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)

Using a modification of the collagenase dispersion method of Dufau et al., we examined changes in DNA synthesis produced by estrogens in the interstitial cells of mice that develop malignant Leydig cell tumors after prolonged estrogen administration. Previous work in cryptorchid mice indicated that during continuous estrogen administration [3H]thymidine incorporation into DNA rises to a maximum in 3 to 4 days and then falls to approximately base levels within 2 to 3 weeks. This was confirmed both in Leydig cell concentrates of estrogen-treated mice after either injection with [3H]thymidine or incubation with [3H]thymidine in vitro. This DNA synthesis was blocked by hydroxyurea. DNA synthesis in cells of estrogen-treated BALB/c mice of the Huseby substrain, which have a high incidence of Leydig cell tumors, was 5 to 11 times that in untreated controls. Cells from estrogen-treated C3H/Bi mice, which have a low incidence of Leydig cell tumors, showed only a 2- to 3-fold increase. In the Huseby substrain the rise of DNA synthesis is a peak and subsequent recession were paralleled by a rise and fall in DNA polymerase alpha activity. DNA polymerase beta did not show this variation. In C3H/Bi mice, neither polymerase showed significant change. The evidence suggests that the early estrogen-stimulated DNA synthesis is probably replicative and is associated with increased DNA polymerase alpha activity.
Cancer Res 1978 Feb
PMID:DNA synthesis and DNA polymerase activity in Leydig cells of diethylstilbestrol-stimulated mouse testes. 62 Apr 11

Corynebacterium parvum induces rapid proliferation of spleen cells with concomitant rapid increases in DNA synthesis as measured by [3H]thymidine uptake and increase in DNA polymerase activity. Cell number increased exponentially over 10 days. DNA polymerase activity increased 8-fold after C. parvum stimulation. The rapidity of response indicated a population response to the stimulus, and the data are consistent with a direct stimulation of spleen cell proliferation by C. parvum.
Cancer Res 1978 Jun
PMID:Induction of spleen cell growth and DNA polymerase activity by Corynebacterium parvum. 64 75

The present studies were initiated to investigate the cell kinetics in spontaneous and transplantable mammary tumors after single doses of cyclophosphamide (Cp). The 3H-thymidine (3H-TdR) labeling index (LI), the DNA synthesis times, and the primer-dependent DNA polymerase labeling index (PDPI) were determined by in vitro methods for spontaneous mammary tumors (SMT) in C3H/HeJ retired breeders and 13762 transplantable rat mammary tumors (RMT) in Fischer 344 rats from 6 hours to 14 days after Cp treatment. The perturbations in the cell kinetics, although quantitatively different in the two tumor models, were qualitatively similar in that transient changes in both PDPI and 3H-TdR LI were observed within the first 24 hours after treatment. These changes were followed by a variable period during which cell proliferation was suppressed. Increases in the PDPI and 3H-TdR LI, presumably reflecting proliferative recovery, were observed prior to the initiation of tumor regrowth. Increases in the 3H-TdR LI and PDPI within the first 24 hours after Cp in C3H/HeJ SMT indicated an interval of increased sensitivity to adriamycin. In the 13762 RMT, combination chemotherapy protocols designed to exploit changes in cell kinetics at early times (24 hours) and during the recovery phase of the response resulted in greater long-term tumor-free survival.
Cancer Treat Rep 1978 May
PMID:Therapeutic implications of cell kinetic changes after cyclophosphamide treatment in "spontaneous" and "transplantable" mammary tumors. 65 58

The effects of 4'-epi-daunorubicin, 4'-epi-adriamycin, and the corresponding beta anomers on the in vitro activity of Escherichia coli DNA polymerase I and RNA polymerase were determined and compared with the effects of the parent compounds. The observed effects parallel the cytotoxic activities, assayed by inhibition of mouse embryo fibroblast proliferation, and the inhibitory activities on DNA synthesis in cultured cells. The data indicate that the inverted configuration at position 1 of the amino sugar results in a markedly reduced biological activity. This conclusion is also substantiated by the data obtained with the beta anomer of adriamycin. A preliminary investigation on the binding properties of these derivatives suggests that the inverted configuration at C-1' produces a significant decrease in the binding to DNA. In contrast, epimerization at position 4' did not produce any significant change in activity. The relationship between biological and biochemical activity and DNA binding properties of the tested compounds are discussed with particularly reference to antitumor activity.
Cancer Res 1976 Jun
PMID:Relationship between activity and amino sugar stereochemistry of daunorubicin and adriamycin derivatives. 77 33

