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PubMedDate not supplied

Failure of mithramycin to control the myeloid blast phase of chronic granulocytic leukemia: a report on nine patients and review of the literature.

After reports of the successful use of mithramycin and hydroxyurea in the myeloid blast phase of chronic granulocytic leukemia, we treated nine patients according to the protocol devised by Koller and Miller (1986). There were no complete responses, but one patient had a partial response with a transient return to the chronic phase. Of the remaining eight patients, two experienced lessening of bone pains, and one a reduction in spleen size, but without hematological improvement. The regimen was associated with significant toxicity, and no overall survival advantage. We present a review of published data regarding the use of mithramycin in chronic granulocytic leukemia which supports the results in our series. The combination of mithramycin and hydroxyurea is largely ineffective in the blast phase of chronic granulocytic leukemia, but may be of value in the accelerated phase.

Adult↗
PubMed1982

Z* DNA, the left-handed helical form of poly[d(G-C)] in MgCl2-ethanol, is biologically active.

The interconversion between the right (R) and left (L) helical forms of poly[d(G-C)] occurs at low concentrations of MgCl2 and EtOH, acting together in a highly synergistic manner. Thus, the cooperative R---L transition is induced by only 0.4 mM and 4 MM MgCl2 in combination with 20% and 10% EtOH, respectively. The L form of poly[d(G-C)] formed under these conditions has the spectroscopic properties (absorption, circular dichroism) previously demonstrated under high salt conditions (Pohl and Jovin, 1972) and thought to correspond to the left-handed Z DNA structures recently established by X-ray crystallography (Wang et al., 1979; Drew et al., 1980). However, L DNA formed in Mg2+-EtOH (which we designate as Z* DNA) has unique properties: a) it can be sedimented readily out of solution at low speed, indicative of condensation and intermolecular aggregation; b) it supports the binding of several intercalating (ethidium bromide, actinomycin D) and non-intercalating (mithramycin) drugs, although these interact preferentially with the R (i.e., B) form of DNA; and c) it functions as a template for Escherichia coli RNA polymerase. B and Z* DNAs can be generated under identical ionic conditions and compared in a number of biochemical systems. Our results suggest that left-handed DNA may form under physiological conditions and serve a biological function.

Crystallography↗
PubMed1987

The effect of low calcium diet, mithramycin, and dichlorodimethylene bisphosphonate on humoral hypercalcemia of malignancy in nude mice transplanted with the canine adenocarcinoma tumor line (CAC-8).

The effect of a low calcium diet, mithramycin, or dichlorodimethylene bisphosphonate were evaluated in nude mice with humoral hypercalcemia of malignancy associated with the transplanted canine adenocarcinoma (CAC-8). Low calcium (0.01%) diet significantly reduced serum calcium levels in hypercalcemic nude mice and reduced urine calcium excretion to control levels. Mithramycin (8 mg/kg) decreased serum calcium concentration and urine calcium excretion to the range of control non-tumor-bearing nude mice at day 5 after a single injection, but there was no change in the number of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from CAC 8-bearing nude mice after mithramycin administration were decreased in size, had small ruffled borders, and increased relative size of clear zones. Dichlorodimethylene bisphosphonate (Cl2MDP) (45 mg/kg) partially reduced serum calcium concentration of hypercalcemic tumor-bearing nude mice, decreased urine calcium excretion to control levels, and markedly reduced the numbers of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from Cl2MDP-treated nude mice were smaller and had a reduced frequency of ruffled borders than saline-treated hypercalcemic nude mice. In vitro bone resorption induced by CAC-8 extract was significantly reduced by Cl2MDP and mithramycin. The results of these investigations suggest that the hypercalcemia and hypercalciuria associated with HHM in nude mice with CAC-8 are the combined result of altered calcium homeostasis in the bone, kidney, and intestine. Chemotherapeutic agents that specifically affect only bone or feeding a low calcium diet alone may not completely ameliorate the hypercalcemia of HHM.

