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Peter Buhl Jensen – One of the best experts on this subject based on the ideXlab platform.

  • Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (Aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle.
    Biochemical pharmacology, 1996
    Co-Authors: Maxwell Sehested, Peter Buhl Jensen
    Abstract:

    Abstract The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme’s catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, it appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme’s binding to its DNA substrate as seen with intercalating drugs such as chloroquine and Aclarubicin; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCl nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and Aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the α and the β isoforms of topoisomerase II. In contrast to ICRF-187, Aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt- and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, Aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types: etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as Aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.

  • Postincubation with Aclarubicin reverses topoisomerase II mediated DNA cleavage, strand breaks, and cytotoxicity induced by VP-16
    Investigational New Drugs, 1994
    Co-Authors: Lone Nørgård Petersen, Peter Buhl Jensen, Boe Sandahl Sorensen, Svend Aage Engelholm, Mogens Spang-thomsen
    Abstract:

    In previous studies, we found that VP-16 (etoposide) induced cytotoxicity and protein-concealed strand break formation was prevented in a small cell lung cancer (SCLC) cell line, when the cells were incubated with Aclarubicin prior to treatment with VP-16. In the present work, we studied the effect of adding Aclarubicin to the cell suspension after VP-16. In a clonogenic assay, we found that the cytotoxicity induced by VP-16 in SCLC cells was inhibited when cells were postincubated with Aclarubicin. The addition of Aclarubicin at any time in relation to VP-16 was able to stop further cytotoxicity induced by the topoisomerase II (topo-II) targeting drug. Aclarubicin was also found to antagonize the cytotoxicity induced by VM-26 (teniposide), and m-AMSA. With the alkaline elution technique we found that postincubating the cells with Aclarubicin inhibited VP-16-induced DNA strand break formation. In an in vitro system with purified topo-II and naked DNA we likewise found, that postincubation with Aclarubicin prevented VP-16 induced cleavage. In the same in vitro system, also baseline cleavage induced by topo-II was inhibited when Aclarubicin was present. Importantly, Aclarubicin exerted the antagonism to topo-II targeting drugs both when administered prior to and after the topo-II targeting agents. Thus, our data suggest that sequential rather than simultaneous administration of Aclarubicin and topo-II targeting agents may be superior with respect to net-cytotoxicity. In conclusion, our results support the notion that Aclarubicin interferes with steps prior to the formation of the cleavable complex in the catalytic cycle of topo-II, and further that the antagonism of Aclarubicin on the effect of topo-II targeting drugs may be due to a decrease in the initial noncovalent binding of topo-II to DNA.

  • In vivo inhibition of etoposide-mediated apoptosis, toxicity, and antitumor effect by the topoisomerase II-uncoupling anthracycline Aclarubicin
    Cancer chemotherapy and pharmacology, 1994
    Co-Authors: Bente Holm, Peter Buhl Jensen, Maxwell Sehested, Heine H. Hansen
    Abstract:

    A number of clinically important drugs such as the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26), the anthracyclines daunorubicin and doxorubicin (Adriamycin), and the aminoacridine amsacrine exert their cytotoxic action by stabilizing the cleavable complex formed between DNA and the nuclear enzyme topoisomerase II. We have previously demonstrated in several in vitro assays that the anthracycline Aclarubicin (aclacinomycin A) inhibits cleavable-complex formation and thus antagonizes the action of drugs such as VP-16 and daunorubicin. The present study was performed to validate these in vitro data in an in vivo model. At nontoxic doses of 6 and 9 mg/kg, Aclarubicin yielded a marked increase in the survival of non-tumor-bearing mice given high doses of VP-16 (80–90 mg/kg) in six separate experiments. In therapy experiments on mice inoculated with Ehrlich ascites tumor cells, Aclarubicin given at 6 mg/kg roughly halved the increase in median life span induced by VP-16 at doses ranging from 22 to 33 mg/kg. An attempt to determine a more favorable combination of VP-16 and Aclarubicin by increasing VP-16 doses failed, as the two drugs were always less effective than VP-16 alone. The way in which VP-16-induced DNA strand breaks lead to cell death remains unknown. However, VP-16 has been reported to cause apoptosis (programmed cell death) in several cell lines. To ascertain whether the protection given by Aclarubicin could have a disruptive effect on the apoptotic process, we used the small intestine as an in vivo model. Whereas VP-16-induced apoptosis in crypt stem cells was detectable at a dose as low as 1.25 mg/kg, Aclarubicin given at up to 20 mg/kg did not cause apoptosis. Indeed, Aclarubicin caused a statistically significant reduction in the number of cells rendered apoptotic by VP-16. The present study thus confirms the previous in vitro experiments and indicates the value of including an in vivo model in a preclinical evaluation of drug combinations.

Boe Sandahl Sorensen – One of the best experts on this subject based on the ideXlab platform.