The chemical class of drugs known as the nitrosoureas are a recently developed group of very active alkylating-agent anticancer drugs which are best represented by BCNU, CCNU, and methyl-CCNU (meCCNU). The nitrosoureas are among the most active, if not the most active, anticancer drugs both quantitatively (log kill of sensitive tumor cells in vivo) and qualitatively (spectrum of mouse, rat, and hamster tumors responding to treatment). Therapeutic anticancer activity of the nitrosoureas has been consistently observed with oral as well as parenteral administration. The nitrosoureas are clearly the most active group of anticancer drugs observed against experimental meningeal leukemias and intracerebrally implanted transplantable primary tumors of central nervous system origin (eg, gliomas, ependymoblastomas, and astrocytomas in mice and hamsters). The nitrosoureas have been observed to be less than additive in lethal toxicity for vital normal cells in the mouse in combination with representatives of the other major classes of anticancer agents, eg, purine antagonists, pyrimidine antagonists, inhibitors of DNA polymerase(s) or ribonucleotide reductase(s), mitotic inhibitors, drugs that bind to or intercalate with DNA, and other alkylating agents. Therapeutic synergism against one or more transplantable or spontaneous tumors of mice, rats, or hamsters with one of several nitrosoureas in two-drug combinations with representatives of most of the major classes of anticancer agents listed above has been reported. With a number of advanced-stages mouse tumors, generally considered to be refractory to treatment with most anticancer agents, long-term cures have been obtained with combination-drug or combined-modality (surgery plus chemotherapy) treatment. The demonstrated lack of cross-resistance of several leukemias and solid tumors of mice selected for resistance to BCNU, meCCNU, or other alkylating agents suggests that the widely held opinion that all alkylating agents are very similar in biologic mechanism of action, and therefore resistance to one alkylating agent probably predicts cross-resistance to all alkylating agents, may no longer be tenable. If not, then alkylating-agent drug combinations, either used alone or combined with other treatment modalities (eg, surgery) which have been reported to result in therapeutic improvement in a number of experimental murine tumor systems, may be indicated for serious consideration as surgical adjuvant chemotherapy by surgeons or as primary therapy by medical oncologists.
Cancer Treat Rep 1976 Jun
PMID:Nitrosoureas: a review of experimental antitumor activity. 78 94

Transplantable fibrosarcomas were developed in two B-locus-defined chicken strains from primary tumors induced by im injection of 2 mg 7,12-dimethylbenz[a]anthracene in 0.1 ml dimethyl sulfoxide into 1- to 2-week-old chicks. Viruses were not important factors in transmission of these tumors as evidenced by 1) transplantability only within the chicken strain of origin, 2) lack of evidence for a filterable agent, 3) maintenance of donor karyotypic characteristics upon transplantation, 4) lack of DNA polymerase and avian leukosis virus group-specific protein production in vitro. Bursectomized inbred SC chickens had a higher incidence of tumor induction than did normals of the same strain. Although the exact interpretation of this finding posed some problems, as discussed, an important function of enhancing antibody in tumor growth appeared excluded.
J Natl Cancer Inst 1976 Aug
PMID:Chemical carcinogen-induced transplantable fibrosarcomas in histocompatible chickens. I. Incidence of tumor induction in normal and bursectomized chickens. 82 48

The 490 quinone, a natural sulfhydryl-arylating reagent from the mushroom, Agaricus bisporus, markedly inhibited L1210 murine leukemia DNA polymerase alpha while resulting in little inhibition of DNA polymerase beta from this source. This quinone was more strongly inhibitory than p-chloromercuri-benzoate or N-ethylmaleimide and was less readily neutralized by sulfhydryl-containing molecules such as dithioerythritol. Preliminary experiments indicate that DNA protects DNA polymerase alpha from inhibition by the 490 quinone. The inhibition of DNA synthesis by quinone 490 may contribute significantly to the cytotoxicity of this compound and to the potential of gamma-L-glutaminyl-4-hydroxybenzene as an antitumor agent.
Cancer Res 1977 Feb
PMID:Inhibition of DNA polymerase from L1210 murine leukemia by a sulfhydryl reagent from agaricus bisporus. 83 67

