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At least 73 records · Page 4Linked to original sources
PubMed1975

The chemotherapy of urologic cancer.

A review of the status of evaluation of chemotherapeutic agents in the urologic malignancies reveals a largely neglected area of investigation. Except for testicular carcinomas, which are highly responsive to drug therapy, active agents have not been clearly established for the other urogenital tumor sites. Published information and data on file in the Cancer Therapy Evaluation Program of the National Cancer Institute are reviewed, and studies currently in progress are outlined. Adequate clinical testing of the standard antitumor agents that are active against other human malignancies should receive high priority in future therapeutic trials in urologic cancer.

Adenocarcinoma↗
PubMed1975

Cardiomyopathy after widely separated courses of adriamycin exacerbated by actinomycin-D and mithramycin.

A 22-year-old man with a synovial cell sarcoma attained an excellent response to therapy with adriamycin (NSC-123127) and dimethyltriazeno imidazole carboxamide (NSC-45388). Therapy was discontinued at a cumulative dose of adriamycin of 600 mg/m2. Relapse occurred 13 1/2 months later, and therapy with adriamycin was restarted. Because of tumor progression, therapy was discontinued after a cumulative dose of adriamycin of 120 mg/m2. Ten weeks later, severe congestive heart failure developed which ultimately caused the patient's death. Exacerbations of the heart failure were temporally related to the administration of the antitumor antibiotics actinomycin-D (NSC-3053) and mithramycin (NSC-24559). Electron microscopic examination of the heart revealed changes characteristic of adriamycin cardiomyopathy. Thus, even after a long hiatus, it may not be safe to exceed the recommended maximum cumulative dose level of adriamycin. The pathogenic mechanisms involved in the development of adriamycin cardiomyopathy are reviewed, and the possible synergistic effect of other antitumor antibiotics is discussed.

Adult↗
PubMed1978

Acquired platelet dysfunction following mithramycin therapy.

The administration of mithramycin to patients with testicular tumors has been accompanied by a hemorrhagic diasthesis, often in the absence of thrombocytopenia. Bleeding time, platelet aggregation, platelet adenine nucleotide levels, and coagulation factor assays were studied in three patients receiving mithramycin for embryonal testicular carcinomas. These studies demonstrated a drug dependent, reversible hemorrhagic diathesis associated with (1) prolongation of bleeding time, (2) decreased platelet aggregation responses to ADP, collagen, and epinephrine, and (3) depleted platelet stores of ADP in the absence of thrombocytopenia. These abnormalities were temporally correlated with the onset of mucocutaneous bleeding in all patients.

Adenosine Diphosphate↗
PubMed1980

Hypercalcemia in the accelerated phase of chronic myelogenous leukemia.

Within a recent one-year period, 3 patients in the accelerated phase of chronic myelogenous leukemia were admitted to our medical center with severe hypercalcemia. Simultaneous determinations of ionized calcium and parathyroid hormone levels in 2 of the patients confirmed the hypercalcemia and revealed suppression of parathyroid hormone. We conclude that hypercalcemia in the accelerated phase of chronic myelogeneous leukemia may be more common than previously described and is not mediated by parathyroid hormone. An elevated parathyroid hormone level accompanying hypercalcemia in these patients should suggest the additional diagnosis of primary hyperparathyroidism. Mithramycin was necessary for control in 2 of our cases as well as in others reported in the medical literature and should be an early therapeutic consideration whenever saline diuresis is inadequate.

Adult↗
PubMed1987

Granulocytic sarcoma presenting as pulmonary nodules and lymphadenopathy.

A patient presented with anterior and posterior cervical lymphadenopathy as well as widespread intrapulmonary nodules. Histologic sections of both lymph node and lung revealed dense infiltration by sheets of cells which were cytochemically positive for chloroacetate esterase and myeloperoxidase, thus suggesting a diagnosis of granulocytic sarcoma. The patient was initially treated with daily hydroxyurea. After 6 weeks, when progression of the disease was apparent, hydroxyurea was discontinued and the patient was placed on mithramycin, an agent reported to induce differentiation of myeloid precursor cells both in vitro and in vivo. On this latter agent, a dramatic response has been noted with a decrease in the pulmonary symptoms, and a marked reduction in the size of the lymph nodes and lung nodules. The authors report this case because it represents a rare presentation of an uncommon disease and because of the striking improvement that followed the initiation of a novel therapeutic modality.

