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

To determine the relation between DNA binding mode and biological activity in compounds related to the clinical anti-leukaemia drug amsacrine, a series of acridine-substituted derivatives has been synthesized and compared for lipophilicity, DNA-binding affinity, DNA-binding geometry and anti-leukaemia activity in vitro and in vivo. DNA-binding affinity, as estimated either by ethidium displacement or equilibrium dialysis, decreased progressively as the bulk of the substituent increased. Substitution at the 2 position provided the largest effects. The DNA unwinding angles, estimated by changes in viscosity of closed circular duplex DNA in the presence of drug, decreased significantly with ethyl and isopropyl substituents. However, with tertbutyl groups in the 2, 3 or 4 position of the acridine ring, unwinding was not observed even though DNA binding was measurable. Anti-leukaemia activity in vivo was also abolished when the acridine ring was substituted with a tertbutyl group. The results suggest that methyl substitution of the acridine ring inhibits DNA binding at the 2 position but not at the 3 and 4 positions, that ethyl and isopropyl substitution inhibits intercalative binding at all positions and that tertbutyl substitution abolishes intercalative binding. Biological activity in vitro is dependent on both lipophilicity and DNA binding and activity in vivo requires intercalative DNA binding.
 ...
PMID:Steric constraints for DNA binding and biological activity in the amsacrine series. 345 Feb 88

A number of new anilino ring variants of the anti-tumour drug amsacrine have been synthesised and their anti-tumour activity evaluated. In vitro selectivity, as measured by the logarithmic ratio of IC50 growth inhibition assays against P388 leukaemia and Lewis lung carcinoma cells, was significantly correlated with the increase in life span in vivo with the P388 leukaemia and Lewis lung lines, whereas the growth inhibition IC50 values alone correlated with the dose potency in mice. It was thus possible to predict both in vivo anti-tumour activity and dose potency, identifying compounds with high therapeutic activity, using a combination of two in vitro assays. Two new compounds have been identified which provide, along with an acridine-substituted analogue of amsacrine which is at present in clinical trial (CI-921), a high proportion of cures against the Lewis lung tumour in vivo. Since amsacrine is thought to interact with the enzyme topoisomerase II, and because the anilino group of 9-anilinoacridine derivatives is thought to project from the DNA intercalation site of the drug-DNA complex, these compounds may be of particular interest in mode of action studies.
 ...
PMID:In vitro and in vivo assessment of activity of new anilino-substituted analogues of amsacrine against Lewis lung carcinoma. 345 Feb 94

Study of a series of aniline-substituted 9-anilinoacridines related to the antileukemic drug amsacrine showed that a 1'-carbamate group provided increased activity against the multidrug-resistant P388/ADR leukemia subline in vivo. Since activity against such resistant tumors is of great clinical significance, a series of acridine-substituted carbamate derivatives were evaluated against both wild-type and ADR/resistant P388 leukemia and the Lewis lung solid tumor in vivo. Structure-activity relationships for all three tumor lines were similar, with 3-halo-5-methyl and 3-halo-5-methoxy compounds proving the most active. This substitution pattern also provided the highest DNA binding. Such compounds (particularly the 3-chloro-5-methyl and 3-chloro-5-methoxy) have in vivo activity against wild-type P388 and Lewis lung comparable to that of the best amsacrine analogues previously developed (greater than 50% cures), as well as P388/ADR activity. This work essentially completes the development of the amsacrine series of antitumor agents.
 ...
PMID:Potential antitumor agents. 52. Carbamate analogues of amsacrine with in vivo activity against multidrug-resistant P388 leukemia. 362 6

m-AMSA (4'-[9'-acridinylamino]-methansulfon-m-anisidide) is an acridine derivative which has shown a wide spectrum of activity in preclinical testing. The mechanism of action is thought to be via interference with synthesis and integrity of DNA chains by intercalation between base pairs and external binding. Initial phase I clinical trials revealed granulocytopenia to be the dose limiting toxicity with occasional thrombocytopenia. Phlebitis, liver function abnormalities, and cardiac abnormalities have also been noted. Early reports suggested activity in leukemia and lymphoma. Based on these results ECOG evaluated m-AMSA in a phase II trial of Hodgkin's disease and non-Hodgkin's lymphoma.
 ...
PMID:m-AMSA in refractory lymphoma. A phase II trial of the Eastern Cooperative Oncology Group. 384 Jun 44