Regenerating rat liver was used as a semisynchronous system in which to investigate the effects of 6-thioguanine on biochemical processes occurring in discrete phases of the cell cycle. 6-Thioguanine inhibited the first wave of DNA biosynthesis in regenerating rat liver. This effect appeared to be the result of a decrease, caused by 6-thioguanine, in the induction of several enzyme activities (i.e., thymidine kinase, deoxycytidylate deaminase, cytidine diphosphate reductase, and DNA polymerase) necessary for the initiation of DNA replication in regenerating liver. There was a fairly short period during which 6-thioguanine could be given to rats to accomplish the inhibition of the appearance of the induced activities of these enzymes; this period corresponded to the time just before enzyme induction. The inhibition of the induced synthesis of this group of enzymes occurred in the presence of an intact translational apparatus and intact polysomes and in the absence of interference with the incorporation of radioactive leucine and tyrosine into total protein of liver. Synthesis of polyadenylate-containing RNA was depressed in 6-thioguanine-treated rats, whereas the synthesis of polyadenylate-lacking RNA was unaffected. It is suggested that the inhibition of the synthesis of polyadenylate-containing RNA by 6-thioguanine is at least in part responsible for the observed decrease in induced enzyme activities and the resulting interference with DNA replication.
Cancer Res 1977 Jun
PMID:Effects of 6-thioguanine on macromolecular events in regenerating rat liver. 87 Jan 91

Cell kinetics in spontaneous C3H/HeJ mammary tumors of retired-breeder mice was studied by in vivo and in vitro techniques. The [3H]TdR labeling index (LI), the DNA synthesis time (TS), and the primer-dependent DNA polymerase assay LI [an in vitro estimate of tumor growth fraction (GF)] were compared to similar measurements made in vivo. These measurements as well as the calculated cell kinetic parameters derived from these data were not different in in vivo and in vitro studies. Furthermore, the cell kinetic parameters in tumors classified histologically as type A or type B mammary tumors were also similar. Although considerable variation in volume doubling times (Td's), [3H]TdR LI's, potential doubling times, cell cycle times (Tc's), and cell loss was found, Ts's were similar in all mammary tumors. No correlation between tumor volume or tumor weight and cell kinetic parameters was seen. However, the most slowly growing tumors (i.e., tumors with the longest Td's) tended to have the lowest [3H]TdR LI's, the longest Tc's, and the highest cell loss factors. No correlation was found between the GF and Td. However, tumors with the most rapidly proliferating cell populations tended to have the highest GF's.
J Natl Cancer Inst 1977 Oct
PMID:Cell kinetics in vivo and in vitro for C3H/He spontaneous mammary tumors. 90 95

An assay has been developed to measure the ability of human lymphocytes to repair damage to DNA. In this assay, purified human lymphocytes are exposed to graded doses of radiation and then stimulated with phytohemagglutinin to undergo DNA replication. The rate of incorporation of thymidine in irradiated lymphocytes during the second and subsequent rounds of DNA replication is taken to be indicative of the ability of the cells to repair damage to DNA. In lymphocytes from normal individuals, X-irradiation with doses of 100 to 800 rads was found to inhibit phytohemagglutinin-stimulated thymidine incorporation proportionally to the dose of radiation without curtailing the induction of DNA polymerase. The response to phytohemagglutinin of lymphocytes from a patient with xeroderma pigmentosum after exposure to graded doses of X-irradiation was found to be similar to that of the normal controls, whereas the response after ultraviolet irradiation was markedly impaired. In contrast, lymphocytes from patients with ataxia telangiectasia were hypersensitive to X-irradiation. The data on these clinical syndromes support the idea that this assay measures DNA repair and indicates the feasibility of using this method for screening individuals for genetic deficits in DNA repair.
Cancer Res 1977 Oct
PMID:Screening for deficits in DNA repair by the response of irradiated human lymphocytes to phytohemagglutinin. 90 9


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