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The Journal of Antibiotics Jun 1985This report defines the transformations that antitumor antibiotic CC-1065 underwent under basic and acidic conditions. The isolation, purification, characterization, and...
This report defines the transformations that antitumor antibiotic CC-1065 underwent under basic and acidic conditions. The isolation, purification, characterization, and biological properties of a cyclopropapyrroloindole fragment, and an acidic fragment, PDE-I dimer, from a mild alkaline fragmentation and the phenolic product, AAP, resulting from alkylation of acetic acid by the cyclopropyl function are described.
Topics: Antibiotics, Antineoplastic; Circular Dichroism; Duocarmycins; Indoles; Leucomycins; Magnetic Resonance Spectroscopy
PubMed: 4019318
DOI: 10.7164/antibiotics.38.746 -
Journal of Controlled Release :... Jul 2017Injectable drug delivery systems that autonomously detect, propel towards, and ultimately treat the cancerous tissue, are the future of targeted medicine. Here, we...
Injectable drug delivery systems that autonomously detect, propel towards, and ultimately treat the cancerous tissue, are the future of targeted medicine. Here, we developed a drug delivery system that swims autonomously towards cancer cells, where it releases a therapeutic cargo. This platform is based on viable bacteria, loaded with nanoparticles that contain the chemotherapeutic-antibiotic drug doxorubicin. The bacteria ferry across media and invade the cancer cells, increasing their velocity in the presence of nutrients that are present within the tumor microenvironment. Inside the cancer cells, doxorubicin is released from the nanoparticles, destroying the bacterial swimmer (antibiotic activity) and executing the therapeutic activity against the cancer cells (chemotherapeutic activity). This mode of delivery, where both the carrier and the cancer cell are destroyed, supports implementing nanoswimmers in drug delivery (Fig. 1).
Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Delivery Systems; Escherichia coli; Liposomes; Mice; Neoplasms; Salmonella typhimurium
PubMed: 27744036
DOI: 10.1016/j.jconrel.2016.10.006 -
Disease Markers 2015High recurrence rate is one representative characteristic of bladder cancer. Intravesical therapy after transurethral resection is often performed in patients with... (Review)
Review
High recurrence rate is one representative characteristic of bladder cancer. Intravesical therapy after transurethral resection is often performed in patients with nonmuscle invasive bladder cancer (NMIBC) to prevent recurrence. Bacillus Calmette-Guérin (BCG) and several anticancer/antibiotic agents, such as mitomycin C and epirubicin, are commonly used for this therapy. BCG treatment demonstrates strong anticancer effects. However, it is also characterized by a high frequency of adverse events. On the other hand, although intravesical therapies using other anticancer and antibiotic agents are relatively safe, their anticancer effects are lower than those obtained using BCG. Thus, the appropriate selection of agents for intravesical therapy is important to improve treatment outcomes and maintain the quality of life of patients with NMIBC. In this review, we discuss the predictive value of various histological and molecular markers for recurrence after intravesical therapy in patients with NMIBC.
Topics: Administration, Intravesical; Antibiotics, Antineoplastic; Apoptosis; Biomarkers, Tumor; Humans; Recurrence; Urinary Bladder Neoplasms
PubMed: 26681820
DOI: 10.1155/2015/857416 -
Proceedings of the National Academy of... Jul 1993Ever since the initial reports of the enediyne anticancer antibiotics in the late 1980s, researchers from a number of disciplines have been devoting increasing attention... (Review)
Review
Ever since the initial reports of the enediyne anticancer antibiotics in the late 1980s, researchers from a number of disciplines have been devoting increasing attention to their chemistry, biology, and potential medical applications. Synthetic chemists and molecular designers have been engaged in attempts to synthesize these molecules and to model their unique architecture. Considerable efforts have been directed at understanding and mimicking the various processes involved in the targeting, activation, and DNA cleavage associated with these natural products. This review summarizes the main contributions to the field, with particular emphasis on work from our laboratories. Highlights include studies of the Bergman reaction, which is central to the mechanism of action of enediynes, the design and chemical synthesis of a number of these systems, and biological studies with selected molecules. Finally, the total synthesis of calicheamicin gamma 1I, the most prominent member of this class of naturally occurring compounds, is discussed.
Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Cell Line; Drug Delivery Systems; Drug Design; Enediynes; Humans; Models, Molecular; Tumor Cells, Cultured
PubMed: 8327459
DOI: 10.1073/pnas.90.13.5881 -
The Journal of Antibiotics Apr 2019Lactacystin exemplifies the role that serendipity plays in drug discovery and why "finding things without actually looking for them" retains such a pivotal role in the... (Review)
Review
Lactacystin exemplifies the role that serendipity plays in drug discovery and why "finding things without actually looking for them" retains such a pivotal role in the search for the useful properties of chemicals. The first proteasome inhibitor discovered, lactacystin stimulated new possibilities in cancer control. New and innovative uses are regularly being found for lactacystin, including as a model to study dementia, while new formulations and delivery systems may facilitate its use clinically as an anticancer agent. All this provides yet more evidence that we need a comprehensive, collaborative and coordinated programme to fully investigate all new and existing chemical compounds, especially those of microbial origin. We need to do so in order to avoid failing to detect and successfully exploit unsought yet potentially life-saving or extremely advantageous properties of microbial metabolites.