Adenocarcinoma↗
PubMed2003

Enhanced binding of Sp1/Sp3 transcription factors mediates the hyperoxia-induced increased expression of the lung type I cell gene T1alpha.

The transcription factor Sp1 plays an important regulatory role in transactivation of the lung type I cell differentiation gene T1alpha. Like other lung cells, type I cells may encounter changes in oxygen concentration during the lifetime of the organism. We found that exposure of mice to hyperoxia rapidly increases expression of T1alpha and other type I cell genes, and that returning the mice to normoxia quickly decreases expression. Likewise hyperoxia increases both endogenous T1alpha expression in lung epithelial cell lines and transcription of luciferase (Luc) from T1alpha promoter deletion constructs. Using wild-type promoter fragments and gel shift assays, we determined that Sp1/Sp3 and a key Sp cis-element in the proximal promoter mediate the hyperoxic response. Mutations of this element and inhibition of Sp-DNA binding by mithramycin block the hyperoxic response. Western analyses of cell homogenates show that the overall abundance of Sp1 and Sp3 proteins is not altered by hyperoxia. However, the abundance of nuclear Sp1 increases after short hyperoxic exposures, suggesting that signaling pathways activated by hyperoxia lead to Sp protein translocation, perhaps as a result of increased Sp phosphorylation.

Animals↗
PubMed1977

Microfluorometric analysis of cellular DNA following incorporation of bromodeoxyuridine.

Bromodeoxyuridine (BrdU) incorporation into cellular DNA has a differential effect on the cell-associated fluorescence of several DNA-specific dyes. After cells were treated with BrdU, flow microfluorometry was used to study the relative increase or decrease influorescence of stained cells. Bromodeoxyuridine incorporation into CHO cells increased the fluorescence of mithramycin-, olivomycin-, or chromomycin-stained cells, decreased that of propidium iodide-stained cells, and had little, if any, effect on the fluorescence of acriflavine Feulgen-stained cells. Changes in relative fluorescence of cell associated dyes are due to changes in the amounts of dye bound to cells with BrdU-substituted DNA. Colorimetric and absorbance measurement of DNA content showed that BrdU does not alter the diploid DNA content of CHO cells; however, BrdU induces perturbations in the distribution of cells about the cell cycle which cause an increase in average DNA content.

Acriflavine↗
PubMed1982

Species specific differences in the toxicity of mithramycin, chromomycin A3, and olivomycin towards cultured mammalian cells.

Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, showed large unexpected differences (up to more than 1000 fold) in their toxicity towards cultured cells from various species (human, Chinese hamster, Syrian hamster, and mouse). Among the cell types examined, human cells (both a diploid fibroblast cell strain and HeLa cells) were maximally sensitive to all these drugs, followed by the Syrian hamster kidney cells (BHK 21). The mouse (LMTK- cells) and Chinese hamster (CHO) cells, which were more resistant, showed interesting differences in their sensitivity towards these drugs. For example, whereas the mouse cells were more resistant to mithramycin than CHO cells, the sensitivity pattern was reversed for both chromomycin A3 and olivomycin. In cell extracts derived from human, mouse, and Chinese hamster cells RNA synthesis, which is the cellular target of these drugs, showed identical sensitivity to both mithramycin and chromomycin A3, indicating that the species specific differences in the toxicity to these drugs are at the level of cellular entry of these compounds. Based on the structures of these glycosidic antibiotics and their patterns of toxicity, it is suggested that the intracellular transport of these drugs involves specific interactions between the sugar residues on these compounds and some type of cell surface receptor(s), which differ among different cell types. Some implications of these results for toxicity studies are discussed.

Animals↗
PubMed1989

Synchronized human diploid fibroblasts: progression capabilities of a subpopulation that fails to keep pace with the predominant, rapidly dividing cohort of cells.

