Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lonidamine (LND), previously reported as a useful antitumor substance in combination with physical or chemical agents, has been studied for its capacity in increasing pharmacological elimination in vitro of residual tumor cells from human bone marrow. Different drugs were tested in association with LND against mixtures of human bone marrow and a tumor cell line, clonogenic human leukemic blast progenitors, and normal human bone marrow precursors. The results demonstrated that LND increased the efficacy of anthracycline derivatives (Adriamycin, Mitoxantrone) both on the tumor cell line and on the leukemic blast progenitors, while VP-16 or ASTA-Z 7654 was not affected by the same substance. The toxicity on normal stem cells reflected that of each drug and was not modified by the addition of LND. While a consistent dose-dependent CFU-GM reduction was observed immediately after treatment with the different drugs, a complete recovery was reached after 7 and 14 days of long-term marrow cultures. Because of the low toxicity and the efficacy demonstrated in association with certain agents in increasing tumor cell elimination in vitro, LND could play an important role in in vitro purging prior to autologous bone marrow transplantation.
Exp Mol Pathol 1989 Apr
PMID:In vitro pharmacological purging of human bone marrow is enhanced by the use of lonidamine. 270 84

The effect of Adriamycin on mitochondria of the rat heart, liver, and Ehrlich ascites tumor mitochondria has been evaluated. The results may be summarized as follows: Adriamycin reduces both ADP- and FCCP-stimulated respiration, inhibits oxidative phosphorylation, decreases mitochondrial ATP-ase activity, and affects the redox state of respiratory carriers. These alterations are common to all types of mitochondria tested with almost similar patterns. However, the severe cardiotoxicity of the drug cannot be ascribed only to an effect on mitochondrial energy-yielding processes. The addition of hexokinase to phosphorylating heart mitochondria does not increase the sensitivity of succinate oxidation to Adriamycin. Experiments to determine the site of action were not able to detect a specific point of attack. It is conceivable, therefore, that the modifications induced by Adriamycin on the functional parameters of mitochondria may be ascribed to alterations of the physical state of some components of the inner mitochondrial membrane, e.g., lipids, which regulate the kinetic properties of the membrane-associated enzymes.
Exp Mol Pathol 1987 Feb
PMID:Effect of adriamycin on electron transport in rat heart, liver, and tumor mitochondria. 287 39

Doxorubicin (Adriamycin) and daunomycin analogs have been examined for their ability to chelate iron and catalyze the oxidative cleavage of DNA. The results show that the C-11-hydroxyl group is essential for iron binding and DNA damage. Thus, the iron complexes of doxorubicin, daunomycin, carminomycin, and 4-demethoxydaunomycin are potent redox catalysts capable of reducing molecular oxygen in the presence of physiologic concentrations of glutathione. They are also effective catalysts of hydroxyl radical formation from hydrogen peroxide. With the exception of daunomycin, generation of hydroxyl radical from hydrogen peroxide is stimulated by greater than 200% by DNA addition. Analogs that lack the C-11-hydroxyl group are relatively inefficient at oxygen reduction, hydroxyl radical formation, and DNA cleavage. The potencies of the anthracycline analogs tested in the H2O2-dependent DNA cleavage reaction correlated well with their relative cardiac toxicities.
Mol Pharmacol 1985 Mar
PMID:Thiol-dependent DNA damage produced by anthracycline-iron complexes. The structure-activity relationships and molecular mechanisms. 298 84

