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)

The pharmacology, chemistry, pharmacokinetics, clinical studies, and adverse effects of amsacrine, an investigational antineoplastic agent, are reviewed. Amsacrine's mechanism of action is not clearly understood, although the drug is known to inhibit DNA synthesis. As an investigational NCI "Group C" agent, amsacrine is available to physicians for the treatment of adult patients with refractory acute nonlymphocytic leukemia (ANLL) under an established protocol. Following intravenous administration, amsacrine has a biphasic plasma clearance. It is extensively metabolized by the liver to inactive compounds that are excreted in the bile. Phase I studies indicated that amsacrine was potentially effective in patients with solid tumors and acute leukemias. Patients with solid tumors could tolerate much lower doses of amsacrine than leukemia patients because of dose-limiting bone-marrow suppression in the former. In Phase II studies, amsacrine appeared effective in treating the acute leukemias, with response rates of 31% and 23% for acute lymphocytic leukemia and ANLL, respectively. Patients with other types of cancers have not responded to amsacrine therapy. Frequently occurring adverse effects of amsacrine include leukopenia and thrombocytopenia in patients with solid tumors; nausea, vomiting, and diarrhea; mucositis in patients receiving higher doses (leukemia patients); alopecia; hepatotoxicity; and phlebitis. The clinical usefulness of amsacrine appears limited to treatment of the acute leukemias. Studies of combination therapies that include amsacrine are currently underway and should further define the therapeutic role of amsacrine.
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PMID:Review of amsacrine, an investigational antineoplastic agent. 676 91

m-AMSA is a synthetic aminoacridine DNA intercalator found to have experimental murine antitumor activity. A phase I investigation was undertaken in 71 patients with solid tumors and acute leukemia. Using an intermittent every 3-week schedule in solid tumors, toxicity encountered was primarily hematologic, predominantly leukopenia with relative platelet sparing. The recommended dose for phase II evaluation in patients with solid tumors is 90 mg/m2 every 3 weeks; patients with minimal prior therapy could be treated at 120 mg/m2 and patients with hepatic dysfunction or marginal bone marrow reserve should have an initial dose reduction to 70 mg/m2. Therapeutic activity was seen in Hodgkin's disease, hepatoma, and epidermoid carcinoma of the esophagus. Various dose schedules were studied in leukemia. The recommended dose for phase II evaluation is 120 mg/m2 daily for 5 days as a daily 30-minute infusion. At this dose, nausea, vomiting, mucositis, alopecia, and hepatic toxicity were noted. Therapeutic activity was seen in AML, blastic CML, and CLL. Further clinical trials with this agent are warranted.
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PMID:Phase I study of m-AMSA in patients with solid tumors and leukemias. 689 83

In vitro studies of 4'(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) with L1210 leukemia cells have demonstrated that a given level of DNA breakage and intraceLlular m-AMSA concentration depends upon the presence of a continuous concentration of extracellular drug and that cytotoxicity increases with an increasing duration of drug exposure. Since previous studies had shown that free m-AMSA has a half-life of 6-8 hours, a trial of m-AMSA given as a continuous infusion was undertaken in patients with solid tumors and lymphomas. Patients were treated with 30 mg/m2/day x 3, 30 mg/m2/day x 4, or 40 mg/m2/ day x 3. Myelosuppression was dose-limiting and occurred at about Day 13 after the start of the infusion. Recovery was noted by Day-21. There was no evidence of cumulative hematologic toxicity. The maximally tolerated dose was 30 mg/m2/day x 3 in our patient population. Mild phlebitis occurred in all patients. There were no instances of gastrointestinal, hepatic, renal, cardiac, or neurologic toxic reactions. Evidence of some antitumor effect was seen in three patients. We conclude that it is possible to given m-AMSA as a continuous infusion and that studies should be undertaken in patients with acute myelogenous leukemias to compare the efficacy of m-AMSA infusion with conventional bolus administration as a means to enhance the duration of response.
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PMID:Phase I-II study of m-AMSA administered as a continuous infusion. 689 13

Thirty-two patients with relapsed or resistant acute leukaemia were treated with m-AMSA at doses ranging from 50-150 mg/m2 daily for 5 days. Complete remission was achieved in three of 18 patients with acute myeloblastic leukaemia, two of nine patients with acute lymphoblastic leukaemia, and none of five patients with blastic crisis of chronic myeloid leukaemia. The complete remissions all occurred at doses of 100 mg/m2 per day or above. Haematological toxicity occurred in all patients and was dose-related. Nausea and vomiting were mild and easily controlled. Alopecia was uncommon at the lower doses but occurred in all patients receiving the higher doses. Stomatitis was noted in only 8% of courses at 50 mg/m2 but was seen in 50% of courses at 150 mg/m2. Mild and transient elevations of liver enzymes were common. m-AMSA is an active drug in acute leukaemia, with acceptable toxicity. Its place in combination chemotherapy is now being explored.
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PMID:A phase I and II study of m-AMSA in acute leukaemia. 694 78