Aged↗
PubMedDate not supplied

Structural basis of DNA recognition by anticancer antibiotics, chromomycin A(3), and mithramycin: roles of minor groove width and ligand flexibility.

Anticancer antibiotics, chromomycin A(3) (CHR) and mithramycin (MTR), inhibit cellular processes like transcription and replication, by binding reversibly to double-stranded DNA via minor groove, in the presence of bivalent metal ions like Mg(2+) with GC base specificity. Here, we have attempted to assess the roles of two parameters-namely DNA groove dimension and flexibility of the ligand-in the structural recognition between the ligands, (drug)(2)Mg(2+) and DNA. For the purpose we have employed three synthetic oligonucleotides with minor groove width lying between B- and A-type structures as model DNA sequences: d(GCGCGCGC)(2) in B-form, d(CCGGCGCCGG)(2) in B-form with unusual wide minor groove, and (GGGGCCCC)(2) in A-form. Association of the (drug)(2)Mg(2+) with the oligomers have been probed using spectroscopic techniques like absorbance, fluorescence, and CD. The binding and thermodynamic parameters for the different association processes have also been characterized. Major conclusions from the above studies are as follows. Groove size of the oligomers influences the conformation of the bound ligand. A saccharide dependent variation in structural rigidity of the ligands, (MTR)(2)Mg(2+) and (CHR)(2)Mg(2+), has been observed that leads to differences in the energetics of recognition of the same DNA sequence by the two ligands. In contrast to (CHR)(2)Mg(2+), higher flexibility in (MTR)(2)Mg(2+) makes its conformation in the DNA bound form less sensitive to the groove dimension of DNA.

Antibiotics, Antineoplastic↗
PubMed2000

The three-dimensional structure of the 4:1 mithramycin:d(ACCCGGGT)(2) complex: evidence for an interaction between the E saccharides.

Mithramycin and chromomycin, two antitumor drugs, each having an identical aglycone and nearly identical disaccharide and trisaccharide side chains, have differing binding properties to a small oligonucleotide, d(ACCCGGGT)(2) (M. A. Keniry et al., Journal of Molecular Biology, 1993, Vol. 231, pp. 753-767). In order to understand the forces that induce four mithramycin molecules to bind to d(ACCCGGGT)(2) instead of two drug molecules in the case of chromomycin, the structure of the 4:2:1 mithramycin: Mg(2+):d(ACCCGGGT)(2) complex was investigated by (1)H-nmr and restrained molecular dynamics. The resulting three-dimensional model showed that in order to accommodate the close approach of one neighboring mithramycin dimer, the inwardly directed CDE saccharide chain of the neighboring mithramycin dimer undergoes a conformational change such that the E saccharide no longer spans the minor groove but reorients so that the hydrophilic face of the E saccharides from the two dimers oppose each other. Two hydrogen bonds are formed between the hydroxyl groups of the two opposing E saccharide groups. The results are interpreted in terms of the differences in stereochemistry and functional group substitutions between mithramycin and chromomycin. A mithramycin dimer is able to self-associate on an oligonucleotide template because it has two hydroxyl groups on the same face of its terminal E saccharide. A chromomycin dimer is unable to self-associate because one of these hydroxyl groups is acetylated and the neighboring hydroxyl group has a stereochemistry that cannot permit close contact of the hydroxyl group with a neighbouring chromomycin dimer.

Antibiotics, Antineoplastic↗
PubMed2000

Increased phosphorylation of transcription factor Sp1 in scleroderma fibroblasts: association with increased expression of the type I collagen gene.