  • Postincubation with Aclarubicin reverses topoisomerase II mediated DNA cleavage, strand breaks, and cytotoxicity induced by VP-16
    Investigational New Drugs, 1994
    Co-Authors: Lone Nørgård Petersen, Peter Buhl Jensen, Boe Sandahl Sorensen, Svend Aage Engelholm, Mogens Spang-thomsen
    Abstract:

    In previous studies, we found that VP-16 (etoposide) induced cytotoxicity and protein-concealed strand break formation was prevented in a small cell lung cancer (SCLC) cell line, when the cells were incubated with Aclarubicin prior to treatment with VP-16. In the present work, we studied the effect of adding Aclarubicin to the cell suspension after VP-16. In a clonogenic assay, we found that the cytotoxicity induced by VP-16 in SCLC cells was inhibited when cells were postincubated with Aclarubicin. The addition of Aclarubicin at any time in relation to VP-16 was able to stop further cytotoxicity induced by the topoisomerase II (topo-II) targeting drug. Aclarubicin was also found to antagonize the cytotoxicity induced by VM-26 (teniposide), and m-AMSA. With the alkaline elution technique we found that postincubating the cells with Aclarubicin inhibited VP-16-induced DNA strand break formation. In an in vitro system with purified topo-II and naked DNA we likewise found, that postincubation with Aclarubicin prevented VP-16 induced cleavage. In the same in vitro system, also baseline cleavage induced by topo-II was inhibited when Aclarubicin was present. Importantly, Aclarubicin exerted the antagonism to topo-II targeting drugs both when administered prior to and after the topo-II targeting agents. Thus, our data suggest that sequential rather than simultaneous administration of Aclarubicin and topo-II targeting agents may be superior with respect to net-cytotoxicity. In conclusion, our results support the notion that Aclarubicin interferes with steps prior to the formation of the cleavable complex in the catalytic cycle of topo-II, and further that the antagonism of Aclarubicin on the effect of topo-II targeting drugs may be due to a decrease in the initial noncovalent binding of topo-II to DNA.

  • Antagonistic effect of Aclarubicin on camptothecin induced cytotoxicity: role of topoisomerase I.
    Biochemical pharmacology, 1994
    Co-Authors: Boe Sandahl Sorensen, Peter Buhl Jensen, Maxwell Sehested, Palle Jensen, Eigil Kjeldsen, Ole F. Nielsen, Jan Alsner
    Abstract:

    The cellular target of camptothecin and several of its derivatives has been identified as topoisomerase I. Central to the cytotoxic action of camptothecin is the drug’s ability to stimulate formation of topoisomerase I mediated DNA cleavages. Here we demonstrate that the intercalating antitumor agent Aclarubicin inhibits camptothecin induced DNA single strand breaks in cells as measured by alkaline elution. When purified topoisomerase I was reacted with DNA, Aclarubicin inhibited the formation of enzyme mediated DNA breaks induced by camptothecin. High Aclarubicin concentrations (10 and 100 microM) caused a slight stimulation of topoisomerase I mediated DNA cleavage at a few distinct DNA sites. The cytotoxicity associated with camptothecin treatment measured in clonogenic assays was antagonized by preincubation with Aclarubicin. This inhibitory effect of Aclarubicin upon camptothecin action holds implications for the scheduling of Aclarubicin in combination therapy with anticancer agents directed against topoisomerase I. Aclarubicin also inhibits the effect of topoisomerase II directed agents [such as etoposide (VP16), amsacrine (mAMSA), etc.] suggesting that Aclarubicin acts against the two topoisomerases.

  • Postincubation with Aclarubicin reverses topoisomerase II mediated DNA cleavage, strand breaks, and cytotoxicity induced by VP-16.
    Investigational new drugs, 1994
    Co-Authors: Lone Petersen, Boe Sandahl Sorensen, Peter Buhl Jensen, Svend Aage Engelholm, Mogens Spang-thomsen
    Abstract:

    In previous studies, we found that VP-16 (etoposide) induced cytotoxicity and protein-concealed strand break formation was prevented in a small cell lung cancer (SCLC) cell line, when the cells were incubated with Aclarubicin prior to treatment with VP-16. In the present work, we studied the effect of adding Aclarubicin to the cell suspension after VP-16. In a clonogenic assay, we found that the cytotoxicity induced by VP-16 in SCLC cells was inhibited when cells were postincubated with Aclarubicin. The addition of Aclarubicin at any time in relation to VP-16 was able to stop further cytotoxicity induced by the topoisomerase II (topo-II) targeting drug. Aclarubicin was also found to antagonize the cytotoxicity induced by VM-26 (teniposide), and m-AMSA. With the alkaline elution technique we found that postincubating the cells with Aclarubicin inhibited VP-16-induced DNA strand break formation. In an in vitro system with purified topo-II and naked DNA we likewise found, that postincubation with Aclarubicin prevented VP-16 induced cleavage. In the same in vitro system, also baseline cleavage induced by topo-II was inhibited when Aclarubicin was present. Importantly, Aclarubicin exerted the antagonism to topo-II targeting drugs both when administered prior to and after the topo-II targeting agents. Thus, our data suggest that sequential rather than simultaneous administration of Aclarubicin and topo-II targeting agents may be superior with respect to net-cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Heine H. Hansen – One of the best experts on this subject based on the ideXlab platform.

