Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idarubicin (IDR) is a new analog of Daunorubicin (DNR) selected for clinical trials because of its outstanding activity in experimental leukemias of mice and in several experimental models when compared to DNR and Doxorubicin. This Phase I trial was designed to determine the maximal tolerated dose in adult patients with acute leukemia refractory to prior treatment, using intravenously (I.V.) daily treatments for 5 consecutive days. Eleven patients were entered in this study. The initial dose of IDR was 4 mg/m2/d X 5 I.V. The highest dose given was 8 mg/m2/d X 5 I.V. Dose limiting toxicity were gastrointestinal side effects at the 8 mg/m2/d X 5 level (mucositis-diarrhea). Antileukemic activity has been detected in acute non-lymphoblastic leukemia not pretreated with anthracyclines. For Phase II adult leukemia studies using this schedule, it is recommended that the IDR dose should be 7 mg/m2/d.
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PMID:Phase I trial of Idarubicin (4-demethoxydaunorubicin) in adult acute leukemia. 659 42

Idarubicin (Ida), an analogue of daunomycin, was linked to a mouse monoclonal antibody against the B cell differentiation antigen CD19. Determination of the activity of both the antibody and drug moieties was carried out in vitro using a pre-B cell human acute lymphoblastic leukaemia cell line (NALM-6). A 23% loss in antibody binding and a 20-fold loss in drug activity were observed upon conjugation. Selective cytotoxicity for CD19+ cells, however, was obtained. Measurement of the cytotoxicity, antibody activity and release of the breakdown product, 14-OH-Ida, showed that the conjugates remained stable for more than 100 days after lyophilization and storage at -20 degrees C. In vivo studies were performed in irradiated nu/nu mice bearing NALM-6 tumours. Initial dose response studies with free idarubicin demonstrated that three i.p. doses (every other day) of 10 micrograms resulted in little antitumour activity, but the death of all the animals by day 23. The same treatment regime using 15 micrograms Ida-anti-CD19 conjugate caused the disappearance of four out of five tumours with three complete cures and no evidence of toxicity as assessed by weight loss. Administration of a conjugate of idarubicin with an irrelevant antibody at this dose led to no significant antitumour response. The administration of free drug at a dose of 6 micrograms resulted in a minor antitumour response but high toxicity, whereas injection of Ida-anti-CD19 conjugate at this dose caused no toxicity and a substantial antitumour effect with eradication of two out of five tumours. These results clearly demonstrate that the administration of Ida-anti-CD19 conjugates can result in complete tumour regression in an experimental model. Idarubicin-containing immunoconjugates should be useful for the treatment of patients with non-Hodgkin's lymphoma.
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PMID:Preclinical investigation of the antitumour effects of anti-CD19-idarubicin immunoconjugates. 768 21

Because of the fact that tumor cell sensitivity to cytotoxic agents may play a major role in cancer treatment, and several anthracyclines are widely used for first-line treatment of leukemia, lymphoma and other tumors, and since the overexpression of the mdr-1 gene-coded 170 Kd glycoprotein (P170) decreases cell sensitivity to anthracyclines, we investigated the relationship between P170 overexpression and the cytotoxicity of two classic anthracyclines (Daunorubicin or DNR and Doxorubicin or DX) and two lipophilic anthracycline derivatives (Idarubicin or IDA and Iododoxorubicin or IDX). For these purposes, we used multidrug resistant (MDR) and non-MDR tumor and leukemia cell lines and the MTT-microcultured tetrazolium colorimetric assay. We showed that mdr-1 gene overexpression was strongly associated with the development of a high level of resistance to DNR and DX, but not to the derivatives IDA and IDX. These data suggest that more lipophilic anthracycline derivatives may also be active in MDR cell systems.
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PMID:A comparative analysis of the sensitivity of multidrug resistant (MDR) and non-MDR cells to different anthracycline derivatives. 809 29