Highly synchronized cultures of HSF-55 human diploid fibroblasts contain subpopulations of cells with intact plasma membranes that do not participate in the parasynchronous division wave. To determine the fate of these laggard cells, cultures were incubated with BrdU for variable periods to label newly replicated DNA in both the readily synchronizable and nonsynchronizable subpopulations. The kinetics of labeling with BrdU were determined with a two-laser flow cytometric technique that did not employ antibody to BrdU, but instead monitored emission of fluorescence from DNA-specific stains that differed in the degree of BrdU-induced quenching of their fluorescence signals. Approximately 90% of the cells rapidly incorporated BrdU and later divided within a 3 hr period. The remaining 10% of the cells, however, were found to reside within a minority subpopulation that maintained the capacity to traverse the cell cycle, but at a greatly reduced rate relative to the progression capacity of the majority of cells. Cells were viably sorted from these cohorts within the synchronized culture, and their kinetic behavior was determined through direct measurement of their growth rates and plating efficiencies. As predicted by the BrdU labeling studies, the sorted cells from the minority, slowly traversing subpopulation divided at a rate that was 30 to 50% lower than that obtained with cells sorted from the readily synchronizable subpopulation. From consideration of the kinetics of entry into S-phase of the majority and minority subpopulations, protocols are described that should allow preparation of relatively pure populations of both early- and late-replicating species of human DNA.

Aphidicolin↗
PubMed1994

Interaction of mithramycin with isolated GC and CG sites.

We have studied the interaction of the GC-specific, minor groove-binding ligand, mithramycin, with cloned DNA inserts containing isolated GC and CG sites flanked by regions of (AT)n and An.Tn using DNase I and hydroxyl radical footprinting. We find that mithramycin binds to GC better than CG and that AGCT is a better site than TGCA. Sites flanked by (AT)n appear to be bound better than those surrounded by An.Tn. Although no footprints are produced at T9GCA9 and T15CGA15, DNase I cleavage is enhanced within the GC sites suggesting that there is some interaction with the ligand. Mithramycin also alters the DNase I cleavage of (GA)n.(CT)n.

Adenine↗
PubMed1984

Fluorometric determination of DNA in cartilage of various species.

A sensitive, modified 3,5-diaminobenzoic acid (DABA), fluorometric DNA assay was developed and compared to mithramycin and ethidium bromide assays in determining the DNA content of dense connective tissues including: Swarm rat chondrosarcoma, rabbit, dog, monkey, and most importantly, adult human articular cartilage. In the more cellular cartilages, the three methods gave equivalent results. However, in the relatively acellular human cartilage, the DABA method was shown to be superior. Both the mithramycin and ethidium bromide gave falsely high values compared to the DABA method, which by subtraction after DNase digestion approached the DABA value. The latter was completely DNase sensitive. With the DABA method, the DNA content of human cartilage can be obtained on less than 5 mg wet weight of fresh, alcohol-fixed, or lyophilized material. While the DNA can also be released by digestion with papain or protease from Streptomyces griseus, proteinase K was preferable. The comparison of literature values for other fluorometric and spectrophotometric assays of human cartilage suggest these methods overestimate human articular cartilage DNA concentrations, whereas the DABA values were in line with those predicted from previous morphometric analysis. Thus, the modified method represents an improvement in DNA analysis of dense connective tissues.

Adult↗
PubMed1976

The valve of chemotherapy in the treatment of testicular dysembryoplastic tumors.

Chemotherapy appears to be of help in treating dysembryoplastic testicular tumors. It seems better to treat first by surgery (lymphadenectomy) if possible, then (a) if no nodes are involved or only one has been discovered by microscope examination, with chemotherapy for one year; or (b) if two or more nodes are involved, with irradiation of the nodes and chemotherapy. Even if lymphadenectomy is not possible, one course of chemotherapy followed by cobalt and more chemotherapy can bring results in some cases.

Cyclophosphamide↗
PubMed1992

Humoral hypercalcemia in seminomas.

