Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported [(Ohno, T., Sweet, R.W., Hu, R., DeJak, D. & Spiegelman, S. (1977) Proc. Natl. Acad. Sci. USA 74, 764-768)] on the purification and characterization of the DNA polymerase from human breast cancer particles. Its preference for certain synthetic templates and its ability to use a viral RNA to fashion a faithful DNA transcript identify it as a reverse transcriptase similar to that found in the mouse mammary tumor virus and in the Mason-Pfizer monkey virus (MPMV). We report here that the human breast cancer enzyme crossreacts immunologically with the reverse transcriptase of MPMV. The crossreactivity was shown both by inhibition of enzyme activity and by complex formation between purified enzyme and isolated IgG against MPMV polymerase. No such interactions were observed with other oncornavirus reverse transcriptases of avian, murine, feline, or simian origin. Further, the IgG failed to neutralize the reverse transcriptases from human mesenchymal neoplasias (leukemias and lymphomas) or the activities of normal cellular DNA polymerases (alpha, beta, gamma).
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PMID:Antigenic relatedness of the DNA polymerase of human breast cancer particles to the enzyme of the Mason-Pfizer monkey virus. 6 75

Previous studies have identified human breast tumor particles possessing many of the features characteristic of RNA tumor viruses. In addition to the expected size (600 S) and density (1.16 g/ml) these include possession of an outer membrane and an inner one surrounding a "core" containing a DNA polymerase and a large-molecular-weight (70S) RNA possessing detectable homology to the RNAs of the mouse mammary tumor virus (MMTV) and of the Mason-Pfizer monkey virus (MPMV). We report here the purification and characterization of the DNA polymerase from the human breast cancer particles. Its key properties are very similar to those ofthe RNA-dependent DNA nucleotidyltransferase (reverse transcriptase) found in MMTV and MPMV. Thus like these viral enzymes, the purified human breast cancer DNA polymerase exhibits the following three features that together distinguish the known viral reverse transcriptases from normal cellular DNA polymerases: (i) a strong preference for oligo(dT)-poly(rA) over oligo(dT)-poly(dA) as a template for the synthesis of poly(dT); (ii) the acceptance of the highly specific oligo(dG)-poly(rCm) as a template for the formation of poly(dG); (iii) the ability to use a viral RNA (AMV) as a template to fashion a faithful DNA complementary copy; and (iv) its preference for Mg++ over Mn++. In summary, the data described here on the enzyme of the human breast cancer particles add further evidence of similarities to the viral agents associated with the corresponding malignancies in the mouse and monkey models. To date, an enzyme with these properties has not been detected in normal breast tissues or in benign tumors of the breast.
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PMID:Purification and characterization of the DNA polymerase of human breast cancer particles. 26 40

Although specific cancer targets are difficult to identify, the recent development of antisense oligodeoxynucleotides (aODNs) as inhibitors of gene expression has been shown to provide a new and useful tool in antiblastic management. aODNs are able to specifically interact with gene or mRNA sequences and inhibit the expression of relevant molecules for cancer pathogenesis and progression. Since alpha-DNA polymerase (pol-alpha) plays an essential role in cell proliferation, aODNs to pol-alpha have been synthesized in order to block mRNA translation and affect the growth of MDA-MB 231, human breast cancer cell line and SW626 ovarian cancer cells. A rapid colorimetric test (MTT assay) which measures cell growth and survival has been employed to evaluate the effects induced by ODN treatment. The present experimental results demonstrate that the aODNs to pol-alpha are able to significantly affect cell proliferation. This study provides an encouraging basis for the exploitation of ODNs as therapeutic agents in vitro and in future clinical application.
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PMID:The use of antisense oligodeoxynucleotides (aODNs) for the therapy of cancer. 184 Oct 51

4-Hydroxyandrostenedione (4-OHA) is a specific inhibitor of aromatase activity used for the treatment of breast cancer in post-menopausal women. Treatment with 4-OHA has been shown to inhibit the peripheral conversion of androstenedione to oestrone and reduce plasma oestrogen concentrations, but the effect of treatment on breast-tissue oestrone concentrations is not known. We have therefore examined the effect of treatment with 4-OHA on oestrone concentrations in normal and malignant breast tissues and also measured plasma and tissue 4-OHA concentrations. Changes in tumour oestrone concentrations were related to DNA polymerase alpha activity, a marker of cellular proliferation. Blood and breast-tissue samples were obtained before and 36 hr after treatment with 4-OHA. The mean plasma concentration of 4-OHA was 27.9 +/- 19.3 ng/ml, compared with levels of 33.7 +/- 25.6 ng/g for breast tumour and 13.5 +/- 11.5 ng/g for normal breast tissue. There was a significant correlation between 4-OHA concentrations in plasma and normal breast tissue (r = 0.91, p less than 0.001). Treatment with 4-OHA resulted in a significant (p less than 0.02) decrease in breast-tissue oestrone concentrations. For 3/4 tumour samples, a marked decrease in the concentration of oestrone (78 +/- 4%) was associated with a similar decrease (64 +/- 16%) in DNA polymerase alpha activity. It is concluded that treatment with 4-OHA effectively reduces breast-tissue exposure to oestrogen.
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PMID:Concentrations of oestrone and 4-hydroxyandrostenedione in malignant and normal breast tissues. 191 57

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent alpha-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polychemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.
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PMID:In vivo manipulation of human breast cancer growth by estrogens and growth hormone: kinetic and clinical results. 198 Oct 14