I have found that antineoplastic drugs which are known to be inhibitors of mammalian DNA topoisomerases have pronounced and selective effects on simian virus 40 DNA replication. Ellipticine, 4'-(9-acridinylamino)methanesulfon-m-aniside, and Adriamycin blocked decatenation of newly replicated simian virus 40 daughter chromosomes in vivo. The arrested decatenation intermediates produced by these drugs contained single-strand DNA breaks. Ellipticine in particular produced these catenated dimers rapidly and efficiently. Removal of the drug resulted in rapid reversal of the block and completion of decatenation. The demonstration that these drugs interfere with decatenation suggests that they may exert their cytotoxic and antineoplastic effects by preventing the separation of newly replicated cellular chromosomes. Camptothecin rapidly breaks replication forks in growing Cairns structures. It is likely that the target of camptothecin is the "swivel" topoisomerase required for DNA replication and that it is located at or very near the replication fork in vivo. Evidence is presented that many of the broken Cairns structures are in fact half-completed sister chromatid exchanges. One pathway for the resolution of these structures is completion of the sister chromatid exchange to produce a circular head-to-tail dimer.
Mol Cell Biol 1986 Dec
PMID:Topoisomerase inhibitors can selectively interfere with different stages of simian virus 40 DNA replication. 302 45

Doxorubicin (Adriamycin), one of the most potent antibiotics used in tumor chemotherapy, shows many undesirable side effects. We studied the effect of different drug concentrations on the biochemistry of cell motility and, in particular, on potassium-induced actin polymerization. It is well known, in fact, that the actin aggregational status could dramatically influence many cell motility manifestations. Our results clearly show that stoichiometric and substoichiometric amounts of doxorubicin negatively influence actin polymerization by inhibiting both the filament growth and the polymer amount at steady-state; the balance between the two different effects seems to be in relation to the drug concentration. The obtained results could explain some of the doxorubicin effects previously observed in vivo.
Exp Mol Pathol 1988 Dec
PMID:Dose-dependence of doxorubicin effect on actin assembly in vitro. 319 12

The effect of Lonidamine, 1-(2,4 dichlorobenzyl)-1-H-indazol-3-carboxylic acid, on the uptake of Adriamycin by Ehrlich ascites tumor cells has been investigated. The uptake of Adriamycin is greatly stimulated by Lonidamine and the increase depends on the energy sources of the cell. In the presence of glucose the intracellular drug content is remarkably lower than that in its absence. This difference lies in the mechanism by which Lonidamine enhances the uptake of Adriamycin. The Adriamycin efflux is via an active transport process and, in the presence of glucose, both aerobic glycolysis and oxidative phosphorylation contribute to ATP synthesis. Although Lonidamine inhibits both these pathways, there is still sufficient ATP to extrude a certain amount of Adriamycin. The elevated intracellular concentration of Adriamycin depends not only on the Lonidamine-inhibited outward transport but also on higher membrane permeability which allows a low concentration of Adriamycin (18 microM) to interfere also with the oxidative metabolism of Ehrlich ascites tumor cells.
Exp Mol Pathol 1988 Dec
PMID:Modulation of adriamycin uptake by lonidamine in Ehrlich ascites tumor cells. 319 18

Free radicals have been suggested to play a role in adriamycin-induced cardiomyopathy. Adriamycin-induced myocardial effects were examined in rats maintained on a vitamin E deficient diet. Animals were divided into four groups: I, control; II, adriamycin-treated; III, vitamin E deficient diet; IV, vitamin E deficient diet plus adriamycin treatment. Adriamycin-treated animals (groups II and IV) were given six injections (i.p.) over two weeks for producing a cumulative dose of 15 mg/kg. Animals in groups III and IV were placed on vitamin E deficient diet starting two weeks prior to the first injection of adriamycin or vehicle. Myocardial tissue analysis were performed on animals sacrificed 1 week after the last injection. Mortality was significantly higher in group IV which also showed doubling of myocardial malondialdehyde content relative to the non-adriamycin-treated vitamin E deficient group (III). Myocardial cell damage in group IV was characterized by separation of the external lamina, subsarcolemmal changes, mitochondrial swelling and myofibril dropout. Group II hearts showed only a mild dilation of the sarcotubules and swelling of the mitochondria. Total sialic acid content of the sarcolemma in groups II, III and IV was 55, 90 and 24% of the control values in group I. These data show a characteristic sarcolemmal injury produced by adriamycin in hearts of animals with reduced antioxidant capacity which is probably mediated by increased free radical activity as well as lipid peroxidation.
Mol Cell Biochem 1988 Dec
PMID:Vitamin E deficiency accentuates adriamycin-induced cardiomyopathy and cell surface changes. 323 Dec 21

