Aclarubicin Plus Cytosine Arabinoside Versus Daunorubicin plus Cytosine Arabinoside in De Novo Acute Myelocytic Leukemia: A Danish National Trial

Hansen, Ole Paaske; Ellegaard, J.; Bastrup-Madsen, P; Brincker, H; Christensen, Bjarne; Killmann, Sven‐Aage; Lauersen, M. L.; Karle, Hans; Drivsholm, Aage; Jensen, MK; Laursen, Birgitte Schantz; Jans, H; Hippe, Erik; Petersen-Bjergaard, J.; Nissen, Neel I.; Thorling, K; Jensen, Kristina Buchardi

doi:10.1007/978-3-642-75720-4_3

Cited by 21 publications

(23 citation statements)

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“…A number of clinical studies have proven the effectiveness of aclarubicin in the therapy of AML. [8][9][10][11][12] Several different apoptosis pathways, including the activation of p53, involvement of the CD-95/FAS-pathway, tumor necrosis factor or cytochrome-C release by mitochondria, have been proposed. 13 Obviously, the pathways that are utilized are specific for different cell types.…”

Section: Introductionmentioning

confidence: 99%

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Gieseler¹,

Bauer

Nuessler³

et al. 1999

Leukemia

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We examined the cellular effects of topo II inhibitors in two human myeloid cell lines, HL-60 and KG-1 cells, with the purpose of finding molecular markers for the sensitivity of leukemia cells to topo II inhibitors. These cell lines are widely used, well characterized and they differ in their sensitivities to topo II inhibitors. Despite the fact that HL-60 cells are p53-negative, they are much more sensitive than KG-1 cells. Three different topo II inhibitors with distinct molecular ways of action have been used. Daunorubicin and aclarubicin are DNA intercalators that secondarily interact with topo II; etoposide, on the other hand, directly binds to the enzyme. In contrast to daunorubicin, which induces protein-associated DNA double-strand breaks due to the blockage of topo II action, aclarubicin inhibits the access of DNA by topo II. No correlation could be established between the drug-induced DNA damage and apoptosis. In fact, the amount and pattern of DNA damage examined with the 'comet assay' was characteristic for each drug in both cell lines. The DNA binding of daunorubicin was slightly higher in HL-60 cells, but there was no notable variance between the cell lines for aclarubicin. The most striking difference could be found for the nuclear topo II activity, which was about half in KG-1 cells and, additionally, less than 1% of the nuclear topo II activity was bound to the DNA in KG-1 cells when compared to HL-60 cells. This fraction of topo II interacts with the inhibitors; subsequently these findings might well explain the variance in the cellular sensitivity. Additional factors are alterations of the apoptotic pathways, eg loss of p53 in HL-60 cells. Although we found no differences in the quantity of DNA damage between the cell lines after drug treatment, the quality of DNA damage appeared to be distinct for each topo II inhibitor. The morphological appearance of the comet tails after treatment was characteristic for each drug. Further studies are necessary to decide whether these in vitro data are compatible with the clinical situation.

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Section: Introductionmentioning

confidence: 99%

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Gieseler¹,

Bauer

Nuessler³

et al. 1999

Leukemia

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“…The anthracycline aclarubicin (ACLA) was isolated in 1975 by Oki et al (1975) and activitiy was found in acute myelogenic leukaemia (AML) refractory to treatment with daunorubicin (DAU) and cytarbine (Pedersen-Bjergaard et al, 1984; Warrel et al, 1982). Recently, a phase III trial has found ACLA to be superior to DAU in the treatment of de novo AML (Hansen et al, 1988). In a previous study on the inter-experimental variation in the clonogenic assay we observed that the sensitivity pattern to ACLA in a panel of small cell lung cancer (SCCL) cell lines was different from the sensitivity to adriamycin (ADR), DAU and mitoxantrone (MITO) after short time incubation (Jensen et al, 1989).…”

mentioning

confidence: 98%

In vitro evaluation of the potential of aclarubicin in the treatment of small cell carcinoma of the lung (SCCL)

