Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity.
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PMID:Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia. 1198 55

Etoposide and teniposide, derivatives of podophyllotoxin, are inhibitors of DNA topoisomerase II and are potent anticancer agents. An adverse effect linked to the use of these drugs is the development of acute myeloid leukemia, a disorder usually associated with chromosomal translocation. To examine podophyllotoxin-induced DNA rearrangement, we developed an assay system to measure illegitimate recombination in Saccharomyces cerevisiae chromosomes. This approach uses juxtaposed CAN1-CYH2 negative selection markers that are introduced into the LEU2 locus, which is located on chromosome III, in a yeast strain carrying the mutated can1 and cyh2 genes. Upon formation of a deletion over the active CAN1-CYH2 genes, a cell becomes resistant to both canavanine and cycloheximide. To introduce drugs into the cell, we used a yeast strain carrying an ISE2 mutation, thereby making the cell drug-permeable. Here we show that treatment of cells with etoposide (VP-16) increases the rate of illegitimate recombination in yeast, indicating that VP-16 stimulates DNA topoisomerase-mediated illegitimate recombination. Structural analysis of the resulting recombinants indicate that most are formed by deletion mutations on chromosome III, which take place between short homologous regions of DNA. We propose a model for illegitimate recombination, in which VP-16 facilitates formation of a cleavable complex between DNA topoisomerase II and DNA, thus promoting DNA double-strand breakage with the resulting DNA ends joined by a non-homologous mechanism.
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PMID:Effect of the DNA topoisomerase II inhibitor VP-16 on illegitimate recombination in yeast chromosomes. 1209 98

In an attempt to improve current therapeutic strategies for acute myelogenous leukemia (AML), we studied the effects of a commercially available drug, dexrazoxane (DEX), which protects against anthracycline-induced cardiotoxicity. The rationale was that DEX would permit higher doses of cardiotoxic drugs to be given. The drug itself may have therapeutic potential as well. Finally, there are concerns that the drug may, as a protective agent, diminish the effectiveness of various chemotherapeutics. To help resolve the question about potential drug antagonism, we undertook a series of in vitro analyses of DEX and various combinations with anthracyclines and other agents. Colony-forming assays were used to evaluate stem-cell renewal of myeloid cells in vitro, and median-effect analysis was used to evaluate antagonism, synergism, and additivity. The anthracyclines doxorubicin, daunorubicin, and idarubicin were individually combined with DEX to study in vitro effects in leukemic myeloid cell lines. In the hope, we could extend the findings to non-anthracyclines, etoposide and cytosine arabinoside were also evaluated in combination with DEX using the same in vitro model and method. We found that the effects of DEX in combination with any of the anthracyclines were schedule dependent. The antitumor effect was greater for each combination than for any anthracycline alone except when DEX was administered 24h before doxorubicin or daunorubicin. These data were corroborated through median-effect analysis. Etoposide in combination with DEX was synergistic for all combinations and schedules, and the combination of cytosine arabinoside and DEX was effective depending on the schedule used. DEX appears to be a promising drug in the treatment of AML and warrants further clinical study involving novel drug combinations.
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PMID:Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. 1268 61

Primary resistant acute myeloid leukemia (AML) has a very poor prognosis. Etoposide-mitoxantrone-cytarabine (EMA) timed sequential chemotherapy including a first sequence combining mitoxantrone (12 mg/m(2) per day over 3 days) with cytarabine (500 mg/m(2) per day over the same period), and a second sequence consisting in etoposide (200 mg/m(2) per day for 3 days) and cytarabine as in the first sequence, has been proposed as a salvage regimen. Over a 10-year period, 66 primary resistant AML patients have been treated by EMA salvage chemotherapy. All patients displayed intermediate- or high-risk karyotypic abnormalities. Of the 66 patients, 24 [36%, 95% confidence interval (CI): 25-49%] achieved complete remission (CR). Thirty-eight patients were resistant to EMA chemotherapy and four patients died from toxicity during aplasia. After CR achievement, 18 patients received consolidation therapy. Five patients with an HLA-identical sibling donor underwent allogeneic stem cell transplantation (SCT), one patient received autologous SCT, two patients received a second course of EMA chemotherapy, and ten were scheduled for 6-monthly maintenance courses (mini-EMA). Median follow-up was 7.3 years. At the time of analysis, 21 of the 24 patients (87%) who achieved CR have relapsed. Median disease-free survival (DFS) was 5 months (95% CI: 4.3-7.7 months). Median overall survival (OS) was 5 months (95% CI: 3.8-6.7 months). There were only two long-term remitters (3%). In the univariate analysis, CR achievement was mainly related to white blood cell (WBC) count at the time of starting salvage therapy with poorer outcome for patients with more aggressive leukemia (WBC count > or =10 x 10(9)/l) (CR rates: 50% vs 10%, p<0.001). Overall survival was also influence by WBC count (median OS: 7.2 months vs 2.8 months, respectively, for WBC <and > or =10 x 10(9)/l, p<0.0001). Initial karyotype was not a significant prognostic factor either for CR achievement or for DFS or OS when comparing patients with normal karyotype and those with chromosomal abnormality. In multivariate analysis, WBC count less than 10 x 10(9)/l with the absence of circulating blasts at the time of starting salvage therapy appeared to be of favorable prognostic value for CR achievement ( p=0.002), while WBC count less than 10 x 10(9)/l appeared to be of favorable prognostic value for survival ( p<0.0001). Using these two objective parameters of proven significance, we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices. Patients with both factors (WBC count <10 x 10(9)/l and no circulating blasts) or with at least one at the time of starting salvage therapy had a CR rate of 50% and were therefore candidates for intensified post-remission therapy. All other patients displayed a very poor outcome and must be oriented after failure of first-line therapy to alternate therapeutic programs based on investigational drugs.
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PMID:Salvage by timed sequential chemotherapy in primary resistant acute myeloid leukemia: analysis of prognostic factors. 1292 54