Twenty-three patients with disseminated refractory malignancies each received a tailored combination of adriamycin-conjugated murine monoclonal antibodies. Tumors were typed using a panel of antibodies. Cocktails of up to six antibodies were selected based on binding greater than 80% of the malignant cells as tested by immunoperoxidase and flow cytometry. These monoclonal antibodies were then conjugated to Adriamycin and administered intravenously. Seventeen of 23 patients had reactions to the administration of immunoconjugates, but these were tolerable in all but two patients. Fever, chills, pruritus, and skin rash were by far the most common transitory reactions. All were well controlled with premedication. In several patients there was limited antigenic drift among various biopsies within the same patient over time. This observation confirms the necessity for the use of a cocktail of antibodies if one wishes to cover all tumor cells. Preliminary serologic evidence suggests that the development of an IgM antibody, which is specific against the mouse monoclonal antibody, has the specificity and sensitivity to predict clinical reactions. Selected patients were re-treated. One patient with chronic lymphocytic leukemia had re-treatment on three occasions and demonstrated regression of peripheral lymph nodes. Two patients with breast carcinoma had definite improvement in ulcerating skin lesions and two patients with tongue carcinoma had shrinkage of their lesions. In the course of the study free Adriamycin released from the monoclonal antibodies was discovered to be a limiting factor in the amount of antibody that could be administered. Up to 1 g of Adriamycin and up to 5 g of monoclonal antibody were administered. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody that unpredictably caused hemopoietic depression. This study demonstrates the feasibility and reviews technical considerations in preparing immunoconjugate cocktails for patients with refractory malignancies. The major technical hurdle appears to be the selection of an effective conjugation method that can be used to optimally bind Adriamycin to monoclonal antibodies for targeted cancer therapy.
Mol Biother 1988
PMID:Adriamycin custom-tailored immunoconjugates in the treatment of human malignancies. 326 48

The objective of this study was to determine whether the antineoplastic agent doxorubicin (adriamycin) affects the microtubule system in isolated cardiac cells. Embryonic chick heart cultures were exposed to adriamycin concentrations of 40, 80, or 200 microM for 3, 12, or 24 h before fixation prior to immunofluorescence. Adriamycin produced marked distortions in the normal microtubule system. This was a function of adriamycin concentration and the duration of the exposure to adriamycin. Even when adriamycin was removed from the medium for a 12 h period, cells treated with adriamycin showed abnormalities of the microtubule system. The effect of adriamycin on the microtubule system extends to its reassembly after colchicine. Cells allowed to recover after colchicine in the presence of adriamycin (40 microM) showed impairment in microtubule regeneration. These data indicate that the microtubule system in cardiac myocytes is affected by adriamycin both by damaging microtubule structure and by impairing microtubule reassembly.
J Mol Cell Cardiol 1987 Nov
PMID:The effect of doxorubicin (adriamycin) on cytoplasmic microtubule system in cardiac cells. 332 51

Circular dichroism was used to compare the binding of several anthracycline antitumor antibiotics to sonicated phosphatidylcholine vesicles. Daunorubicin analogues, differing from the parent by structural changes in the amino sugar moiety of the molecule, were tested both with vesicles that contained negatively charged phospholipids and with neutral vesicles. The self-association properties of the analogues were also investigated. Binding to negatively charged vesicles was not strictly dependent on electrostatic interactions, since the characteristics of daunorubicin binding were totally different from those of Adriamycin (doxorubicin). Furthermore, the cardiotoxicity of these molecules did not have its origin in their quantitatively preferential electrostatic binding to negatively charged cardiolipin-containing membranes: DR-19, a daunorubicin derivative having lower cardiotoxicity than the parent compound, which bound to negatively charged vesicles in a manner quite similar to that of Adriamycin, whereas DR-10, another daunorubicin derivative with higher cardiotoxicity, bound poorly to negatively charged vesicles.
Mol Pharmacol 1988 May
PMID:Structural basis for the binding of antitumor anthracycline antibiotics to model membranes: circular dichroism studies. 336 5


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