Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Probucol [(4,4'-(-(isopropylidenedithio) bis (2,6-di-t-butylphenol)], a hypolipidemic drug, was evaluated for its effects on the clastogenic activity of ADM in Swiss albino mice. Male mice were treated i.p. with different doses (25, 50 and 100 mg/kg, body weight/day) of probucol for 7 days. Some of the mice in each dose group of probucol and those in the positive control group were injected i.p. with Adriamycin (ADM, 8 mg/kg, body weight) and killed after 24 hr. Femoral cells of mice were collected and studied for the frequency of micronuclei and the ratio of polychromatic erythrocytes to Normochromatic erythrocytes. Furthermore, proteins, DNA, RNA, Malondialdehyde (MDA) and non-protein sulfhydryl (NP-SH) levels were determined in the hepatic cells. Probucol treatment failed to induce any significant clastogenic, cytotoxic and biochemical changes. However, pre-treatment with probucol was found to reduce the ADM-induced micronuclei without any alteration in its cytotoxicity. The DNA, RNA, proteins and NP-SH levels in the hepatic cells of these animals were increased and the MDA concentrations were reduced. The inhibition of ADM-induced clastogenicity by probucol may be attributed to its lipids lowering, iron chelating, free radical scavenging and topoisomerase-II-depleting action.
 ...
PMID:Effect of probucol on the cytological and biochemical changes induced by adriamycin in Swiss albino mice. 902 75

We have established an Adriamycin (ADM)-resistant small cell lung cancer (SCLC) cell line, SBC-3/ADM 100, which shows multifactorial mechanisms of resistance to ADM, such as over-expression of P-glycoprotein, an enhanced detoxifying system and a decrease in topoisomerase II activity. In the present study, we confirmed that SBC-3/ADM 100 showed collateral sensitivity to methotrexate and TNP-351, a new antifolate, though this cell line showed a typical multidrug resistance (MDR) pattern. We also demonstrated a faster uptake and higher accumulation (1.3-fold) of TNP-351 in the SBC-3/ADM 100 cells than those in the parent SBC-3 cells. These results explain one of the mechanisms for collateral sensitivity in the resistant cells. Furthermore, this cell line was found to have no cross-resistance to edatrexate and minimal cross-resistance to trimetrexate, 254-S (cisplatin analog), 5-fluorouacil and 4-hydroperoxyifosfamide. These drugs will have clinical importance in patients with SCLC who were previously treated with an ADM-containing regimen. Thus, antifolates, especially TNP-351 and edatrexate, can be expected to eradicate residual multidrug resistant SCLC cells selected by ADM.
 ...
PMID:Growth inhibitory effects of antifolates against an adriamycin-resistant human small cell lung cancer cell line. 922 90

We examined the genetic and biochemical bases for drug resistance and the order of appearance of different mechanisms underlying the increasingly more resistant murine erythroleukemia cell lines established in Adriamycin (ADR). In the first-step low-level resistant cell line PC4-A5 (able to grow in 5 ng/mL ADR), there was a 2-fold reduction in topoisomerase IIalpha and topoisomerase IIbeta mRNA levels, as well as topoisomerase IIalpha protein and activity levels as compared with the parental cell line. The topoisomerase IIalpha activity levels remained reduced as the cells became increasingly more resistant. In contrast, the topoisomerase II mRNA and protein levels returned to approximately the parental levels in resistant cells growing in higher drug concentrations (40-160 ng/mL). Parental cells expressed the multidrug resistance protein (MRP), but beginning with PC4-A5 MRP expression decreased and remained reduced in increasingly resistant cell lines. At high levels of ADR resistance, the cells expressed the mdr3 gene concomitant with the appearance of vincristine resistance and energy-dependent daunomycin and vincristine efflux. Glutathione levels, internal pH, and expression of the major vault protein (MVP) remained unchanged in all cell lines. Fluorescence microscopy revealed no alterations in daunomycin distribution or vesicle numbers between the parental and resistant cell lines. Different resistance mechanisms emerge sequentially as cells become more resistant to ADR; the mechanisms are retained during the development of multidrug resistance (MDR). In intermediate-level MDR cell lines (PC4-A10 and PC4-A20), resistance involves an as yet undetermined mechanism(s).
 ...
PMID:Emergence of different mechanisms of resistance in the evolution of multidrug resistance in murine erythroleukemia cell lines. 939 72

N-benzyladriamycin-14-valerate (AD 198) is pharmacologically superior to Adriamycin (ADR) based upon comparable cytotoxicity, decreased cardiotoxicity and the ability of AD 198 to circumvent multidrug resistance conferred by either P-glycoprotein overexpression or reduced topoisomerase II activity. AD 198, however, suffers from systemic lability of the 14-O-valerate moiety to enzymatic and non-enzymatic cleavage to yield N-benzyladriamycin (AD 288), which is more similar to ADR in activity. The purpose of this study was to determine whether stability of the ester linkage could be achieved while preserving the favorable characteristics of AD 198 by using a series of N-benzylated ADR congeners containing 14-O-acyl substitutions of incrementally shorter carbon chain lengths. Results from this study indicate that the linear five-carbon valerate substitution is the minimum length necessary to circumvent P-glycoprotein and prevent inhibition of topoisomerase II activity. In addition, although AD 198 is not a pro-drug of AD 288, intracellular 14-O-acyl cleavage appears to contribute to the cytotoxicity of AD 198.
 ...
PMID:Cytotoxicity and intracellular biotransformation of N-benzyladriamycin-14-valerate (AD 198) are modulated by changes in 14-O-acyl chain length. 949 93