Few t(9;11) translocations in DNA topoisomerase II inhibitor-related leukemias have been studied in detail and the DNA damage mechanism remains controversial. We characterized the der(11) and der(9) genomic breakpoint junctions in a case of AML following etoposide and doxorubicin. Etoposide-, etoposide metabolite- and doxorubicin-induced DNA topoisomerase II cleavage was examined in normal homologues of the MLL and AF-9 breakpoint sequences using an in vitro assay. Induction of DNA topoisomerase II cleavage complexes in CEM and K562 cell lines was investigated using an in vivo complex of enzyme assay. The translocation occurred between identical 5'-TATTA-3' sequences in MLL intron 8 and AF-9 intron 5 without the gain or loss of bases. The 5'-TATTA-3' sequences were reciprocally cleaved by DNA topoisomerase II in the presence of etoposide, etoposide catechol or etoposide quinone, creating homologous 4-base 5' overhangs that would anneal to form both breakpoint junctions without any processing. der(11) and der(4) translocation breakpoints in a treatment-related ALL at the same site in MLL are consistent with a damage hotspot. Etoposide and both etoposide metabolites induced DNA topoisomerase II cleavage complexes in the hematopoietic cell lines. These results favor the model in which the chromosomal breakage leading to MLL translocations in DNA topoisomerase II inhibitor-related leukemias is a consequence of DNA topoisomerase II cleavage.
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PMID:Reciprocal DNA topoisomerase II cleavage events at 5'-TATTA-3' sequences in MLL and AF-9 create homologous single-stranded overhangs that anneal to form der(11) and der(9) genomic breakpoint junctions in treatment-related AML without further processing. 1462 86

A 21-year-old male presented with right scrotal discomfort. Right high orchiectomy revealed non-seminoma and he was diagnosed with stage I non-seminoma. Since acute myeloid leukemia (AML) was diagnosed incidentally, no adjuvant therapy was given and he received chemotherapy for AML. One year later, he complained of lumbago and general malaise. Complete remission of AML had been achieved and bone marrow puncture revealed no signs of recurrence. Computed tomography showed retroperitoneal lymph node swelling, inferior vena caval embolus distal to the hepatic vein, and multiple lung nodules. Metastasis of testicular neoplasm was suspected and chemotherapy with Bleomycin, Etoposide, and Cisplatin was started. On the fourth day of chemotherapy, the patient complained of sudden dyspnea and acutely went into shock. Pulmonary embolism was diagnosed and an inferior vena cava filter was placed. Chemotherapy was continued for four courses and the tumor showed complete remission. He has been free of disease for 24 months. In rare cases of testicular cancer with inferior vena caval embolus, the physician should be aware of the possibility of causing pulmonary embolism after chemotherapy.
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PMID:[Testicular cancer with inferior vena caval embolus causing pulmonary embolism following chemotherapy: a case report]. 1523 86

We investigated whether etoposide might be a suitable alternative to anthracyclins for the treatment of elderly patients with acute myeloid leukemia (AML) in whom anthracyclins are contraindicated. In total, 88 patients over 60 years old were treated in our department between 1988 and 2000 for de novo or secondary AML. Of these 88 patients, 21 had severe cardiac disease and received a combination of etoposide and cytosine arabinoside (group A). They were compared with 23 patients who received daunorubicin plus cytosine arabinoside (group B) and 44 patients who received mitoxantrone, cytosine arabinoside and etoposide (group C). In group A, the complete remission (CR) rate was 33% (7/21), median disease-free survival (DFS) was 365 days and median overall survival (OS) was 214 days. These results were not statistically different from those for the anthracyclin-based regimens (CR 43%, DFS 210 days, OS 150 days for group B and CR 47%, DFS 216, OS 295 days for group C). Moreover, there was no significant difference in the number of treatment-related toxic events and deaths in the 3 treatment groups. Etoposide combined with a standard dose of cytosine arabinoside is relatively safe and effective in elderly patients with AML and offers an alternative approach to patients with cardiac contraindications to anthracyclin treatment.
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PMID:Acute myeloid leukemia in the elderly: etoposide when anthracyclins are contraindicated. 1562 30

