Anthracycline dose intensification in young adults with acute myeloid leukemia

Padron, Eric; Fernandez, Hugo F.

doi:10.1177/2040620711427069

Cited by 11 publications

(10 citation statements)

References 51 publications

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“…1 Even though the majority of these patients achieve remission, disease relapse is frequent within the first year following treatment. 2 As notion of that, the persistence of minimal residual disease (MRD) is involved in disease relapse.…”

Section: Introductionmentioning

confidence: 99%

Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia

Piya¹,

Kornblau²,

Ruvolo³

et al. 2016

Blood

112

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• Atg7 expression is associated with shorter remission duration in AML.• Atg7 inhibition is a proapoptotic phenotype and enhances sensitivity to chemotherapy.Autophagy is a cellular adaptive mechanism to stress, including that induced by chemotherapeutic agents. Reverse phase protein array suggested that high expression of the essential autophagy-related protein, Atg7, was associated with shorter remission in newly diagnosed acute myeloid leukemia (AML) patient samples, indicating a role in chemoresistance. Knockdown of Atg7 in AML cells using short hairpin RNA markedly increased apoptosis and DNA damage following treatment with cytarabine and idarubicin. Interestingly, coculture of AML cells with stromal cells increased autophagy and chemoresistance in the AML cells exposed to chemotherapeutic agents, and this was reversed following Atg7 knockdown. This effect was further enhanced by concomitant knockdown of Atg7 in both AML and stromal cells. These findings strongly suggest that Atg7, and likely microenvironment autophagy in general, plays an important role in AML chemoresistance. Mechanistic studies revealed that Atg7 knockdown induced a proapoptotic phenotype in AML cells, which was manifested by an increased NOXA expression at the transcriptional level. Finally, in a mouse model of human leukemia, Atg7 knockdown extended overall survival after chemotherapy. Thus, the inhibition of Atg7 appears to be a valid strategy to enhance chemosensitivity, and it could indeed improve outcomes in AML therapy. (Blood. 2016;128(9):1260-1269

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Section: Introductionmentioning

confidence: 99%

Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia

Piya¹,

Kornblau²,

Ruvolo³

et al. 2016

Blood

112

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“…18 Recent evidence suggests that intensification of the anthracycline dose in young adults has a significant survival benefit. 19 Anthracyclines exert their cytotoxic effects through apoptosis via intrinsic mitochondrial pathways, mediated through the production of reactive oxygen species (ROS) and concomitant oxidative stress. 20 Among the various combinations of intracellular mechanisms for the cytotoxic effects of anthracyclines, a number of oxidoreductases catalyse the one-electron reduction of the quinone moiety of anthracyclines to generate a semiquinone free radical that covalently interacts with and damages DNA.…”

Section: Introductionmentioning

confidence: 99%

Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia

Yin

et al. 2014

Clin Exp Pharma Physio

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The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate-risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate-risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele-specific matrix-assisted laser desorption ionization time-of-flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms-related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse-free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.

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“…A gemtuzumab ozogamicinnel (GO) kiegészített 3 + 7 protokoll azonban nem hatékonyabb, de toxikusabb, mint a nagy dózisú DNR-t tartalmazó "3 + 7". A kezelés okozta (főleg) hepaticus toxicitás és elhúzódó thrombocytopenia végül az Amerikai Egyesült Államok piacáról való kivonását eredmé-nyezte [12,13]. A szer azonban újból érdeklődésre tarthat számot, mivel bizonyos esetekben (például kedvező rizikó, CBF-pozitivitás stb.)…”

Section: Az Aml Terápiájaunclassified

“…A 60 év, de különösen az 50 év alatti, jó biológiai állapotú, a kedvező és az intermedier rizikójú citogenetikai sajátosságokkal rendelkező betegek esetén a nagy dózisú DNR előnyös. A 90 mg/m 2 dózisú DNR a 45 mg/m 2 DNR-hez képest a CR-t 57,6%-ról 70,6%-ra, a medián túlélést 15,7 hónapról 27,3 hónapra növelte [13,14]. Bizonyos mutációk (DNMT3A, MLL-fúzió stb.)…”

Section: Fiatal (60-65 éV Alatti) Betegek Kezeléseunclassified

Az akut myeloid leukaemia gyógyszeres kezelése. Jelenlegi lehetőségek, jövőbeli kilátások

et al. 2016

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Az akut myeloid leukaemia heterogén betegség. A mutációs vizsgálatoknak köszönhetően genetikailag és molekulá-risan is jellemezhető típusok váltak ismertté. Kezelése -az akut promyelocytás leukaemia kivételével -egyforma. Kezelésében több mint 40 éve a "3 + 7" protokoll a meghatározó. Míg a cytarabin dózisa az eltelt idő során nem változott, a daunorubicin adagjának növelése (90 mg/m 2 ) a 60-65 év alatti, jó állapotú betegekben javította a túl-élést. A 60 évnél idősebbek azonban az intenzív kemoterápiát általában rosszul tolerálják. Időskorban a kezelés nem kuratív, a cél a hosszabb túlélés és a megfelelő életminőség biztosítása. A szupportív kezelés mellett újabban a kis intenzitású terápia (azacitidin, decitabin) kerül előtérbe. Az innovatív terápiától a jövőben további javulás remélhető. Orv. Hetil., 2016, 157(22), 843-848.Kulcsszavak: akut myeloid leukaemia, génmutációk, "3 + 7" protokoll, nagy dózisú daunorubicin, decitabin, azacitidin, innovatív terápia Drug treatment of acute myelogenous leukaemia Current options and future perspectivesAcute myelogenous leukemia is a heterogeneous disease. Recent molecular mutational analysis techniques have shed more light on different, genetically well characterised types of the disease. Treatment approach is uniform except for acute promyelocytic leukemia. Application of the "3 + 7" induction treatment has been the gold standard in the past 40 years. While the dose of cytarabine has not been changed, escalating daunorubicine dose in younger (<60 years) patients with good performance status to 90 mg/m 2 had a positive impact on overall survival. High dose chemotherapy is tolerated poorly in patients older than 60 years of age and, as treatment is not curative in the elderly, improvement of overall survival and quality of life remains the main goal of management in these patients. Low intensity treatment is beneficial and can provide additional advantage over supportive care. Innovative and targeted therapy approaches might give promise to better management of patients with acute myelogenous leukemia.

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Anthracycline dose intensification in young adults with acute myeloid leukemia

Abstract: Initial therapy The most widely used induction therapy in the United States remains the so-called '7 + 3' regimen. This has traditionally combined a 7-day

Cited by 11 publications

References 51 publications

Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia

Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia

Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia

Az akut myeloid leukaemia gyógyszeres kezelése. Jelenlegi lehetőségek, jövőbeli kilátások

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