Previous studies have demonstrated decreased levels of DNA topoisomerase II alpha protein and messenger RNA in the Adriamycin-resistant P388 murine leukemia cell line P388/ADR/7 compared to the sensitive P388/4 cell line. An allelic fusion event involving the topoisomerase II alpha and the retinoic acid receptor a genes has been identified in these cells that probably contributes to the decreased topoisomerase II activity in P388/ADR/7 cells. However, this allelic mutation may be a minor contributor or even incidental to the resistance phenotype, since these cells display other candidate mechanisms of resistance, including increased P-glycoprotein, increased glutathione-S-transferase activity and an increased onset of DNA repair. To establish a role for topoisomerase II alpha in mediating the Adriamycin resistance phenotype, complementation of the mutant allele was attempted by transfecting the murine P388/ADR/7 cells with a human topoisomerase II alpha expression construct under the control of the human metallothionein IIA promoter. The majority of transfected cell lines that were obtained by selection in hygromycin B contained copies of the integrated expression construct that were rearranged. Only two of thirty-two transfected cell lines were found to contain a single, unrearranged copy of the human topoisomerase II alpha cDNA. P388/ADR/7 cell lines carrying an integrated, intact human topoisomerase II alpha expression vector were more sensitive to Adriamycin, daunorubicin, mitoxantrone, and etoposide, but not to actinomycin D and vincristine compared to control cells transfected with vector alone or cell lines with rearranged topoisomerase II alpha expression constructs. These findings suggest that topoisomerase II alpha is a selective and significant contributor to multifactorial resistance.
 ...
PMID:Selective sensitization of adriamycin-resistant P388 murine leukemia cells to antineoplastic agents following transfection with human DNA topoisomerase II alpha. 949 16

A human stomach-adenocarcinoma cell line (MKN-45) was selected for resistance to Adriamycin by stepwise exposure to increasing concentrations of this agent. The resulting cell line (MKN/ADR) exhibited a high level of cross-resistance to topoisomerase II (topo II)-targeted drugs such as Adriamycin, mitoxantrone, and etoposide but showed no cross-resistance to other chemotherapeutic agents such as cisplatin, carboplatin, 5-fluorouracil, or mitomycin-C. P-glycoprotein encoded by the mdr-1 gene was not overexpressed in the MKN/ADR cell line. The doubling time of the MKN/ADR cell line (2.1 days) increased only slightly as compared with that of the MKN cell line (1.7 days). The patterns of cross-resistance to various chemotherapeutic agents led us to examine the cellular contents of topo II in both the drug-sensitive and the drug-resistant cells. Extractable topo II enzyme activity was 3-fold lower in MKN/ADR cells as compared with the parental MKN cells. Levels of topoisomerase I (topo I) catalytic activity were similar in both wild-type MKN and drug-resistant MKN/ADR cells. Southern-blot analysis of genomic DNA probed with topo IIalpha or IIbeta showed no sign of either gene rearrangement or hypermethylation. Northern-blot analysis revealed that both topo IIalpha and topo IIbeta mRNA transcripts were essentially identical in the MKN and MKN/ADR cells. In contrast, Western-blot analysis revealed an approximately 20-fold lower level of topo IIalpha in drug-resistant cells as compared with drug-sensitive cells, whereas topo IIbeta levels were similar in both lines. Moreover, the amount of in vivo topo IIalpha-DNA covalent complexes formed in the presence of etoposide was also approximately 20-fold lower in drug-resistant cells. No mutation was detected in the promoter region of the topo IIalpha gene in resistant cells as compared with sensitive cells. Thus, low levels of topo IIalpha polypeptide cannot be ascribed to changes in the mRNA levels. Collectively, the data suggest that a quantitative reduction in topo IIalpha may contribute to the resistance of MKN cells to Adriamycin and other topo II-targeted drugs.
 ...
PMID:Reduced activity of topoisomerase II in an Adriamycin-resistant human stomach-adenocarcinoma cell line. 952 30

