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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 -
European Journal of Medicinal Chemistry Jan 2021Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine... (Review)
Review
Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine natural products, arouse interests because of their strong antitumor activities and similar structures to the first marine antitumor agent ecteinascidin-743, approved by the European Union. According to the literatures, researches on the pharmacological activities of renieramycins mainly focus on their antitumor activities. In addition, by structural modification, derivatives of renieramycins show stronger antiproliferative activity and less accidental necrosis activity on cells. Nevertheless, the difficulties in extraction and separation hinder their further development. Hence, the synthetic chemistry work of renieramycins plays a key role in their further development. In this review, currently reported researches on the synthetic chemistry, pharmacological activities and structural modification of renieramycins are summarized, which will benefit future drug development and innovation.
Topics: Alkaloids; Anti-Infective Agents; Antibiotics, Antineoplastic; Antiprotozoal Agents; Biological Products; Molecular Structure; Neoplasms; Tetrahydroisoquinolines
PubMed: 33333398
DOI: 10.1016/j.ejmech.2020.113092 -
Seminars in Ophthalmology 2014Lymphatic malformations (LM) are associated with significant morbidity, and in the orbit, can lead to vision loss. Treatment of these lesions is complicated by their... (Review)
Review
PURPOSE
Lymphatic malformations (LM) are associated with significant morbidity, and in the orbit, can lead to vision loss. Treatment of these lesions is complicated by their infiltrative nature, making surgical excision challenging. Bleomycin has been used since the 1970s for sclerosis of LM to reduce the need for or improve the success of surgical excision. This paper reviews the complications associated with intralesional bleomycin in the treatment of orbital LM.
METHODS
A comprehensive literature search was performed on PubMed. Thirty full-length English articles were reviewed.
RESULTS
The pathophysiology and imaging characteristic of LM were first reviewed. The head and neck literature was heavily cited given the dearth of specific orbital data. This review highlights the common techniques and dosages for injection, the overall success rate of this treatment, and its common side effects. The orbital data were then reviewed, and differentiated from the head and neck literature.
CONCLUSION
Sclerotherapy of most LM with bleomycin appears to be safe and effective, but the lack of specific orbital data means we must extrapolate LM data from other fields to orbital LM with caution. Additional research is warranted, though the risk-benefit ratio remains unknown.
Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Humans; Injections, Intralesional; Lymphangioma; Orbital Neoplasms; Sclerotherapy
PubMed: 25325873
DOI: 10.3109/08820538.2014.959617 -
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 -
Tumori Jun 2016In May 1960, the Farmitalia CEO Dr. Bertini and the director of the Istituto Nazionale dei Tumori of Milan Prof. Bucalossi (talent scout and city's Mayor) signed a... (Review)
Review
In May 1960, the Farmitalia CEO Dr. Bertini and the director of the Istituto Nazionale dei Tumori of Milan Prof. Bucalossi (talent scout and city's Mayor) signed a research agreement for the discovery and development up to clinical trials of new natural antitumor agents. This agreement can be considered as a pioneering and fruitful example of a translational discovery program with relevant transatlantic connections. Owing to an eclectic Streptomyces, found near Castel del Monte (Apulia), and to the skilled and motivated participants of both institutions, a new natural antitumor drug, daunomycin, was ready for clinical trials within 3 years. Patent interference by the Farmitalia French partner was overcome by the good quality of the Italian drug and by the cooperation between Prof. Di Marco, director of the Istituto Ricerche Farmitalia Research Laboratories for Microbiology and Chemotherapy, and Prof. Karnofsky, head of the Sloan-Kettering Cancer Institute of New York, leading to the first transatlantic clinical trials. The search for daunomycin's sister anthracyclines led to the discovery and development of adriamycin, one of the best drugs born in Milan. This was the second act prologue of the history of Italian antitumor discovery and clinical oncology, which started in July 1969 when Prof. Di Marco sent Prof. Bonadonna the first vials of adriamycin (doxorubicin) to be tested in clinical trials. This article reviews the Milan scene in the 1960s, a city admired and noted for the outstanding scientific achievements of its private and public institutions in drugs and industrial product discovery.