Pb¹,

Vindeløv²,

Roed³

et al. 1989

Br J Cancer

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Summary The sensitivity of eight cell lines established from treated and untreated patients with small cell carcinoma of the lung (SCCL) was tested in the clonogenic assay with 1 h and continuous exposure to aclarubicin (ACLA), adriamycin (ADR), daunorubicin (DAU) and mitoxantrone (MITO). The sensitivity to ADR, DAU and MITO covariated, and varied with a factor of five. The sensitivity to ACLA was independent of the sensitivity to ADR and varied only within a factor of two. Only ACLA showed pronounced increased potency with continuous incubation, and ACLA was the most potent drug in the three cell lines least sensitive to ADR. Two resistant cell lines were selected by treating NCI-H69 in vitro with DAU. One cell line (9-fold resistant to DAU) expressed large amounts of P-glycoprotein, the other cell line (4-fold resistant to DAU) had barely detectable glycoprotein. Both lines acquired resistance to ADR, ACLA and MITO. The cross-resistance to ACLA and MITO was only partial and ACLA was still the most potent drug on these lines. The sensitivity to ACLA of the cell lines least sensitive to ADR suggest that ACLA partially circumvents mechanisms of multidrug resistance. Together with the pronounced increase in potency with prolonged exposure, these results suggest that ACLA has a mechanism of action different from the 'classical' anthracyclines. In this context mitoxantrone is more similar to the classical anthracyclines although its structure is more dissimilar.The anthracyclines are among the most potent drugs in the treatment of a wide range of human neoplasms. Development of resistance to the drugs is a major problem, and much effort is devoted to the search of new anthracyclines without cross-resistance to the parent drugs. The anthracycline aclarubicin (ACLA) was isolated in 1975 by Oki et al. (1975) and activitiy was found in acute myelogenic leukaemia (AML) refractory to treatment with daunorubicin (DAU) and cytarbine (Pedersen-Bjergaard et al., 1984; Warrel et al., 1982). Recently, a phase III trial has found ACLA to be superior to DAU in the treatment of de novo AML (Hansen et al., 1988). In a previous study on the inter-experimental variation in the clonogenic assay we observed that the sensitivity pattern to ACLA in a panel of small cell lung cancer (SCCL) cell lines was different from the sensitivity to adriamycin (ADR), DAU and mitoxantrone (MITO) after short time incubation (Jensen et al., 1989). The present investigations were initiated to further elucidate the differences between ACLA and the other analogues. A murine tumour has recently been described to be relatively more sensitive to MITO than the tested human tumours (Hill et al., 1989). The murine tumour cells P388 and Ehrlich were included in the present study for comparision to the human cell lines and the in vivo antitumour models. As the relationship between duration of drug exposure and cytotoxicity can give valuable information on mechanisms of toxicity (Roed et al., 1986), the patterns of sensitivity to ACLA, ADR, DAU and MITO after shor...

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“…Aclarubicin has been shown to be an effective drug in the remission induction of AML. 36 In addition, low doses of aclarubicin may induce differentation of malignant cells in acute myeloid leukemia and myelodysplastic syndrome. 38 Etoposide has achieved a recognized positition in several protocols in untreated as well as in refractory and relapsed AML.…”

Section: Discussionmentioning

confidence: 99%

Comparison between four and eight cycles of intensive chemotherapy in adult acute myeloid leukemia: a randomized trial of the Finnish Leukemia Group

et al. 1998

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In acute myelogenous leukemia (AML) intensive postremission treatment is needed for an optimal result. However, it is not known how long the treatment should last and how many courses are necessary. The object of this prospective study was to compare four and eight intensive chemotherapy cycles in the treatment of adult de novo AML. In a multicenter study, 248 consecutive patients, aged from 16 to 65 years, were treated with intensive induction treatment. The patients in remission after two courses were randomized to receive either two (short arm) or six (long arm) additional intensive cycles of chemotherapy. The median follow-up time of the living patients is 68 months. Of the patients, 77% achieved complete remission, and 36% of all patients survived for 5 years. Seventy-three patients were randomized to the short arm and 66 to the long arm. There was no significant difference in the relapse-free survival (median 21 months vs 17 months) or overall survival (43 months vs 39 months) between the short and long arms, respectively. Treatment-related deaths occurred in 31 patients (13%), 11 of them in first remission. More than onethird of the patients survived for 5 years. It seems probable that the first few months after diagnosis are decisive for the prognosis if the chemotherapy is intensive, and further treatment cannot markedly influence the outcome.

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Aclarubicin Plus Cytosine Arabinoside Versus Daunorubicin plus Cytosine Arabinoside in De Novo Acute Myelocytic Leukemia: A Danish National Trial

Cited by 21 publications

References 0 publications

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

In vitro evaluation of the potential of aclarubicin in the treatment of small cell carcinoma of the lung (SCCL)

Comparison between four and eight cycles of intensive chemotherapy in adult acute myeloid leukemia: a randomized trial of the Finnish Leukemia Group

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