Flow cytometry with acridine orange was used in 111 cases of childhood acute lymphoblastic leukaemia (ALL) to determine simultaneously DNA index, cell cycle distribution and cellular RNA content in bone marrow samples. The overall incidence of DNA aneuploidy in the population was 40%. Significantly higher incidence of DNA aneuploidy was present in the L2 (70.6%) as compared to the L1 (34.1%) group (P = 0.007), using the FAB classification. No difference in the frequency of normal and abnormal DNA stemlines was found between newly diagnosed and relapsed patients. The L2 group had significantly higher proliferation (S phase = 12.4%) than L1 (S phase = 5.8%) (P = 0.01), but RNA content was not significantly different. The aneuploid group had significantly more (P = 0.01) cases with L2 morphology (28.6%) compared to the diploid group (8%) and proliferation was higher in DNA aneuploid (S-phase = 9.5%) compared to DNA diploid (S-phase = 4.7%) leukaemias. Likewise, RNA content was significantly higher in aneuploid than in diploid ALL (P = 0.006). These correlations between morphology, cell kinetics and DNA index elucidate biological properties of leukaemic cells with potentially prognostic value.
 ...
PMID:DNA and RNA determination in 111 cases of childhood acute lymphoblastic leukaemia (ALL) by flow cytometry: correlation of FAB classification with DNA stemline and proliferation. 386 Nov 95

Separate quantitations of nucleic acids of isolated nuclei and cells of L3 leukemia/Burkitt's lymphoma cell populations of peripheral blood (PB), bone marrow (BM) and lymph node (LN) cell suspensions of 17 patients were performed by acridine orange (AO) flow cytometry (FCM). The cell populations were analysed with respect to cell cycle characteristics and DNA/RNA distribution histograms of cells in various compartments of the cell cycle using mean value, coefficient of variation (CV), third moment about the mean as a measure of skewness (MOM3). The correlations between numbers of L3 blasts detected by microscopy and aneuploid cells quantified by FCM in 10 patients with aneuploid disease were r = 0.75 and r = 0.85 for BM and PB cell populations, respectively. Content of both nuclear and cellular RNA was 3-4 times higher in L3 cells than in normal donor lymphocytes. Percentages of cells in SG2M phase of L3 populations were significantly different from control populations in BM (p less than 0.01) and PB (p less than 0.0001). All samples with L3 blasts had abnormal CV of the DNA, and abnormal CV and MOM3 of the RNA peaks of G0/1 cell histograms. All samples with no blasts by morphology had normal DNA and RNA patterns. AO FCM correctly classified all specimens as involved or not involved with disease in accordance with the cytomorphological diagnoses. Combining AO FCM with prior cell separation increased the sensitivity of the method to detect abnormal cells to 0.02%, or 0.5 L3 cells per microliter of blood.
 ...
PMID:Identification of L3 leukemia and Burkitt's lymphoma cells by flow cytometric quantitation of nuclear and cellular RNA and DNA content. 395 Dec 53

A virus resembling type C murine leukemia viruses, which is associated with transplantable hamster tumors, was partially characterized with respect to certain biological, biophysical, and cytochemical features. As determined by electron microscopy, high concentrations of the virus appeared in the blood plasmas of tumor-bearing hamsters. Hamsters inoculated with virus concentrates did not show gross evidence of disease, and preliminary attempts to infect various hamster cells in tissue culture were unsuccessful. A line of cells from a virus-containing tumor which had been established in tissue culture released large numbers of the virus into the supernatant fluids by budding. The buoyant density peak of virus concentrates in potassium tartrate density gradients was 1.13 g/cm(3) by ultraviolet absorption and electron microscopic analysis. Acridine orange staining and nuclease digestion methods have indicated that the virus is probably a ribonucleic acid virus.
 ...
PMID:Biophysical, biological, and cytochemical features of a virus associated with transplantable hamster tumors. 572 16

Nuclei were isolated from various cell types including Chinese hamster ovary (CHO) and L1210 leukemia cell lines, primary cultures of fibroblasts, nonstimulated and stimulated human lymphocytes and mouse liver cells, by using different isolation techniques. The isolated nuclei were subsequently stained with acridine orange (AO) and their fluorescence was measured by flow cytometry. Various procedures designed to stain DNA versus RNA differentially with AO were tested, and the staining of isolated nuclei was compared with that of whole cells. Control incubations with RNase and DNase were performed to estimate in whole cells and in nuclei the contribution of DNA and RNA to the fluorescence intensity at the respective wavelength bands of maximum emission for DNA (F530) and RNA (F greater than 600). Depending on the cell type, 10-20% of total cell RNase-sensitive F greater than 600 is localized in the nuclei. The RNase-resistant portion of F greater than 600 of isolated nuclei represents the stainability of DNA. Suppression of cell proliferation in subconfluent cultures results in a decrease in both whole cell and in nuclear RNA content. Nonstimulated lymphocyte nuclei have considerably lower RNA content than nuclei from lymphocytes stimulated by pokeweed mitogen. Two subpopulations of nuclei having the same (2C) DNA content but differing in RNA content, are present in mouse liver; the cells entering S phase originate from the high RNA population.
 ...
PMID:RNA and DNA content of isolated cell nuclei measured by multiparameter flow cytometry. 618 86