The effect of growth stimulation on the sensitivity of normal and leukemic human bone marrow progenitors to idarubicin and doxorubicin was studied. Clonogenic assays from colony-forming units of the granulocyte-macrophage lineage (CFU-GM) and leukemic clonogenic cells (CFU-L) were applied using human placenta conditioned medium (HPCM) as source of growth factors. Before seeding cells in clonogenic assay they were exposed to the anthracyclines for 2 h without preincubation, or following a 48 h preincubation period in the presence of HPCM. Drug concentrations used ranged from 0.001-0.1 microgram/ml for idarubicin and from 0.1-1.5 microgram/ml for doxorubicin. In addition, a limited number of bone marrow samples were exposed to the cytostatically active metabolite of idarubicin; idarubicinol (Idol; range 0.001-0.1 microgram/ml). Proliferation of CFU-GM and CFU-L during 48 h was measured by iododeoxyuridine (IdUrd) incorporation. Spontaneous proliferation of CFU-GM increased from 38 to 88% after 48 h stimulation by HPCM. The mean number of proliferating CFU-L increased from 40 to 77% when stimulated with HPCM. Doxorubicin inhibited colony formation of CFU-GM and CFU-L to 50% (IC50CFU-GM, IC50CFU-I) at mean concentrations of 0.355 microgram/ml and 0.103 microgram/ml when applied before preincubation with HPCM, and 0.108 microgram/ml and 0.055 microgram/ml when applied after preincubation. Idarubicin appeared the most potent drug in all experiments regardless of the preincubation procedure or sample origin, with average IC50CFU-GM and IC50CFU-L of 0.008 microgram/ml and 0.006 microgram/ml, respectively, when applied before preincubation with HPCM, and 0.006 microgram/ml and 0.005 microgram/ml when applied after preincubation with HPCM. Idarubicinol showed intermediate potency with average IC50CFU-GM of 0.022 microgram/ml and 0.023 microgram/ml when applied before and after preincubation with HPCM, respectively. In order to assess the effect of growth stimulation on drug sensitivity, samples were evaluated pair-wise (sensitivity of the same sample before vs. after preincubation with HPCM) and were submitted to the Wilcoxon test for matched pairs. Statistically significant enhancement of cytotoxicity was demonstrated for Doxorubicin vs. CFU-GM (p < or = 0.021) and a strong trend versus CFU-L (p = 0.06). The data further demonstrate that proliferation-dependency of doxorubicin toxicity is more pronounced for CFU-GM than for CFU-L. These data also show that idarubicin and idarubicinol toxicity is proliferation-independent. Idarubicin is relatively more potent than doxorubicin in suppressing the growth potential of low or nonproliferating progenitors.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994 Mar
PMID:Toxicity of idarubicin and doxorubicin towards normal and leukemic human bone marrow progenitors in relation to their proliferative state. 812 43

The anthracycline antibiotics constitute a major series of anti-cancer drugs, the best known and most widely used being doxorubicin. Among hundreds of analogues, only a few have reached routine clinical use. Their main metabolic feature is the reduction of a ketone group to an hydroxyl group, giving an -ol derivative generally less active than the parent compound. Anthracyclines are characterized by a rapid distribution phase and a slow elimination phase. The successive half-lives of doxorubicin in plasma are about 5 minutes, 1 hour and 30 hours. Its total plasma clearance is about 30 l/hr/m2, and its total volume of distribution at steady state is approximately 15 l/kg. Anthracyclines are excreted mostly through bile, and special care must be taken with their use in patients with hepatic dysfunction. The new anthracyclines of clinical interest in solid tumours (epirubicin, pirarubicin) are more lipophilic than doxorubicin and have a higher volume of distribution and an increased total plasma clearance. Idarubicin is active in leukaemia rather than against solid tumours, and an oral form is available. Because of their high tissue fixation, these new anthracyclines are of particular interest for locoregional therapy, especially through the hepatic artery. Myelosuppression is the dose-limiting toxicity of anthracyclines and is related to drug exposure, so that pharmacokinetic-pharmacodynamic relationships have been clearly established for these drugs. A new subfamily, characterized by a morpholino group, presents very original features such as direct covalent linking to DNA after cytochrome P450 activation. These molecules are active at 100-fold lower concentrations than the conventional anthracyclines and are currently in clinical trials.
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PMID:Pharmacokinetics and metabolism of anthracyclines. 813 42

Idarubicin (4-demethoxy-daunorubicin) is a new commercially available anthracycline antibiotic which is more active than daunorubicin, the accepted reference drug, in the treatment of acute myelogenous leukaemia, which generally involves the combination of an anthracycline and cytarabine [corrected]. It is characterised by metabolic transformation into a 13-dihydro derivative, idarubicinol, which is as active as the parent drug in in vitro models. The pharmacokinetics of idarubicin follow a 2- or 3-compartment plasma disappearance with half-life (t1/2) values of 13 min, 2.4h and 16h, clearance approximately 60 L/h/m2 and volume of distribution at steady-state of 1,500 L/m2. Idarubicinol is characterised by a very long elimination t1/2 of 55h. The ratio of metabolite: parent drug area under the plasma concentration-time curve is often > 2 and is even higher after 2 or 3 daily injections of the drug, the normal drug protocol used in induction or consolidation treatments of acute leukaemias. Idarubicin can also be administered orally and the pharmacokinetics are similar to those after intravenous administration, except that the idarubicinol: idarubicin ratio is increased, probably due to a liver first-pass effect. The bioavailability of idarubicin is 20 to 25%, but if the activity of idarubicinol is taken into account, it is effectively about 40%. After idarubicin administration by either route, there is a progressive accumulation of idarubicinol after multiple once-daily but not after once-weekly doses. About 10% of the injected dose is recovered in urine as idarubicin and idarubicinol, and only slightly higher proportions are recovered in bile. This suggests that other unidentified metabolites must be excreted by either or by both pathways.
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PMID:Clinical pharmacokinetics of idarubicin. 849 Oct 56

