Phase II Study of Aclarubicin in Acute Myeloblastic Leukemia

Case, David B.; Ervin, Thomas J.; Boyd, Marjorie A.; Bove, Louis G.; Sonneborn, Henry; Paul, Steven

doi:10.1097/00000421-198712000-00014

Cited by 18 publications

(10 citation statements)

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“…More recently, it appeared that the maximum tolerated dose of epirubicin may be as high as 150 to 180 mg/m 2 in previously untreated patients with a good performance status and 105 to 120 mg/m 2 in patients who have been treated previously (Case et al 1987(Case et al , 1988. Because of the lower cumulative cardiac toxicity of epirubicin, it is possible to increase the dosage administered per course of treat- Clin.…”

Section: Overview Of Clinical Activitymentioning

confidence: 99%

Clinical Pharmacokinetics of Epirubicin

Robert

1994

Clinical Pharmacokinetics

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Epirubicin (4'-epidoxorubicin) is a new anthracycline that has activity similar to doxorubicin (adriamycin) in a variety of solid neoplasms and haematologic malignancies. Importantly, epirubicin causes less cardiotoxicity than doxorubicin. There is extensive distribution of epirubicin into tissues and the elimination of the drug is predominantly biliary, with less than 15% of the drug excreted in the urine. The metabolism of epirubicin is characterised by complex biotransformation to relatively or totally inactive metabolites, including a 13-dihydro derivative, epirubicinol, 2 glucuronides and 4 aglycones. Quantitatively, the glucuronides of epirubicin and epirubicinol are very important, and this pathway, which is unique to epirubicin metabolism in humans, might explain the better tolerability of this drug compared with doxorubicin. Epirubicin pharmacokinetics may be described by a 3-compartment model, with median half-life values of 3.2 minutes, 1.2 and 32 hours for each phase. Total plasma clearance is 46 L/h/m2 and volume of distribution at steady-state is 1000 L/m2. The pharmacokinetics of epirubicin appears to be linear for doses up to the maximal tolerated dose of 150 to 180 mg/m2. Both intraperitoneal and intravesical administration of epirubicin are feasible, but remain of a rather restricted interest. The area under the plasma concentration-time curve of epirubicin is fairly well correlated with the relative kill of white blood cells. Therefore, epirubicin clearance can be used to predict haematological toxicity.

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Section: Overview Of Clinical Activitymentioning

confidence: 99%

Clinical Pharmacokinetics of Epirubicin

Robert

1994

Clinical Pharmacokinetics

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“…[2][3][4] Thus far, many compounds with topoisomerase inhibitory activity have been successfully used in clinical practice for the treatment of various neoplasms. For example, aclarubicin and suramine prevent binding between DNA and topoisomerase IIa, [10,11] merbarone prevents DNA cleavage, [12] bisdioxipiperazine (e.g., compound ICRF-187) derivatives inhibit ATP hydrolysis, [13] and purine analogues (e.g., compounds 2 and 3) inhibit ATP binding. Poisons (group I) act by stabilizing a transient covalent DNA-enzyme complex, thereby causing damage to the DNA molecule.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Mono‐ and Disubstituted 1H‐Pyrazolo[3,4]pyrimidines and 9H‐Purines as Catalytic Inhibitors of Human DNA Topoisomerase IIα

et al. 2014

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Human DNA topoisomerase IIα (htIIα) is a validated target for the development of anticancer agents. Based on structural data regarding the binding mode of AMP-PNP (5'-adenylyl-β,γ-imidodiphosphate) to htIIα, we designed a two-stage virtual screening campaign that combines structure-based pharmacophores and molecular docking. In the first stage, we identified several monosubstituted 9H-purine compounds and a novel class of 1H-pyrazolo[3,4]pyrimidines as inhibitors of htIIα. In the second stage, disubstituted analogues with improved cellular activities were discovered. Compounds from both classes were shown to inhibit htIIα-mediated DNA decatenation, and surface plasmon resonance (SPR) experiments confirmed binding of these two compounds on the htIIα ATPase domain. Proposed complexes and interaction patterns between both compounds and htIIα were further analyzed in molecular dynamics simulations. Two compounds identified in the second stage showed promising anticancer activities in hepatocellular carcinoma (HepG2) and breast cancer (MCF-7) cell lines. The discovered compounds are suitable starting points for further hit-to-lead development in anticancer drug discovery.

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“…In elderly patients with non-Hodgkin's lymphoma, pirarubicin may cause severe cardiac dysfunction at cumulative doses as low as 360 mg/m 2 (Niitsu et al, 1998). Aclarubicin, a trisaccharide anthracycline, was shown to be active and cardiac-tolerable in adult patients with acute myeloblastic leukemia (Case et al, 1987;Wojnar et al, 1989). However, aclarubicin induced late cardiac events in a phase II study of adult patients with refractory acute myelogenous or lymphoblastic leukemia (Dabich et al, 1986) and proved to be inactive in women with metastatic breast cancer (Natale et al, 1993).…”

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confidence: 99%