PubMed · 5575813
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
P Cappelaere, L Adenis, B Vankemmel. 1971. [Bleomycin in antineoplastic chemotherapy].. https://pubmed.ncbi.nlm.nih.gov/5575813/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Conjugation of an anthracycline to a triplex-forming oligonucleotide (TFO) allows delivery of this drug to a specific DNA site, preserving the intercalation geometry of this class of anticancer agents. Conjugate 11, in which the TFO is linked via a hexamethylene bridge to the O-4 on the D ring of the anthraquinone moiety, affords the most stable triple helix, through intercalation of the planar chromophore between DNA bases and binding of both the TFO and the amino sugar to the major and the minor groove respectively.
The application of detailed structural data bases has now culminated in the successful design of a new generation of bisanthracyclines that form ultratight DNA complexes [Chaires, J. B., Leng, F., Przewloka, T., Fokt, I., Ling, Y. H., Perez-Soler, R., & Priebe, W. (1997) J. Med. Chem. 40, 261-266]. Daunomycin dimers were designed to bind to DNA in complexes resembling those of monomers intercalated at adjacent sites. The goal of the work described here was to determine, with X-ray crystallography, if a potent member of this newly designed and synthesized class of bisanthracyclines (WP631) binds as intended. WP631 is composed of two daunomycin molecules, linked N3' to N3' by a xylyl group. We have solved the 2.2 A X-ray crystal structure of a complex of WP631 bound to [d(CGATCG)]2. We demonstrate, on a detailed molecular level, that the WP631 design strategy is a success. The structures of WP631 and two daunomycin molecules bound to [d(CGATCG)]2 provide the unprecedented opportunity for detailed comparison of mono- and bis-intercalated complexes of the same chromophore, allowing us to distinguish effects of mono-intercalation from those of bis-intercalation. Differences are focused primarily in the centers of the complexes. DNA unwinding and other helical distortions propagate more efficiently to the center of the WP631 complex than to the center of the daunomycin complex.
The anthracycline antibiotic, daunorubicin, can induce programmed cell death (apoptosis) in cells. Recent work suggests that this event is mediated by ceramide via enhanced ceramide synthase activity. Since the generation of ceramide has been directly linked with the activation of the transcription factor, NFkappaB, this was investigated as a novel target for the action of daunorubicin. Here we describe how treatment of HL-60 promyelocytes and Jurkat T lymphoma cells with daunorubicin results in the activation of the transcription factor NFkappaB. The effect of daunorubicin was evident following 1-2 h treatment, which was in contrast to the time course of activation obtained with the cytokine, tumor necrosis factor, where NFkappaB activation was detected within minutes of cellular stimulation. Activated complexes were shown to contain predominantly p50 and p65/RelA subunit components. Daunorubicin also induced IkappaB degradation and increased the expression of an NFkappaB-linked reporter gene. In addition, the drug was found to strongly potentiate the ability of tumor necrosis factor to induce an NFkappaB-linked reporter gene, suggesting a synergy between these two agents in this response. These events were sensitive to the iron chelator, deferoxamine mesylate (desferal), and the anti-oxidant and metal chelator pyrrolidine dithiocarbamate. A structurally related compound, mitoxantrone, which, unlike daunorubicin, is unable to undergo redox cycling in cells, also activated NFkappaB in a pyrrolidine dithiocarbamate-sensitive manner. A specific inhibitor of ceramide synthase, fumonisin B1, had no effect on daunorubicin induced NFkappaB activation at a range of concentrations previously reported to block apoptosis induced by this drug. However, this agent could inhibit increases in ceramide induced by daunorubicin, in addition to blocking ceramide synthase activity from HL-60 cells which was activated in response to daunorubicin treatment. These data therefore suggest that the effect of daunorubicin on NFkappaB is unlikely to involve ceramide, but may involve reactive oxygen species generated as a result of endogenous cellular processes rather than reductive metabolism of the drug. As NFkappaB may be involved in apoptosis, this effect may be an important aspect of the cellular responses to this agent.