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)

Aphidicolin, a reversible inhibitor of DNA polymerase alpha and delta, has recently been reported to reverse the resistance to cisplatin (DDP) of an ovarian cancer cell line. We investigated the pharmacokinetics of aphidicolin in mice and examined its activity either alone or in combination with DDP in the DDP-sensitive M5076 (M5) murine reticular cell sarcoma as well as in a DDP-resistant subline (M5/DDP). The drug was cleared from plasma very rapidly (clearance, 41.6 ml min-1 kg-1), showing a half-life of 15 min. Aphidicolin concentrations in the tumor were approximately 50% of those found in plasma at steady state. Using several dose schedules and continuous infusions we failed to detect significant antitumor activity for aphidicolin glycinate. Potentiation of the activity of DDP by aphidicolin glycinate was moderate in mice bearing M5 tumor as well as in those bearing M5/DDP tumor. These data do not support the possible clinical use of aphidicolin in combination with DDP. However, further studies should be carried out in different tumor models before this possibility is conclusively ruled out.
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PMID:Activity of aphidicolin glycinate alone or in combination with cisplatin in a murine ovarian tumor resistant to cisplatin. 139 2

The association of the production of CA125 with the cell cycle was investigated in two cell lines derived from human ovarian cancer, one from a serous cystadenocarcinoma (HTOA) and the other from a mucinous cystadenocarcinoma (RMUG-s). HTOA and RMUG-s cells secreted CA125 at about 50 and 30U/ml/10(5) cell/24hr, respectively, in the logarithmic growth phase and at about 75 and 100U/ml/10(5) cell/24hr in the steady phase. Analysis by FCM revealed that cultures of both cell lines cultured for 7 days contained more cells in the G0/G1 phase and less cells in the S phase than those cultured for 3 days. The positive rate of immunologically stained DNA polymerase alpha was 31% in HTOA cells and 39% in RMUG-s cells after cultivation of the cells for 3 days. The addition of EGF at 0.01, 0.1 or 1.0nM did not affect the production of CA125 in HTOA or RMUG-s cells while the addition of NaBT at 1, 3 and 5mM raised production in both cell lines as the dose rose. With RMUG-s cells, the addition of EGF at 0.01nM to the culture media accelerated both logarithmic and steady phase growth without a significant change in the production of CA125. In contrast, the addition of NaBT at 1mM suppressed growth, but tended to increase the production of CA125 per cell. With the effect of EGF on the cell cycle of both cell lines, cells in the S phase increased by about 20% as compared with the control, 48 hours after its addition at 0.01nM. In contrast, after cultivation for 48 hours in the presence of 1mM NaBT, cells in the S phase were decreased while those in the G0/G1 phase increased. The results presented above suggested the possibility that some factors other than the cell cycle were involved in the production of CA125. There also is close correlation between cells in the G0/G1 phase and the production of CA125 in the culture of human ovarian cancer cells.
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PMID:[Production of CA125 in cell lines derived from human ovarian carcinoma: in relation to the cell cycle]. 150 33

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

We have studied the effect of glutathione reduction by buthionine sulfoximine (BSO), a specific inhibitor of gamma -glutamyl cysteine synthetase, on DNA repair after cisplatin damage in an ovarian cancer cell line with in vitro induced resistance to cisplatin. In addition, we have examined the effect of aphidicolin, a specific inhibitor of DNA polymerase alpha, in combination with BSO on cisplatin-associated DNA repair. BSO treatment was found to partially inhibit DNA repair, and the addition of aphidicolin caused nearly a 100% inhibition in DNA repair activity. Treatment of cells with glutathione ester after BSO resulted in complete recovery of DNA repair activity or partial recovery if aphidicolin was present. The significance of these results to the chemosensitizing effects of BSO medicated glutathione reduction is discussed.
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PMID:Effect of glutathione on DNA repair in cisplatin-resistant human ovarian cancer cell lines. 249 24

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

A human ovarian cancer cell line, A2780, derived from an untreated ovarian cancer patient and relatively sensitive to cisplatin was treated by stepwise incubation with cisplatin to produce a cisplatin-resistant variant, 2780CP. The relative abilities of these cell lines to repair cisplatin-induced damage to cellular DNA then was examined by measure of [3H]thymidine incorporation into normal density DNA separated from bromodeoxyuridine-substituted DNA on alkaline cesium chloride gradients. These studies revealed that primary cisplatin resistance present in 2780CP was associated with a near twofold-increased ability to repair damage induced by the drug under conditions where 2780CP was approximately 5-fold resistant to cisplatin. Aphidicolin, a specific inhibitor of DNA polymerase alpha, showed a dose-dependent capacity to inhibit DNA repair in this system with maximum inhibition of 63% at 4 micrograms/ml. It was also found that inhibition of DNA repair during and shortly after cisplatin exposure resulted in an approximately threefold increase in the cytotoxicity of cisplatin as monitored by clonogenic cell survival in the resistant but not the sensitive parental cell line.
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PMID:Increased DNA repair as a mechanism of acquired resistance to cis-diamminedichloroplatinum (II) in human ovarian cancer cell lines. 313 81