Topics: Academies and Institutes; Anthracyclines; Antibiotics, Antineoplastic; Clinical Trials as Topic; Daunorubicin; Doxorubicin; Drug Approval; Drug Discovery; Drug Industry; France; History, 20th Century; History, 21st Century; Humans; Interdisciplinary Communication; Italy; Medical Oncology; Neoplasms; Patents as Topic; Public-Private Sector Partnerships; Streptomyces; Translational Research, Biomedical; United States
PubMed: 27103205
DOI: 10.5301/tj.5000507 -
Clinical Science (London, England :... Jun 2021Significant improvements in cancer survival have brought to light unintended long-term adverse cardiovascular effects associated with cancer treatment. Although capable... (Review)
Review
Significant improvements in cancer survival have brought to light unintended long-term adverse cardiovascular effects associated with cancer treatment. Although capable of manifesting a broad range of cardiovascular complications, cancer therapy-related cardiac dysfunction (CTRCD) remains particularly common among the mainstay anthracycline-based and human epidermal growth factor receptor-targeted therapies. Unfortunately, the early asymptomatic stages of CTRCD are difficult to detect by cardiac imaging alone, and the initiating mechanisms remain incompletely understood. More recently, circulating inflammatory markers, cardiac biomarkers, microRNAs, and extracellular vesicles (EVs) have been considered as early markers of cardiovascular injury. Concomitantly, the role of the endothelium in regulating cardiac function in the context of CTRCD is starting to be understood. In this review, we highlight the impact of breast cancer therapies on the cardiovascular system with a focus on the endothelium, and examine the status of circulating biomarkers, including inflammatory markers, cardiac biomarkers, microRNAs, and endothelial cell-derived EVs. Investigation of these emerging biomarkers may uncover mechanisms of injury, detect early stages of cardiovascular damage, and elucidate novel therapeutic approaches.
Topics: Antibiotics, Antineoplastic; Cardiovascular Diseases; Cardiovascular System; Heart; Heart Diseases; Humans; Neoplasms
PubMed: 34136902
DOI: 10.1042/CS20210059 -
Die Pharmazie Oct 2019In this study, micelles were designed to deliver an antitumor agent and a fluorescent marker to a tumor site. The micelles simultaneously encapsulated epirubicin (EPI)...
In this study, micelles were designed to deliver an antitumor agent and a fluorescent marker to a tumor site. The micelles simultaneously encapsulated epirubicin (EPI) and polyethylene glycol (PEG)-modified graphene quantum dots (GQDs-PEG), and employed a PEG-polylactic acid block copolymer amphiphilic block polymer as a nanocarrier. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were used to characterize the functional groups in the synthesized GQDs-PEG. A Malvern particle size meter and transmission electron microscopy were used to show that the particle size of the GQDs-PEG is approximately 2-9 nm, and that of the bifunctional EPI-loaded micelles (EPI-FIDCR) is 19.59±1.21 nm, with zeta potential at -22.87±0.85 mV. The EE% and DL% for EPI in EPI-FIDCR are 74.02±0.55 % and 3.78±0.28 %, respectively. The IC values of EPI-FIDCR and EPI solution (EPI-Free) for tumor cells were 7.03 μg/mL and 5.54 μg/mL, showing that EPI-FIDCR still maintained strong cytotoxicity. Fluorescence micrographs of HeLa cells incubated with GQDs-PEG and EPI-FIDCR for 6 h, respectively, show that only EPI-FIDCR could enter the cells. cellular uptake assays and an inhibition study indicated that EPI-FIDCR could deliver both EPI and GQDs-PEG into tumor cells, while maintaining an inhibitory effect similar to that of unencapsulated EPI. A pharmacokinetic study showed that EPI-FIDCR could persist in the circulation for a significant period of time. The AUC calculated for the EPI-FIDCR formulation was 159.5-fold compared with that of EPI-Free, based on its improved stability and prolonged blood circulation time. The EPI-FIDCR enables both fluorescence imaging and controlled drug-release, exhibits prolonged systematic circulation time and has potential for the treatment of cancer.