Topics: Acetylcysteine; Antibiotics, Antineoplastic; Biological Products; Dementia; Drug Discovery; Humans; Neoplasms; Neuroprotective Agents; Proteasome Inhibitors
PubMed: 30755736
DOI: 10.1038/s41429-019-0141-8 -
Technology in Cancer Research &... Dec 2008Anthracycline antibiotics are among the most effective and commonly used anticancer drugs. Unfortunately, their clinical use is restricted by dose-dependent toxicity.... (Review)
Review
Anthracycline antibiotics are among the most effective and commonly used anticancer drugs. Unfortunately, their clinical use is restricted by dose-dependent toxicity. Doxorubicin is an anthracycline antibiotic and cytotoxic (antineoplastic) agent. It is commonly used against ovarian, breast, lung, uterine and cervical cancers, Hodgkin's disease, soft tissue and primary bone sarcomas, as well against in several other cancer types. It has been shown that free radicals are involved in doxorubicin-induced toxicity. Doxorubicin causes the generation of free radicals and the induction of oxidative stress, associated with cellular injury. This review illustrates recent applications of different natural products, drugs, drug delivery systems, and approaches for protection against doxorubicin-induced toxicity (2006-present).
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antioxidants; Doxorubicin; Drug Delivery Systems; Free Radicals; Humans; Liposomes; Nanoparticles; Neoplasms; Oxidative Stress
PubMed: 19044329
DOI: 10.1177/153303460800700611 -
Applied Microbiology and Biotechnology Jun 2019The antitumor antibiotic pactamycin is a highly substituted aminocyclopentitol-derived secondary metabolite produced by the soil bacterium Streptomyces pactum. It has... (Review)
Review
The antitumor antibiotic pactamycin is a highly substituted aminocyclopentitol-derived secondary metabolite produced by the soil bacterium Streptomyces pactum. It has exhibited potent antibacterial, antitumor, antiviral, and antiprotozoal activities. Despite its outstanding biological activities, the complex chemical structure and broad-spectrum toxicity have hampered its development as a therapeutic, limiting its contribution to biomedical science to a role as a molecular probe for ribosomal function. However, a detailed understanding of its biosynthesis and how the biosynthesis is regulated has made it possible to tactically design and produce new pactamycin analogues, some of which have shown improved pharmacological properties. This mini-review describes the biosynthesis, regulation, engineered production, and biological activities of pactamycin and its congeners. It also highlights the suitability of biosynthetic methods as a feasible approach to generate new analogues of complex natural products and underscores the importance of utilizing biosynthetic enzymes as tools for chemoenzymatic production of structurally diverse bioactive compounds.
Topics: Anti-Infective Agents; Antibiotics, Antineoplastic; Biosynthetic Pathways; Gene Expression Regulation, Bacterial; Metabolic Engineering; Pactamycin; Streptomyces
PubMed: 31025074
DOI: 10.1007/s00253-019-09831-x -
Journal of Inorganic Biochemistry Mar 2016The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung...
The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me(2+))-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM=MTM SDK>MTM SA-Trp>MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents.
Topics: Antibiotics, Antineoplastic; DNA; Dimerization; Plicamycin
PubMed: 26760230
DOI: 10.1016/j.jinorgbio.2015.12.011 -
Current Topics in Medicinal Chemistry 2008The enediyne polyketides are secondary metabolites isolated from a variety of Actinomycetes. All members share very potent anticancer and antibiotic activity, and... (Review)
Review
The enediyne polyketides are secondary metabolites isolated from a variety of Actinomycetes. All members share very potent anticancer and antibiotic activity, and prospects for the clinical application of the enediynes has been validated with the recent marketing of two enediyne derivatives as anticancer agents. The biosynthesis of these compounds is of interest because of the numerous structural features that are unique to the enediyne family. The gene cluster for five enediynes has now been cloned and sequenced, providing the foundation to understand natures' means to biosynthesize such complex, exotic molecules. Presented here is a review of the current progress in delineating the biosynthesis of the enediynes with an emphasis on the model enediyne, C-1027.
Topics: Actinobacteria; Antibiotics, Antineoplastic; Enediynes; Multigene Family; Polyketide Synthases
PubMed: 18397168
DOI: 10.2174/156802608783955656 -
The Journal of Antibiotics Apr 1979A new antitumor antibiotic, named auromomycin, was isolated from the culture broth of Streptomyces macromomyceticus, a macromomycin-producing strain. The antibiotic was...
A new antitumor antibiotic, named auromomycin, was isolated from the culture broth of Streptomyces macromomyceticus, a macromomycin-producing strain. The antibiotic was recovered from the culture filtrate by salting out with ammonium sulfate and further purified by successive application of ion-exchange chromatography on Amberlite IRA-93 (Cl form) and DEAE-Sephadex (OH form), Gel filtration on Sephadex G-50 and hydrophobic chromatography on Octyl-Sepharose CL-4B. The antibiotic is an acidic polypeptide with a molecular weitht of 12,500 and an isoelectric point of pH 5.4 and consists of 16 different amino acids. It has characteristic absorption maxima at 273 nm and 357 nm in the ultraviolet spectrum and two minima at 280 nm and 350 nm in the optical rotatory dispersion spectrum. Auromomycin exhibits antibacterial activity not only against Gram-positive bacteria, but also Gram-negative bacteria. Antitumor activities of auromomycin were revealed against EHRLICH ascites carcinoma, ascites sarcoma 180, L1210 leukemia and LEWIS lung carcinoma. Auromomycin was found to be converted into macromomycin by adsorption chromatography on Amberlite XAD.
Topics: Amino Acids; Animals; Antibiotics, Antineoplastic; Bacteria; Chemical Phenomena; Chemistry; Chemistry, Physical; Fermentation; Mice; Neoplasms, Experimental; Peptide Biosynthesis; Peptides; Streptomyces
PubMed: 468720
DOI: 10.7164/antibiotics.32.330