Proliferating cells, independent of their position in the cell cycle, contain a primer-dependent alpha-DNA polymerase (PDP); we have, therefore, tested the feasibility of the PDP assay in breast, ovarian, and head and neck tumors. Experimental results demonstrate that the PDP labeling index (PDP-LI) is constantly superior to the thymidine labeling index (TLI), which indicates the percentage of S phase cells. The PDP-LI/TLI ratios observed were 5.0 in breast cancer, 3.6 in ovarian cancer, and 2.5 in head and neck tumors. Higher PDP-LI scores have been obtained in metastatic breast tumor samples (PDP-LI = 8.8) compared to nonmetastatic tumors (PDP-LI = 4.9).
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PMID:Proliferative activity of human solid tumors evaluated by thymidine labeling index and primer-dependent alpha-DNA polymerase. 380 72

Aphidicolin, an inhibitor of DNA polymerases alpha and delta, is cytotoxic in vitro against tumor cells. The poor solubility of aphidicolin has led to the development of aphidicolin glycinate (AG; NSC 303812), a water soluble ester currently in early clinical trials. The antitumor activity of AG was investigated in a series of transplantable murine tumors in vivo. The drug demonstrated activity against the i.p. implanted B16 melanoma, producing maximum increased life spans of 75% following i.p. administration every 3 h for three doses on days 1-9. Treatment schedules involving both single injections per day on days 1-9 and multiple injections per day on days 1, 5, and 9 were less effective, indicating that this antitumor activity is schedule dependent. Similarly, greater activity was observed against the i.p. M5076 sarcoma when three daily injections were given on days 1-9 (57% increased life span) than with a single injection either on days 1-9 (36% increased life span) or on days 1, 5, 9, and 13 (inactive). Further scheduling studies in the s.c. M5076 sarcoma model showed that a 7-day infusion was superior to both a 24-h infusion and a 7-day course of three bolus treatments per day. On the assumption that DNA polymerase inhibition is the basis for this antitumor activity, inhibition of DNA synthesis in BALB/c x DBA/2 F1 mice was investigated by measuring incorporation of [3H]thymidine (20 microCi, i.v.) into DNA of spleen and jejunum. At 2 h after administration of AG, inhibition of DNA synthesis was dose dependent (median inhibitory dose, 60 mg/kg in both tissues) and was > 99% at 300 mg/kg. The inhibition was rapid in onset; AG (100 mg/kg i.p.) produced maximal (> 98%) inhibition in both tissues at 30 min. Recovery occurred in the intestine within 16 h; in spleen recovery was delayed to 24 h, and was followed by a rebound incorporation at 48 h (203%). A comparison of the inhibition of thymidine incorporation in tumor cells (B16 melanoma and P388 leukemia) and normal jejunum revealed no significant differences in the extent of inhibition or the rapidity of recovery in these tissues. The rapid recovery of DNA synthesis inhibition supports the use of prolonged infusion schedules in clinical trials, but the lack of evidence of selectivity for tumor cells suggests that AG may be of limited therapeutic value as a single agent. Thus, we evaluated AG in combination with cisplatin in an in vivo model of cisplatin refractory human ovarian cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antitumor activity and biochemical effects of aphidicolin glycinate (NSC 303812) alone and in combination with cisplatin in vivo. 830 34

The reliability of the competitive polymerase chain reaction (competitive PCR) for the detection and quantitation of gene expression in small tumor samples was evaluated. DNA polymerase-beta gene expression was detected in human ovarian cancer cell lines displaying a different degree of cisplatin resistance. The level of DNA polymerase-beta cDNA in the resistant cell line was threefold that of the parental sensitive line. Our results indicate that competitive PCR is a reproducible and sensitive method to detect differences in gene expression in small samples and open the possibility of using this approach to detect DNA polymerase beta cDNA in small samples from clinical tumors.
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PMID:Detection of DNA polymerase-beta gene expression by competitive polymerase chain reaction in human ovarian carcinoma cells. 847 2

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of gemcitabine are reviewed. Gemcitabine is a deoxycytidine-analogue antimetabolite with activity against some solid tumors. Gemcitabine is phosphorylated intracellularly to difluorodeoxycytidine triphosphate, which terminates DNA-chain elongation and competitively inhibits DNA polymerase and ribonucleotide reductase. After i.v. administration, gemcitabine is rapidly distributed into total body water. The drug is deaminated in the plasma to inactive difluorodeoxyuridine; both gemcitabine and difluorodeoxyuridine are primarily renally eliminated. In clinical studies, gemcitabine reduced pain and improved function in patients with advanced pancreatic cancer. Gemcitabine has shown some activity against non-small-cell lung cancer, particularly when combined with cisplatin or ifosfamide. The agent has also shown modest activity against advanced ovarian and breast cancer. Adverse effects include dose-limiting myelosuppression, flu-like symptoms, nausea, vomiting, and rash. Gemcitabine has FDA-approved labeling for use in the treatment of locally advanced and metastatic pancreatic cancer. The recommended dosage for this indication is 1000 mg/m2 (as the hydrochloride salt) i.v. given over 30 minutes weekly for seven weeks, followed after one week of rest by 1000 mg/ m2 i.v. given over 30 minutes weekly for three weeks every four weeks. Gemcitabine palliates symptoms in patients with advanced or metastatic pancreatic cancer. More study is needed to determine gemcitabine's role in the treatment of non-small-cell lung cancer, ovarian cancer, and breast cancer.
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PMID:Gemcitabine: a cytidine analogue active against solid tumors. 911 4


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