Disease relevance of Amsidyl

• Treatment of SV40 virus infected monkey cells with m-AMSA resulted in both single- and double-stranded breaks on SV40 viral chromatin [1].
• Sensitivities to m-AMSA did not differ significantly between normal marrow and blood CFC, between normal and CML CFC, or between CML CFC obtained from patients with leukemias in chronic phase and blast transformation [2].
• Derivatives of amsacrine: determinants required for high activity against Lewis lung carcinoma [3].
• Because the development of resistance to cancer chemotherapeutic agents represents a major limitation of cancer chemotherapy, we investigated the mechanism of resistance by murine P388 leukemia to camptothecin (topoisomerase I inhibitor) or amsacrine (topoisomerase II inhibitor) [4].
• Because the bacteriophage T4-encoded topoisomerase resembles the mammalian enzyme, we are using T4 as a simple model system to investigate the mechanism of action of m-AMSA [5].

High impact information on Amsidyl

• These cells were also markedly sensitive to mitoxantrone, amsacrine, and etoposide (drugs that induce double-strand breaks) (two-sided P = .002) and to ionizing radiation (two-sided P = .001) [6].
• Resistant cell lines were derived by exposure to either amsacrine or doxorubicin [7].
• However, when the substituents on the anilino side chain of amsacrine were changed, the in vitro cross-resistance of the P/AMSA line could be substantially reduced and even overcome [8].
• Four main patterns were evident: a transport-related multidrug-resistance pattern (three sublines), a pattern similar to that for a murine P388 leukemia subline resistant to amsacrine, and two patterns not observed previously [7].
• The difference between the HT1080 and DR4 lines in AMSA- and 5-iminodaunorubicin-induced cleavage was similar in cells and nuclei and could be due to the lower amount of DR4 topoisomerase II [9].

Chemical compound and disease context of Amsidyl

• Antitumor activity against the Lewis lung carcinoma in mice is reported for the series of 36 acridine-substituted derivatives of the antileukemia agent amsacrine [3].
• We have used 3-azido-AMSA [4'-(3-azido-9-acridinylamino)methanesulfon-m-anisidide], a photo-activatible analog of the inhibitor m-AMSA [4'-(9-acridinylamino)methanesulfon-m-anisidide], to localize the inhibitor binding site in a cleavage complex consisting of an oligonucleotide substrate and the bacteriophage T4 type II DNA topoisomerase [10].
• Thirty-six patients with relapsed acute lymphoblastic leukemia (ALL) and four with primary refractory ALL were treated with a regimen that included amsacrine, 200 mg/m2, intravenously daily for three days with cytarabine, 3 gm/m2, by infusion over three hours daily for five days [11].
• The topoisomerase (topo) II-directed agents etoposide, daunorubicin (DNR), and amsacrine (m-AMSA) are widely used in the treatment of acute myelogenous leukemia (AML) [12].
• The aim was to investigate interspecies relationships between body weight (W) (kg) and various pharmacokinetic parameters for the anti-tumor agents amsacrine and its 4-methyl-5-(N-methylcarboxamide) analogue, CI-921, and examine which pharmacokinetic parameter, if any, might be used to predict the toxicity of these agents [13].

Biological context of Amsidyl

• A survey of 115 analogues of amsacrine indicates that a low ratio of IC50 values (HCT-8/L1210) is necessary but not sufficient for good antitumor activity against the solid tumor [3].
• Considerable variations in resistance factors were noted for each cell subline as the amsacrine substituents were altered [7].
• In addition, the gene 39 subunit from the m-AMSA-resistant mutant phage has an altered net charge, strongly indicating that the drug-resistance mutation is within gene 39 [5].
• The agreement between in vitro and in vivo studies suggests that mammalian DNA topoisomerase II may be the primary target of m-AMSA and that the drug-induced complex formation between topoisomerase II and DNA may be the cause of cytotoxicity and other effects such as DNA sequence rearrangements and sister-chromatid exchange [14].
• It was demonstrated that transient exposure to low concentrations of amsacrine inhibited replicon initiation but did not substantially affect DNA chainelongation within operating replicons [15].