Seminomas are germ cell tumors that are rarely associated with hypercalcemia. In this report, four cases of seminoma with concomitant hypercalcemia are presented and another three from the literature are reviewed. All seven patients exhibited hypercalcemia with a normal serum concentration of inorganic phosphorus and no evidence of skeletal metastases. The peripheral venous level of parathyroid hormone (PTH) was normal in four of the five patients in whom it was measured. The serum concentration of calcitriol was elevated in the two patients in whom it was measured. After systemic chemotherapy, the serum "corrected" total calcium concentration returned to normal and remained normal; the decrease in the levels temporally paralleled the decrease in tumor volume. Both patients with elevated calcitriol levels remained eucalcemic after treatment of the malignancy, suggesting that the increased serum calcitriol level was linked to the development of hypercalcemia as this humoral agent was inappropriately elevated by patients with this syndrome. In contrast to many forms of malignancy, the development of hypercalcemia did not adversely affect the prognosis of the patients with seminoma, since all seven patients entered complete remission. Hypercalcemia appears to be heretofore unrecognized paraneoplastic syndrome associated with seminoma.

Adult↗
PubMed1993

The majority of osteoclasts require mRNA and protein synthesis for bone resorption in vitro.

Mithramycin is an mRNA synthesis inhibitor that has been used to decrease bone resorption in patients with humoral hypercalcemia and Paget's disease. During studies on the mechanism of action of mithramycin it became clear that the compound has a direct inhibitory effect on osteoclastic bone resorption in the in vitro bone slice assay. At concentrations of 0.1-100 nM mithramycin directly inhibited osteoclastic bone resorption dose-dependently up to 66 +/- 5% at 100 nM (mean +/- SEM, 3 expts.). Another mRNA synthesis inhibitor, actinomycin D (0.1-100 nM) and the protein synthesis inhibitor, cycloheximide (0.1-10 microM), also dose-dependently inhibited osteoclastic bone resorption by 78 +/- 7% at 100 nM and 76 +/- 7% at 10 microM, respectively. Mithramycin and actinomycin D at 100 nM did not affect osteoclast survival on bone slices and were therefore not cytotoxic at the concentrations used. Mithramycin (100 nM) and cycloheximide (10 microM) both slightly decreased osteoclast cytoplasmic spreading. Addition of 100 nM mithramycin 6 hr after osteoclast adhesion to bone slices still inhibited subsequent resorption by 50%, indicating a continued but lesser requirement for mRNA synthesis during bone resorption. These results show that approximately 75% of osteoclasts obtained from neonatal rat long bones are activated by adhesion to mineralized bone surfaces and require mRNA and protein synthesis in order to resorb bone in vitro.

Animals↗
PubMed1995

A DNA-binding antitumor antibiotic binds to spectrin.

Aureolic acid group of antibiotics inhibit transcription by reversible binding to DNA in presence of divalent magnesium. We for the first time report binding of the one of such antitumor antibiotic, mithramycin (MTR), to the major protein component of erythrocyte cytoskeleton, spectrin. A reasonably high apparent dissociation constant was estimated to be 1.5 microM. The binding of mithramycin in the absence of any divalent cation to the large cytoskeletal protein led to quenching in the tryptophan fluorescence of the protein. Stern-Volmer quenching of the tryptophan residues by acrylamide revealed conformational change in the MTR-bound spectrin. This preliminary study might be useful in understanding other possible sites of actions after translocation.

Acrylamide↗
PubMed2001

Interaction of antitumor drug, mithramycin, with chromatin.

Mithramycin (MTR) is an anticancer drug that blocks macromolecular biosynthesis via reversible interaction with DNA in the presence of bivalent cation such as Mg2+. Mithramycin forms two types of complexes with Mg2+: complex I (1:1 in terms of MTR:Mg2+) and complex II (2:1 in terms of MTR:Mg2+). In vivo antibiotic would interact with chromatin, a protein-DNA complex. For the first time we have demonstrated and characterized the association of both complexes of MTR with chromatin and nucleosome core. From an evaluation and comparison of the binding and thermodynamic parameters and CD spectra of bound complexes, we have shown the following. Histone(s) stand in the say of the access of the ligand(s) to chromosomal DNA. Chromatin and core particle interact differentially with the same ligand. Mode of interaction of the two complexes, I and II, with the same system is different. Significance of these results to understand the transcription inhibitory property of the drug in eukaryotic chromosome is discussed.

Animals↗