Etoposide-induced treatment-related acute myelogenous leukemia (t-AML) is characterized by rearrangements of the mixed lineage leukemia (MLL) gene with one of its >50 partner genes, most probably as a consequence of etoposide-induced DNA double-strand breaks (DSBs). Recent studies have shown that etoposide-induced DSBs occur predominantly within the breakpoint cluster region (bcr) of the MLL gene. However, bcr-specific DSBs induced by etoposide are not topoisomerase II-linked but the result of apoptotic nuclease-mediated DNA cleavage. Here, we test the involvement of caspase-activated DNase (CAD) and other apoptotic components in etoposide-induced gene rearrangements using two methods. First, we measured the effect of etoposide on the integration frequency of a transfected plasmid. Etoposide strongly stimulated plasmid integration in CAD cDNA-complemented mouse embryonic fibroblasts (MEFs) but not in CAD knockout (KO) MEFs. Consistently, down-regulation of ICAD (inhibitor of CAD, also required for proper folding of CAD) in an HT29-derived cell line, which leads to decreased CAD activity, significantly reduced etoposide-induced plasmid integration. Second, we used long-template inverse PCR to focus on gene rearrangements at the MLL locus. Etoposide stimulated MLL fusion product formation in CAD cDNA-complemented MEFs but not in CAD KO MEFs. Together, these results suggest that CAD and other apoptotic components may play an important role in etoposide-induced t-AML.
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PMID:Role of apoptotic nuclease caspase-activated DNase in etoposide-induced treatment-related acute myelogenous leukemia. 1698 37

We studied the pharmacokinetics of etoposide in 45 children treated for newly diagnosed acute myeloid leukemia. Etoposide, 100 mg/m body surface area/24 h, was administered by 96-h continuous intravenous infusion. Concomitantly, the children received cytarabine 200 mg/m/24 h by intravenous infusion and 6-thioguanine 100 mg/m twice daily orally. Median total body clearance in children 0.5-1.8 (n=4) and 2.3-17.7 years old (n=36) without Down's syndrome was 17.1 and 17.6 ml/min/m, respectively (P=0.96). Five children with Down's syndrome had a median clearance of 13.6 ml/min/m (P=0.067 compared with non-Down's syndrome children). Eighteen of the children received a second identical treatment course 3-4 weeks later; there was a significant correlation between individual clearance values (rho=0.56; P=0.017). We found no significant correlation between etoposide pharmacokinetics and the remission rate or the relapse rate. In conclusion, our findings indicate that special dose-calculation guidelines for infants above 3 months old are not substantiated by age-dependent pharmacokinetics of etoposide. Down's syndrome children might be candidates for dose reduction if our data are confirmed in larger numbers of patients. Low course-to-course variability indicates that pharmacokinetically guided dosing of etoposide might be clinically relevant, if larger studies can demonstrate that this approach decreases toxicity or increases response rates.
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PMID:Etoposide pharmacokinetics in children treated for acute myeloid leukemia. 1700 Nov 83

Primary gut involvement by Aspergillus is an exceedingly rare and often a fatal complication of intensive chemotherapy in patients with acute leukaemia. We report a 46-yr-old patient with granulocytic sarcoma of the testis. He received acute myeloid leukaemia type treatment with ADE chemotherapy (Cytosine Arabinoside, Daunorubicin and Etoposide). While neutropenic he presented with pyrexia, abdominal pain and massive abdominal distention. He was treated with intravenous antibiotics and antifungals according to our usual institutional protocol without any response. He was found to have toxic megacolon on plain X-ray and subsequently underwent total colectomy and ileostomy. The colon histology showed Aspergillus fungal hyphae infiltrating the bowel wall. There was no any evidence of pulmonary, hepatic, splenic or renal lesions on the computerised tomography scan. Following colectomy, he was treated with 2 wk of antifungal treatment. He recovered well and was discharged home. The increased awareness, high degree of clinical suspicion of unusual presentation and early surgical intervention with aggressive antifungal treatment, has a key role in the management of these rare and often fatal cases.
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PMID:Invasive aspergillosis localised to the colon presenting as toxic megacolon. 1732 84


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