OBJECTIVE: To determine the potential roles of transcription factors Sp1 and Sp3 in the increased expression of the human alpha2(I) collagen gene in scleroderma fibroblasts. METHODS: Dermal fibroblasts from 7 patients with diffuse systemic sclerosis (SSc; scleroderma) of recent onset and from 7 healthy individuals were studied. The levels of expression of alpha2(I) procollagen, Sp1, and Sp3 messenger RNA (mRNA), with or without stimulation by transforming growth factor beta (TGFbeta) or oncostatin M (OSM), were evaluated by Northern blot analysis, and the respective protein levels were determined by immunoblotting. The DNA binding activity of nuclear proteins recognizing the cis-acting elements in the human alpha2(I) collagen promoter was examined by gel mobility shift assays. The levels of Sp1 phosphorylation were investigated by immunoprecipitation using an antiphosphoserine-specific antibody. RESULTS: SSc fibroblasts showed basal alpha2(I) collagen mRNA levels that were approximately 3 times higher than those in normal fibroblasts. TGFbeta or OSM increased human alpha2(I) collagen mRNA expression in normal dermal fibroblasts, but these cytokines failed to increase alpha2(I) collagen mRNA levels in SSc fibroblasts. There were no significant differences in the levels of expression of Sp1 or Sp3 between SSc and normal fibroblasts. However, increased Sp1 phosphorylation was detected in SSc fibroblasts compared with normal fibroblasts. Mithramycin, a specific inhibitor of Sp1 binding, abolished the increased expression of the alpha2(I) collagen gene in SSc fibroblasts, in a dose-dependent manner. CONCLUSION: These results demonstrate the involvement of Sp1 in the up-regulation of expression of the alpha2(I) collagen gene in SSc fibroblasts.

Collagen↗
PubMed1979

Long term effectiveness of low dose mithramycin for Paget's disease of bone.

Nineteen patients with Paget's disease of bone were studied 7 months to 5 years after therapy with mithramycin in a dose averaging 11.5 microgram/kg body weight daily for 10 days. Thirteen patients, including 3 with the longest followup intervals, remained free of pain. Objective measures of disease activity (serum alkaline phosphatase level and 99mtechnetium pyrophosphate bone scan) were less favorable. There was no evidence of long term toxicity.

Aged↗
PubMed2001

Differential interactions of antitumor antibiotics chromomycin A(3) and mithramycin with d(TATGCATA)(2) in presence of Mg(2+).

The antitumor antibiotics chromomycin A(3) (CHR) and mithramycin (MTR) are known to inhibit macromolecular biosynthesis by reversibly binding to double stranded DNA with a GC base specificity via the minor groove in the presence of a divalent cation such as Mg(2+). Earlier reports from our laboratory showed that the antibiotics form two types of complexes with Mg(2+): complex I with 1:1 stoichiometry and complex II with 2:1 stoichiometry in terms of the antibiotic and Mg(2+). The binding potential of an octanucleotide, d(TATGCATA)(2), which contains one potential site of association with the above complexes of the two antibiotics, was examined using spectroscopic techniques such as absorption, fluorescence, and circular dichroism. We also evaluated thermodynamic parameters for the interaction. In spite of the presence of two structural moieties of the antibiotic in complex II, a major characteristic feature was the association of a single ligand molecule per molecule of octameric duplex in all cases. This indicated that the modes of association for the two types of complexes with the oligomeric DNA were different. The association was dependent on the nature of the antibiotics. Spectroscopic characterization along with analysis of binding and thermodynamic parameters showed that differences in the mode of recognition by complexes I and II of the antibiotics with polymeric DNA existed at the oligomeric level. Analysis of the thermodynamic parameters led us to propose a partial accommodation of the ligand in the groove without the displacement of bound water molecules and supported earlier results on the DNA structural transition from B --> A type geometry as an obligatory requirement for the accommodation of the bulkier complex II of the two drugs. The role of the carbohydrate moieties of the antibiotics in the DNA recognition process was indicated when we compared the DNA binding properties with the same type of Mg(2+) complex for the two antibiotics.

Antibiotics, Antineoplastic↗