Topics: Antibiotics, Antineoplastic; Drug Carriers; Drug Delivery Systems; Epirubicin; HeLa Cells; Humans; Micelles; Particle Size; Polyethylene Glycols; Polymers; Quantum Dots; Spectroscopy, Fourier Transform Infrared
PubMed: 31685080
DOI: 10.1691/ph.2019/9059 -
British Journal of Cancer Oct 2018Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity,... (Review)
Review
Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity, long-term complications and even death in extreme cases. There is a lack of evidence or consensus on how to prevent and monitor bleomycin toxicity. We surveyed 63 germ cell cancer physicians from 32 cancer centres across the UK to understand their approach to using bleomycin. Subsequent guideline development was based upon current practice, best available published evidence and expert consensus. We observed heterogeneity in practice in the following areas: monitoring; route of administration; contraindications to use; baseline and follow-up investigations performed, and advice given to patients. A best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours has been developed and includes recommendations regarding baseline investigations, the use of pulmonary function tests, route of administration, monitoring and patient advice. It is likely that existing heterogeneity in clinical practice of bleomycin prescribing has significant economic, safety and patient experience implications. The development of an evidence-based consensus guideline was supported by 93% of survey participants and aims to address these issues and homogenise practice across the UK.
Topics: Antibiotics, Antineoplastic; Bleomycin; Clinical Trials as Topic; Consensus; Evidence-Based Medicine; Humans; Male; Neoplasms, Germ Cell and Embryonal; Respiratory Function Tests; Testicular Neoplasms; United Kingdom
PubMed: 30356125
DOI: 10.1038/s41416-018-0300-x -
Cell Chemical Biology Sep 2018The enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the...
The enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the enediyne producers-apoproteins for the nine-membered enediynes and self-sacrifice proteins for the ten-membered enediyne calicheamicin. Here we show that: (1) tnmS1, tnmS2, and tnmS3 encode tiancimycin (TNM) resistance in its producer Streptomyces sp. CB03234, (2) tnmS1, tnmS2, and tnmS3 homologs are found in all anthraquinone-fused enediyne producers, (3) TnmS1, TnmS2, and TnmS3 share a similar β barrel-like structure, bind TNMs with nanomolar K values, and confer resistance by sequestration, and (4) TnmS1, TnmS2, and TnmS3 homologs are widespread in nature, including in the human microbiome. These findings unveil an unprecedented resistance mechanism for the enediynes. Mechanisms of self-resistance in producers serve as models to predict and combat future drug resistance in clinical settings. Enediyne-based chemotherapies should now consider the fact that the human microbiome harbors genes encoding enediyne resistance.
Topics: Anthraquinones; Antibiotics, Antineoplastic; Drug Resistance, Bacterial; Enediynes; Genes, Bacterial; Humans; Models, Molecular; Multigene Family; Streptomyces
PubMed: 29937405
DOI: 10.1016/j.chembiol.2018.05.012 -
Acta Pharmacologica Sinica Oct 2015Rapamycin and its analogs (rapalogs) are the first generation of mTOR inhibitors, which have the same molecular scaffold, but different physiochemical properties.... (Review)
Review
Rapamycin and its analogs (rapalogs) are the first generation of mTOR inhibitors, which have the same molecular scaffold, but different physiochemical properties. Rapalogs are being tested in a wide spectrum of human tumors as both monotherapy and a component of combination therapy. Among them, temsirolimus and everolimus have been approved for the treatment of breast and renal cancer. However, objective response rates with rapalogs in clinical trials are modest and variable. Identification of biomarkers predicting response to rapalogs, and discovery of drug combinations with improved efficacy and tolerated toxicity are critical to moving this class of targeted therapeutics forward. This review focuses on the aberrations in the PI3K/mTOR pathway in human tumor cells or tissues as predictive biomarkers for rapalog efficacy. Recent results of combinational therapy using rapalogs and other anticancer drugs are documented. With the rapid development of next-generation genomic sequencing and precision medicine, rapalogs will provide greater benefits to cancer patients.
Topics: Animals; Antibiotics, Antineoplastic; Computational Biology; Humans; Molecular Targeted Therapy; Neoplasms; Phosphatidylinositol 3-Kinases; Precision Medicine; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 26299952
DOI: 10.1038/aps.2015.68