The action of two structurally related DNA intercalating agents has been studied and compared, namely 4'-(9-acridinylamino) methanesulphon-m-anisidide (amsacrine, mAMSA) and 1,4-bis(butylamino)benzo[g]phthalazine (ABP) on the cell cycle and differentiation of U-937 human promonocytic leukemia cells. mAMSA (0.1 microM) and ABP (4 microM) reduced the proliferation activity to a similar extent and caused little cell mortality. At these subcytotoxic concentrations mAMSA induced the cells to accumulate at the G2 phase of the cycle, while cycle inhibition provoked by ABP was not phase specific. In addition, mAMSA caused an increase in the cell mass while ABP provoked cell shrinkage. This was consistent with the fact that ABP considerably inhibited protein synthesis, while mAMSA did not significantly affect this activity. SDS/K+DNA precipitation assays indicated that mAMSA, but not ABP, stimulated protein-DNA covalent complex formation. Finally, it was found that mAMSA, but not ABP, elicited the expression of differentiation markers, namely nitroblue tetrazolium reduction, activation of vimentin and leukocyte integrin (CD11b/CD18 and CD11c/CD18) expression, and downregulation of c-myc expression. The DNA intercalators doxorubicin and mitoxantrone, which like mAMSA induced the cells to accumulate at the G2 phase and increased the cell mass, induced the expression of differentiation markers. In contrast, the intercalators aclarubicin and caffeine and the non-intercalator novobiocin, which produced minor alterations on cell-cycle distribution and caused cell shrinkage, did not significantly elicit differentiation. These results support the conclusion that differentiation of myeloid leukemia cells by cytostatic drugs depends on the perturbations of the cell cycle, leading to disproportionate increases in cell mass.
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PMID:The action of the DNA intercalating agents 4'-(9-acridinylamino) methanesulphon-m-anisidide and 1,4-bis(butylamino) benzo[g]phthalazine in U-937 human promonocytic cells: relationship between cell cycle and differentiation. 751 13

Acute myeloid leukemia (AML) is frequently encountered in elderly patients (> 65) whereas most myelosuppressive chemotherapy protocols are restricted to younger patients. We retrospectively reviewed the 21 patients older than 65 (median age: 70, range: 66-86) hospitalized in our leukemia unit for recently diagnosed AML between 1. 1. 1988 and 31. 3. 1993. 16 had de novo AML (n-AML) and 5 had AML secondary to myelodysplastic syndromes (s-AML). Induction therapy consisted of cytarabine and either daunorubicine or mitoxantrone at conventional dosage in 18/21 patients. Early consolidation therapy was given to 14/21 patients and consisted of m-AMSA and VP-16 in 11 of them. The response to, and toxicity from, myelosuppressive chemotherapy was different according to the type of AML. In patients with n-AML a complete remission (CR) was obtained in 63% (10/16) and only 19% (3/16) died of MCT-related toxicity. In contrast, only 1/5 patients with s-AML achieved CR while 4/5 died of toxicity. The median duration of CR was 40 weeks (range: 5-147+) and median overall survival 23 weeks (range: 1-211+), with an estimated 3-year overall survival rate of 9.5% (2/21). Overall survival of patients with n-AML was significantly longer than that of patients with s-AML (p < 0.05). Hospital stay in relation to survival time was 100% for patients with s-AML, 49% for patients with n-AML not achieving CR and 25% for patients with n-AML with CR. In conclusion, elderly patients with AML can benefit from myelosuppressive chemotherapy providing they present with de novo AML.
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PMID:[Should patients over 65 years old with acute myeloid leukemia be treated with myelosuppressive chemotherapy?]. 789 71

Studies were done to determine (a) the subcellular distribution of the alpha (170 kDa) and beta (180 kDa) isozymes of topoisomerase II, and (b) the extent to which each isozyme forms complexes with DNA in tumor cells incubated with and without VM-26. Western blotting revealed that topoisomerase II beta was highly unstable during cell fractionation. However, preincubation of human CEM leukemia cells with 5-100 microM VM-26 for 30 min protected the beta isozyme from degradation by progressively increasing the amount of this isoform bound to DNA. The amount of topoisomerase II beta detected in nuclei of CEM cells incubated for 30 min with 25 microM VM-26 was 7-fold greater than in nuclei from untreated control cells. VM-26 also had a protective effect on topoisomerase II beta in HL-60 leukemia and WiDR colon carcinoma cells. In contrast, the intercalating agents mitoxantrone and m-AMSA did not protect topoisomerase II beta from degradation during cell fractionation. The stabilization of topoisomerase II beta by VM-26 allowed subsequent studies of the subcellular distribution of the topoisomerase II isozymes. Both isozymes were detected in the nonmatrix (high salt-soluble) fraction of nuclei from CEM cells, but only topoisomerase II alpha was present in the nuclear matrix. VM-26 stabilized binding of the alpha and beta topoisomerase II isoenzymes to nonmatrix DNA and topoisomerase II alpha to matrix DNA. The differences observed in the subnuclear distribution and DNA binding pattern of the topoisomerase II isozymes support the hypotheses that each isozyme has a distinct cellular function, and that both the alpha and beta isozymes are potential targets for VM-26 in intact cells. In addition, the results demonstrated that pretreatment of various cell lines with VM-26 is a useful way to stabilize topoisomerase II beta during cell fractionation.
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PMID:Subcellular distribution of the alpha and beta topoisomerase II-DNA complexes stabilized by VM-26. 798 Jun 48