Idarubicin (IDA) possessed high antitumor activity against mouse P388 leukemia. When P388 leukemia bearing mice were administered an optimal dose of IDA intravenously, 200-250% of T/C and some cured mice were obtained. IDA showed a partial but significant effect against daunorubicin (DNR)-resistant P388 leukemia, whereas DNR, its parent drug, did not. Although IDA failed to show activity against doxorubicin (DX)- and aclarubicin (ACR)-resistant P388 leukemia in this study, IDA might have chemotherapeutic effects in patients in relapse and refractory to other anthracyclines. This assumption is supported by the results on the growth inhibition study in vitro. Among the metabolites, only idarubicinol showed cytotoxicity against P388 leukemia and idarubicinol showed 38% of the activity of IDA, indicating that the active components in animals could be IDA and idarubicinol. The combination of IDA and Ara-C induced some additive effect in P388 leukemia bearing mice as compared to the results with single drug usage.
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PMID:Antitumor activity of idarubicin, a derivative of daunorubicin, against drug sensitive and resistant P388 leukemia. 851 47

Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy at an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under the curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicin in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24-h trough levels shows high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4 - 445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two-fold from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r=0.78, indicating that the interindividual variations of idarubicin AUC reflects differences in absorptions rather than metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24-h trough level shows such an excellent correlation (r=0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24-h trough level may allow the assessment of the impact of interindividual variations in AUC of clinical outcome and toxicity.
Leukemia 1996 Apr
PMID:Oral idarubicin pharmacokinetics--correlation of trough level with idarubicin area under curve. 861 51

The antitumor effects of Behenoyl-ara-C (BH-AC) in combination with Idarubicin (IDA) on leukemia were studied. First, a combination of IDA with Ara-C, which is the main metabolite of BH-AC, was evaluated with regard to its in vitro cytotoxic activity on mouse P 388 leukemic cells. The effect of this combination proved to be additive according to isobologram analysis. Secondly, the antitumor activity of an intravenous bolus-administration of a combination of BH-AC and IDA was evaluated by the life span of P 388 bearing mice, and compared with the activity of the Ara-C and IDA combination. The antitumor activity of Ara-C administered alone was clearly dependent on the administration schedule and was most intense when Ara-C was administered with the most frequent injections (3 bolus injections/day x 3 days), whereas antitumor activity of BH-AC was less dependent on the schedule. IDA administered alone showed dose-dependency in its antitumor activity up to 3 mg/kg. The maximum effects of IDA were observed with amounts of 3 - 4 mg/kg. In the same leukemia model, the combination of frequent injections of BH-AC and a single injection of IDA (increased life span: ILS>300%; cure ratio: CR = 3/5) conferred a more potent effect compared to the results of BH-AC (ILS = 133%, CR = 0/5) or IDA (ILS = 67%, CR = 2/5) alone. The effect of BH-AC and IDA combination was comparable or superior to that of the Ara-C and IDA (ILS = 233%, CR = 2/5) combination. These results indicated the possibility of clinical usefulness with a combination therapy of BH-AC and IDA against leukemia.
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PMID:[Antitumor effects of Behenoyl-ara-C (BH-AC) in combination with Idarubicin (IDA) in P 388 leukemic cell bearing mice]. 871 21

A patient with acute monoblastic leukemia (AML, M5A) was treated successfully in December 1987. In 1993 after 6 years in complete remission, she presented with an intracutaneous nodular mass on her right upper arm which was resected in toto and shown to be undifferentiated monoblastic leukemia. Two further chloroma lesions were excised in July 1994 and March 1995 respectively. Bone marrow cytology and histology always showed a continuing complete remission with no evidence of leukemia relapse. In July 1995 she presented with a disseminated skin infiltrate and a relapse with 80% monoblasts in the bone marrow. After one course of chemotherapy (Idarubicin/Ara-C), a second complete remission was achieved and her leukemic skin infiltrate disappeared completely. This case illustrates that chloromas of the skin can occur as late as 6 years after treatment for AML and also emphasizes that the occurrence of a chloroma does not necessarily mean immediate leukemia relapse. It also stresses that a second complete remission can be achieved with standard AML-induction therapy despite widespread leukemic skin infiltrates in such patients.
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PMID:Cutaneous monoblastic leukemia as a first sign of relapse six years after autologous bone marrow transplantation for acute leukemia. 888 69


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