above found a wide range in the dexamethasone-to-prednisolone LC50 and.