The effect of treatment with the aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA) on the peripheral conversion of androstenedione to estrone has been examined in eight postmenopausal women with advanced breast cancer. Before treatment conversion of androstenedione to estrone ([p]AEIBB) ranged from 0.81 to 3.7% and was almost completely inhibited after treatment with 4-OHA (two doses of 500 mg i.m. with an interval of 12 days between doses). Transfer constants were also measured by the urinary method ([p]AEIBU) for some subjects and decreased from 2.3 +/- 0.52% to 0.24 +/- 0.11% after treatment, a mean reduction of 90%. Mean plasma concentration of estradiol (37.4 +/- 16.6 pmol/liter) and estrone (99.0 +/- 32.2 pmol/liter) decreased significantly (P less than 0.01) to 15.7 +/- 4.6 pmol/liter and 52.4 +/- 8.9 pmol/liter, respectively, after treatment. Aromatase and DNA polymerase alpha (a marker of cell proliferation) activities were measured in seven samples of breast tumor tissue obtained before and after treatment. For three samples there was a marked (67 +/- 17%) decrease in tumor aromatase activity after treatment, for two, little change occurred, while tumor aromatase activity in the other two samples appeared to be resistant to the effect of 4-OHA. The correlation between tumor aromatase and DNA polymerase alpha activities (r = 0.45) failed to reach a significant level.
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PMID:Effect of treatment with 4-hydroxyandrostenedione on the peripheral conversion of androstenedione to estrone and in vitro tumor aromatase activity in postmenopausal women with breast cancer. 229 55

The effect of treatment with the progestogen medroxyprogesterone acetate (MPA) on the peripheral conversion of androstenedione to oestrone and tumour aromatase activity has been examined in post-menopausal women with advanced breast cancer. In addition to being a potent progestational compound, MPA also possesses glucocorticoid properties and glucocorticoids have been shown to stimulate in vitro aromatase activity. While some evidence was obtained of an increase in aromatase activity in tumour tissue after treatment with MPA, peripheral conversion of androstenedione to oestrone was similar when measured before (2.12 +/- 0.67%) and after (1.89 +/- 0.16%) treatment. DNA polymerase alpha activity, measured as a marker of cellular proliferation, decreased from 331 +/- 145 to 156 +/- 93 pmol thymidine triphosphate (TTP)/mg protein per h (P less than 0.02) in tumour samples examined before and after treatment. It is concluded that treatment with high doses of MPA has no effect on the peripheral conversion of androstenedione to oestrone but results in a significant reduction in tumour DNA polymerase alpha activity.
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PMID:The effect of medroxyprogesterone acetate on aromatase and DNA polymerase alpha activities in breast tumours. 253 50

DNA polymerase alpha activity is associated with cell proliferation, independently of the cell cycle phase, and a simple and reproducible method for the immunohistochemical demonstration of DNA polymerase alpha has been developed. In an analysis of a total of 76 human breast cancer tissues using this procedure, the clinico-pathological findings revealed that only the estrogen receptor (ER) significantly correlated with the DNA polymerase alpha activity. Therefore, this suggests that ER-negative tumors had a higher proliferative activity.
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PMID:[A study of the proliferative activity of DNA polymerase alpha immunoreactivity in breast cancer]. 268 77

An isotopic infusion technique has been used in an attempt to determine the contribution that local, in situ, oestrone synthesis makes to the oestrogen content of breast tumours. 3H-Androstenedione and 14C-oestrone were infused into women with advanced breast cancer for 12 hr before operation. At surgery, normal breast and breast tumour biopsy samples were obtained and 3H-androstenedione, 3H-oestrone derived from 3H-androstenedione and 14C-oestrone were isolated and measured. DNA polymerase alpha activity, a marker of cellular proliferation, was also measured to examine whether local synthesis of oestrone exerted a biological effect. The study was repeated after patients had been treated with the aromatase inhibitor, 4-hydroxyandrostenedione, before undergoing further surgery for removal of their tumours. In 4/6 tumours examined, in situ synthesis of 3H-oestrone from 3H-androstenedione accounted for the major part (84.3 +/- 9.0%) of the 3H-oestrone detected, while no significant in situ synthesis occurred in 2 other tumours. Although treatment with 4-hydroxyandrostenedione did not significantly alter the uptake of 3H-androstenedione or 14C-oestrone into breast tissues, in situ formation of 3H-oestrone was only detected in one tumour sample after treatment. DNA polymerase alpha activity decreased in 4/6 tumours after treatment with 4-hydroxyandrostenedione. Overall, however, there was no significant correlation between the level of 3H-oestrone formed in situ and DNA polymerase alpha activity (r = 0.38, NS). It is concluded that in some, but not all, breast tumours in situ formation of oestrone can make an important contribution to the oestrogen content of breast tumours.
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PMID:In situ oestrone synthesis in normal breast and breast tumour tissues: effect of treatment with 4-hydroxyandrostenedione. 275 29

Pirarubicin (THP-adriamycin or THP-doxorubicin) was found during a search of new anthracycline antibiotics among 4'-O-substituted compounds having less toxicities than other anthracycline anticancer drugs in 1979 by Umezawa et al. In its preclinical studies, this compound possessed almost similar antitumor efficacies to doxorubicin, but was effective against doxorubicin-resistant P388 and other murine tumor cell lines. This compound was rapidly incorporated into tumor cells, inhibiting DNA polymerase alpha and subsequently DNA synthesis. Inhibition of RNA synthesis was also noted. In the clinical studies, clinical responses were established against head and neck cancer, breast cancer, urogenital cancers, ovarian cancer, uterine cancer, acute leukemia, and malignant lymphoma, showing a wide antitumor spectrum clinically. Among the side effects, cardiac toxicity, alopecia and disturbance of the digestive organs were mild. From these results, THP-adriamycin seems to be a useful clinical drug for human solid tumors.
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PMID:[Pirarubicin (THP-adriamycin)]. 304 96


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