  • In vivo inhibition of etoposide-mediated apoptosis, toxicity, and antitumor effect by the topoisomerase II-uncoupling anthracycline Aclarubicin
    Cancer chemotherapy and pharmacology, 1994
    Co-Authors: Bente Holm, Peter Buhl Jensen, Maxwell Sehested, Heine H. Hansen
    Abstract:

    A number of clinically important drugs such as the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26), the anthracyclines daunorubicin and doxorubicin (Adriamycin), and the aminoacridine amsacrine exert their cytotoxic action by stabilizing the cleavable complex formed between DNA and the nuclear enzyme topoisomerase II. We have previously demonstrated in several in vitro assays that the anthracycline Aclarubicin (aclacinomycin A) inhibits cleavable-complex formation and thus antagonizes the action of drugs such as VP-16 and daunorubicin. The present study was performed to validate these in vitro data in an in vivo model. At nontoxic doses of 6 and 9 mg/kg, Aclarubicin yielded a marked increase in the survival of non-tumor-bearing mice given high doses of VP-16 (80–90 mg/kg) in six separate experiments. In therapy experiments on mice inoculated with Ehrlich ascites tumor cells, Aclarubicin given at 6 mg/kg roughly halved the increase in median life span induced by VP-16 at doses ranging from 22 to 33 mg/kg. An attempt to determine a more favorable combination of VP-16 and Aclarubicin by increasing VP-16 doses failed, as the two drugs were always less effective than VP-16 alone. The way in which VP-16-induced DNA strand breaks lead to cell death remains unknown. However, VP-16 has been reported to cause apoptosis (programmed cell death) in several cell lines. To ascertain whether the protection given by Aclarubicin could have a disruptive effect on the apoptotic process, we used the small intestine as an in vivo model. Whereas VP-16-induced apoptosis in crypt stem cells was detectable at a dose as low as 1.25 mg/kg, Aclarubicin given at up to 20 mg/kg did not cause apoptosis. Indeed, Aclarubicin caused a statistically significant reduction in the number of cells rendered apoptotic by VP-16. The present study thus confirms the previous in vitro experiments and indicates the value of including an in vivo model in a preclinical evaluation of drug combinations.

  • Antagonistic effect of Aclarubicin on daunorubicin-induced cytotoxicity in human small cell lung cancer cells: relationship to DNA integrity and topoisomerase II.
    Cancer research, 1991
    Co-Authors: Peter Buhl Jensen, Boe Sandahl Sorensen, Maxwell Sehested, Palle Jensen, Erland J. F. Demant, Ellen Friche, Karsten Wassermann, Lars Vindeløv, Ole Westergaard, Heine H. Hansen
    Abstract:

    The effect of combinations of the anthracyclines Aclarubicin and daunorubicin was investigated in a clonogenic assay using the human small cell lung cancer cell line OC-NYH and a multidrug-resistant (MDR) murine subline of Ehrlich ascites tumor (EHR2/DNR+). It was found that the cytotoxicity of daunorubicin in OC-NYH cells was antagonized by simultaneous exposure to nontoxic concentrations of Aclarubicin. Coordinately, Aclarubicin inhibited the formation of daunorubicin-induced protein-concealed DNA single-strand breaks and DNA-protein cross-links in OC-NYH cells when assayed by the alkaline elution technique. Aclarubicin had no influence on the accumulation of daunorubicin in these cells. In contrast, the accumulation of daunorubicin in EHR2/DNR+ cells was enhanced by more than 300% when the cells were simultaneously incubated with the MDR modulator verapamil, Aclarubicin, or the two agents combined. Yet the cytotoxicity of daunorubicin was potentiated significantly only by verapamil. The increased cytotoxicity of daunorubicin in the presence of verapamil was completely antagonized when Aclarubicin was used together with the MDR modulator. Finally, the effect of daunorubicin on the DNA cleavage activity of purified topoisomerase II in the presence and absence of Aclarubicin was examined. It was found that daunorubicin stimulated DNA cleavage by topoisomerase II at specific DNA sites. The addition of Aclarubicin completely inhibited the daunorubicin-induced stimulation of DNA cleavage. Taken together, these data indicate that Aclarubicin-mediated inhibition of daunorubicin-induced cytotoxicity is due mainly to a drug interaction with the nuclear enzyme topoisomerase II. This antagonism at the nuclear level explains why Aclarubicin is a poor modulator of daunorubicin resistance even though Aclarubicin is able to increase the intracellular accumulation of daunorubicin in a MDR cell line.