Many of the conceptual advances in the treatment of advanced cancer have resulted from studies of the hematologic malignancies: The signal importance of complete remission, the complete disappearance of evident disease, as the major contributor to significant palliation; the first studies of adjuvant therapy, that is chemotherapy given to patients free of disease, which demonstrated prolongation of disease-free periods; the first studies of intensification, including early, intermittent, and late; combination chemotherapy; and finally, the important observation that advanced metastatic malignancies can be cured were made in studies of these important diseases. Because of treatment advances that have occurred over the last 10 to 20 years, the majority of patients with adult hematologic malignancies that were once considered universally fatal can be either cured or have substantial palliation. Treatment for adult acute leukemia has advanced such that 15% to 20% of patients have prolonged disease and treatment-free survivorship; in Hodgkin's disease, over 70% of patients can be cured; and for the lymphomas, the majority or 50% to 60% of patients can be cured with available treatments. Major treatment advances in supportive treatment such as allogeneic transfusion and allogeneic and autologous bone marrow transplantation improve the perspective for control of the hematologic malignancies. In addition, the potential for biologic response modifiers or the biologic products of normal cells that are normally involved in the regulation of both proliferation and differentiation show enormous potential for the treatment of advanced disease. Studies of interferon have shown promising early results in chronic granulocytic leukemia and in hairy cell leukemia. A new class of drugs, the acridine analogs, of which AMSA (4'-[9-acridinylamino]methanesulfon-M-anisidide) is a member, has been introduced and has established activity against acute leukemia. VP-16 (etoposide) has just become commercially available and is an important drug both in leukemia and lymphoma. Finally, the discovery of new knowledge about the biochemical pharmacology of drugs such as arabinosyl cytosine has offered a major advance in salvage treatment and the potential for substantial further improvement in the frontline management of these diseases. The rapid advances in both palliative and curative treatment for the hematologic malignancies have generally found broad application to the management of advanced cancer arising from other organ systems.
 ...
PMID:The hematologic malignancies. Leukemia, lymphoma, and myeloma. 620 91

A study was undertaken to determine the usefulness of flow cytometric analysis of bone marrow cells as an objective means for diagnosis, classification and prognosis in patients with leukemia. Abnormal DNA content as a marker of neoplastic disease was found in only 15% of 264 adult patients with acute leukemia (13% in AML, 26% in ALL/AUL). Alternative means of tumor cell detection in heterogeneous marrow samples include determination of nucleolar antigen density and double-stranded RNA content. Phenotypic characterization of leukemia subtypes can be afforded by RNA content analysis of acridine orange-stained cells, demonstrating significantly higher mean RNA content values in AML, compared to ALL/AUL. Cytokinetic parameters amenable to flow cytometric analysis include measurements of cell cycle compartment distribution by DNA content, of cycle traverse rate by BUdR-induced modification of fluorescence intensity of DNA specific dyes and of growth fraction employing the method of in situ DNA denaturation and subsequent acridine orange staining. Determination of cell cycle distribution and RNA content pretreatment and serially during remission induction in 82 patients demonstrated a significantly lower pretreatment biopsy S phase proportion in responding patients with AML compared to individuals failing treatment whereas an opposite trend was noted in patients with ALL/AUL. While of no prognostic impact pretreatment, serial determinations of the RNA content during the first chemotherapy induction course revealed significant differences between responding and failing patients with AML. Also, patients attaining remission demonstrated a rise in marrow biopsy S phase compartment size by day 10 to 14 of treatment, thus, predicting remission during marrow hypoplasia. We conclude that quantitative cytologic examination of marrow cells from patients with acute leukemia provides useful diagnostic and prognostic information that should aid in the stratification of patients with poor prognosis to receive new agents.
 ...
PMID:Quantitative cytology in leukemia research. 634 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>