Anatomical context of Amsidyl

• Exposure to amsacrine or etoposide caused at least 50-fold less DNA cleavage in CLL and normal lymphocytes as compared to L1210 cells [16].
• The fact that these breaks reverse rapidly in cells programmed to die, led us to investigate further the cytotoxic mechanisms of topoisomerase I (camptothecin) and topoisomerase II inhibitors (VP-16 and amsacrine) in Chinese Hamster lung fibroblasts (DC3F) [17].
• To determine whether topoisomerase II poisons that produce double-strand breaks by trapping of cleavable complexes would, likewise, induce mutations specific to plateau-phase cells, aprt mutations induced by amsacrine in both log-phase and plateau-phase CHO cells were analyzed [18].
• The results of fractionation of nuclear DNA show that m-AMSA induces 20- to 45-fold more DPC in nuclear matrix-associated DNA than in the majority distal loop DNA, supporting the notion that topoisomerase II is located at the nuclear matrix [19].
• The frequency of DNA strand breaks induced by amsacrine was higher (1.5- to 13-fold) in the testis cells than in the bladder cells [20].

Associations of Amsidyl with other chemical compounds

• CI-921 is a di-substituted analogue of amsacrine currently in phase 1 clinical trial [21].
• Ethidium bromide, acridine orange, 4'-(9-acridinylamino)methanesulfon-o-anisidide (o-AMSA), and m-AMSA induce the rapid binding of RecA protein to double-stranded (ds) DNA [22].
• These sublines are cross-resistant to daunorubicin, VP16-213, Vinca alkaloids, colchicine, gramicidin D, and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) [23].
• Two classes of drugs have been distinguished: (i) those that bind to RecA protein and induce assembly at low relative concentrations (e.g., ethidium bromide) and (ii) those that do not appear to interact directly with RecA protein and must be present at relatively high drug concentrations to stimulate assembly (e.g., m-AMSA) [22].
• Suramin did not stabilize the covalent DNA-topoisomerase II reaction intermediate ("cleavable complex"), whereas other inhibitors of this enzyme, such as amsacrine, etoposide, and the ellipticines, are known to stabilize the intermediate [24].

Gene context of Amsidyl

• Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II [25].
• However, unlike the Pgp-expressing cells, it was not cross-resistant to vincristine or amsacrine [26].
• Using the alkaline comet assay, we showed that amsacrine at concentrations from the range 0.01 to 10 microM induced DNA damage in normal human lymphocytes, human promyelocytic leukemia HL-60 cells lacking the p53 gene and murine pro-B lymphoid cells BaF3 expressing BCR/ABL oncogene measured as the increase in percentage tail DNA [27].
• Results from this study demonstrated that, in progressively DOX-resistant L1210 mouse leukemia cells with the MDR phenotype, a better relation existed between the degree of resistance and reduced VP-16- and m-AMSA-induced topoisomerase II mediated DNA cleavage, than between increases in P-glycoprotein and concomitant reduction in DOX accumulation [28].
• MRP-overexpressing SW-1573 cells are resistant to doxorubicin, daunorubicin, vincristine, VP-16, colchicine, and rhodamine 123, but not to 4'-(9-acridinylamino)methanesulfon-m-anisidide or taxol [29].

Analytical, diagnostic and therapeutic context of Amsidyl

• Chemotherapy consisted of fludarabine (4 x 30 mg/m(2)), cytarabine (4 x 2 g/m(2)), and amsacrine (4 x 100 mg/m(2)), followed 4 days later by RIC, comprising 4 Gy total body irradiation (TBI), cyclophosphamide, and antithymocyte globulin [30].
• Hypoxia has little effect on the toxicity of m-AMSA, and repair of potentially lethal damage has not been observed after treatment with this agent [31].
• Toxicity of 4'-(9-acridinylamino)methanesulfon-m-anisidide in exponential- and plateau-phase Chinese hamster cell cultures [31].
• Amsacrine is an antileukemia drug being widely used in North America, Europe, Australia, and New Zealand. In the initial clinical trials, patients treated with amsacrine developed occasional instances of acute cardiac arrhythmias and cardiomyopathy [32].
• CI-921 and amsacrine were quantitated by high-performance liquid chromatography after extraction from plasma and from liver and tumor homogenates [33].

References