A series of 9-anilinoacridines, based on the anticancer drug amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide; m-AMSA], were synthesized and evaluated for their ability to inhibit both the growth of Jurkat leukaemia cells and human DNA topoisomerase II in vitro. Inhibition of topoisomerase II activity occurred via one of two mechanisms of drug action: (i) direct inhibition of the strand-passing activity or (ii) stabilization of cleavable complex formation. Although the majority of compounds evaluated inhibited P4 DNA unknotting activity catalysed by DNA topoisomerase II up to 100 microM, derivatives bearing 1'-substituents containing SO2 moieties (e.g. 1'-NHSO2Me and 1'-SO2NH2 groups) were generally the most potent inhibitors of DNA topoisomerase II-mediated DNA religation, being effective at concentrations of 1-5 microM. No obvious correlation was observed between the cytotoxicity of individual drugs and linear DNA formation in the in vitro topoisomerase II assays, either across the whole drug series or within similar subgroups. However, a selected group of drugs with different cytotoxicities (compounds 5, 12 and 30; Table I) stimulated DNA topoisomerase II-mediated DNA strand breaks in intact Jurkat cells by 3.5-, 11- and 2.2-fold, respectively, at a concentration of 10 microM, while compounds 31 and 32 did not produce protein-associated DNA strand breaks in whole cells. There was a good correlation between the ability of these selected compounds to induce topoisomerase II-mediated DNA strand breaks in vitro or in whole cells, and their cytotoxicity to Jurkat cells.
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PMID:Structure-activity relationships of 9-anilinoacridines as inhibitors of human DNA topoisomerase II. 803 52

KW-2149, a new mitomycin C (MMC) derivative, inhibited the growth of murine P388 leukemia in vitro at 20-fold lower concentrations than those of MMC. KW-2149 was also effective in inhibiting the growth of MMC-resistant P388 (P388/MMC) cells. To elucidate these characteristics of KW-2149, its uptake and efflux were compared with those of MMC in MMC-sensitive and -resistant P388 cells. Both MMC and KW-2149 accumulated rapidly in P388 cells after incubation at the concentration of 0.47 and 0.024 microM, respectively, which were the IC50 values at 1-h exposure. Although this concentration of KW-2149 was 20 times lower than that of MMC, its intracellular concentration was little more than that of MMC, suggesting that KW-2149 accumulated in the cells quite efficiently. The accumulated KW-2149 in the cells after 1-h treatment remained for as long as 24 h after the incubation of the cells in drug-free medium, suggesting that most of the intracellular KW-2149 or MMC was bound to cellular components. The ratios of resistance of P388/MMC cells to MMC and KW-2149 were 34 and 8.8, respectively, at 1-h exposure, suggesting that P388/MMC cells were partially resistant to KW-2149 in vitro. P388/MMC cells also showed partial resistance to cisplatin, Adriamycin, m-AMSA, and etoposide. The accumulation of MMC in P388/MMC cells was lower than that in P388 cells, although the size of the former cells was almost equal to that of the latter. As a result, the amount of DNA-bound MMC was lower in P388/MMC cells than in P388 cells, suggesting its involvement in the mechanisms of MMC resistance in P388/MMC cells.
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PMID:Comparison of uptake of mitomycin C and KW-2149 by murine P388 leukemia cells sensitive or resistant to mitomycin C. 809 40

Neutropenic typhlitis (NPT) was observed in 4 of 5 adult patients with acute leukemia treated with etoposide (VP16; 100 mg/m2/d for 6 days) and high-dose cytosine-arabinoside (HD ARAC, 2 g/m2 twice daily for 6 days) in a period of 11 months. One additional patient developed NPT after combination therapy with amsacrine (mAMSA, 120 mg/m2/d for 5 days) and etoposide (80 mg/m2/d for 5 days) during the same period. These 5 cases of NPT meant a drastic rise in the incidence of NPT at our institution, where a careful retrospective review of the charts of the 128 adult patients with leukemia treated during the preceding 5 years revealed only one case of NPT. Nonsurgical treatment led to recovery in all cases. No recurrence of NPT was observed during 3 further courses of aplasia with the use of selective (2 patients) or complete (1 patient) bowel decontamination. Etoposide may potentiate the gastrointestinal toxicity of high-dose cytosine-arabinoside with a higher incidence of NPT.
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PMID:[Neutropenic typhlitis: a frequently missed complication of aplasia-inducing tumor therapy with a possible association to the combination of etoposide with high-dose cytosine-arabinoside]. 812


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