HER2 (erbB-2) proto-oncogene amplification and/or overexpression correlate with poor prognosis in many malignancies. The precise biological role of this oncogenic signaling pathway (which also involves the HER4 gene) in breast cancer is unclear. One property conferred by this oncogene relates to response to drug therapy. Clinical studies support an association between HER2 overexpression and resistance to alkylating agents (cisplatinum and cyclophosphamide). Data from the Cancer and Leukemia Group B 8869/8541 study indicate enhanced dose responsiveness to doxorubicin (Adriamycin) in patients who overexpress the HER2 receptor. Heregulin beta-2, a naturally occurring ligand that activates the HER2 receptor by inducing its heterodimerization with the HER4 receptor, has recently been cloned. The ability of this ligand to phosphorylate the HER2 receptor exogenously allows us to study the effect of HER2 activation on cancer cell behavior. To study the relationship between chemotherapy response and activation of HER2, MCF-7 cells expressing biologically active heregulin were assessed for response to doxorubicin and etoposide, both of which are topoisomerase IIalpha (topo IIalpha) inhibitors. Several clones show markedly increased sensitivity to these drugs. In addition, the same wild-type MCF-7 cells transfected with heregulin beta-2 under the control of an inducible promoter also show this dose-response relationship to doxorubicin after the expression of heregulin beta-2 is activated by zinc. The modulation of topo IIalpha was studied in the cell lines transfected with heregulin. topo IIalpha mRNA and protein (total protein and enzymatic decatenating activity) were found to be up-regulated in heregulin beta-2-transfected cells. Moreover, topo IIalpha promoter activity was also modestly increased in heregulin beta-2-transfected cells. Because up-regulation of topo IIalpha in vitro and in clinical specimens is associated with increased response to doxorubicin (presumptively by an increase in drug substrate), this may be the mechanism of the increased sensitivity to doxorubicin seen in heregulin beta-2-transfected cells. This implies that activation of HER2 or one of the other members of the receptor family may increase sensitivity to doxorubicin by up-regulation of topo IIalpha. This finding suggests the use of receptor/ligand expression to direct patient-specific therapeutic choices (e.g., doxorubicin versus alkylator-based regimens) and the use of biological agents (such as heregulin) in combination with certain chemotherapeutic agents to enhance response to treatment in breast cancer patients.
 ...
PMID:Induction of sensitivity to doxorubicin and etoposide by transfection of MCF-7 breast cancer cells with heregulin beta-2. 956 96

A cisplatin-resistant cell line, SBC-3/CDDP, was established from a human small-cell lung cancer cell line, SBC-3. The SBC-3/CDDP cells were 13.1-fold more resistant to cisplatin than the parent SBC-3 cells. We investigated the cellular changes of this cell line with regard to the development of resistance to cisplatin. The SBC-3/CDDP cells showed various characteristics as follows: a) increased intracellular glutathione and glutathione S-transferase content b) decreased intracellular accumulation of cisplatin, c) increased topoisomerase I activity and the same topoisomerase II activity as the parent SBC-3 cells, and 4) strong cross-resistance to the platinum analogues and mitomycin C, moderate cross-resistance to 7-ethyl-10-hydroxy-camptothecin (SN-38), 4-hydroperoxy cyclophosphamide, etoposide, Adriamycin and methotrexate, and collateral sensitivity to vinca alkaloids and 5-fluorouracil. From these observations, the SBC-3/CDDP cells could be useful as a well characterized cisplatin-resistant cell line, and the resistance pattem in this cell line will give us much information for eradication of cisplatin-resistant tumor cells.
 ...
PMID:Cisplatin-resistant human small cell lung cancer cell line shows collateral sensitivity to vinca alkaloids. 961 43

Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to the development of breast cancer, ovarian cancer, and other malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may function in the sensing and/or repair of DNA damage. To investigate this possibility, we determined the effects of various DNA-damaging agents and other cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other human breast cancer cell lines. We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin (a topoisomerase I inhibitor), and ultraviolet radiation induced significant decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 mRNAs were observed within 6-12 h after treatment with adriamycin and persisted for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; but these decreases required several days. U.V. radiation induced dose-dependent down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed at doses that yielded relatively little cytotoxicity and little or no apoptotic DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and time-dependent alterations in the cell cycle distribution; but these alterations did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels was correlated with p53 functional status. MCF-7 cells transfected with a dominant negative mutant p53 (143 val-->ala) required at least tenfold higher doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental MCF-7 cells or control-transfected MCF-7 clones. These results suggest that BRCA1 and BRCA2 may play roles in the cellular response to DNA-damaging agents and that there may be a p53-sensitive component to the regulation of BRCA1 and BRCA2 mRNA expression.
 ...
PMID:Regulation of BRCA1 and BRCA2 expression in human breast cancer cells by DNA-damaging agents. 961 32

The mechanisms responsible for the antiproliferative and cytotoxic effects of the anthracycline antibiotics doxorubicin (Adriamycin) and daunorubicin (daunomycin) have been the subject of considerable controversy. This commentary addresses the potential role of DNA synthesis inhibition, free radical formation and lipid peroxidation, DNA binding and alkylation, DNA cross-linking, interference with DNA strand separation and helicase activity, direct membrane effects, and the initiation of DNA damage via the inhibition of topoisomerase II in the interaction of these drugs with the tumor cell. One premise underlying this analysis is that only studies utilizing drug concentrations that reflect the plasma levels in the patient after either bolus administration or continuous infusion are considered to reflect the basis for drug action in the clinic. The role of free radicals in anthracycline cardiotoxicity is also discussed.
 ...
PMID:A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. 1007 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>