C1027, a new macromolecular antitumor antibiotic produced by a Streptomyces strain, shows highly potent cytotoxicity to cultured cancer cells and marked DNA cleaving ability. The structure of its chromophore, responsible for most of the biological activities of the antibiotic, was recently determined and found to contain a nine-membered enediyne. In contrast to other enediyne antibiotics, such as neocarzinostatin, calicheamicin, esperamicin, and recently found kedarcidin, C1027 damages duplex DNA even in the absence of thiols. The DNA damage caused by C1027 includes double-strand breaks, single-strand breaks, and abasic sites. Experiments with plasmid DNA and 32P-end-labeled restriction fragments demonstrated that the chromophore, extracted from the protein-containing holoantibiotic, interacts in the DNA minor groove and cleaves double-helical DNA with a remarkable sequence-selectivity causing direct double-strand breaks. The double-strand cleavage sites, occurring predominantly at CTTTT/AAAAG, ATAAT/ATTAT, CTTTA/TAAAG, CTCTT/AAGAG, and especially GTTAT/ATAAC, consist of five nucleotide sequences with a two-nucleotide 3'-stagger of the cleaved residues (cutting sites are underlined). The chemical structures of the damaged residues at the GTTAT/ATAAC cleavage site suggest a model in which a C1027-induced double-strand break results from abstraction, by a single molecule of the diradical form of the chromophore, of a C4' hydrogen atom from the A residue of GTTAT and a C5' hydrogen atom from the A of ATAAC on the opposite strand. Single-strand breaks, which are mainly produced at adenylate and thymidylate residues, appear to be separate events presumably resulting from different binding modes of the drug to DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC.
The enediyne antibiotics, the potent anticancer agents that contain diyne-ene functional groups, are appreciated for their novel molecular architecture, their remarkable biological activity and their fascinating mechanism of action. Their anticancer activity is apparently due to their ability to damage DNA through radical-mediated hydrogen abstraction. The enediyne antibiotics show markedly cytotoxicities against cancers in vitro and in vivo. Lidamycin is a member of the enediyne anticancer antibiotic family. This review examines lidamycin with particular emphasis on the discovery, the biological properties and its structure-activity relationships. In addition, the possible mechanisms of action of lidamycin are described. Recent progress, particularly in the areas of biosynthesis, and immunoconjugates are highlighted. Finally, the pharmacological applications of lidamycin in cancer therapy and its potential use as anticancer agents are also discussed.
C-1027, a new macromolecular antitumor antibiotic produced by Streptomyces globisporus C-1027, showedextremely potent cytotoxicity toward cultured cancer cells. Comparedin terms of IC50 values, antibiotic C-1027 showed muchmore potent cytotoxicity than doxorubicin, mitomycin C and neocarzinostatin. Spermatogonial assay, a prescreen for anticancer drugs, was highly sensitive for detection of C-1027. At tolerable doses, C-1027 exhibited markedinhibition on a panel of transplantable tumors in mice, which included leukemia L1210, P388, ascites hepatoma H22, sarcoma 180 and melanoma Harding-Passey. The new antitumor antibiotic C-1027 was discovered during antitumor screening of microbial metabolites by use of a spermatogonial assay, a new prescreen for detection of antitumor drugs0, and was isolated from the culture filtrate of a new isolate identified as Streptomyces globisporus C-1027. The procedure for isolation and purification, as well as physico-chemical and biological properties, of C-1027 were reported previously2>3). Antibiotic C-1027, an acidic protein with a molecular weight of 1 5,000 daltons, had moderate antimicrobial activity against Gram-positive bacteria, but was shown to be inactive against Gram-negative bacteria except for some strains of Escherichia coli and fungi tested. Our studies have shown that antibiotic C-1027 is highly active in the spermatogonial assay, exhibits extremely potent cytotoxicity toward various human cancer cells in vitro, and displays inhibitory effect on a panel of transplantable tumors in mice. This paper reports data on the antitumor activity of antibiotic C-1027. Materials and Methods Antibiotics Highly purified antibiotic C-1027 was prepared from a culture filtrate of S. globisporus C-1027 by a purification procedure improved over the previous one3). C-1027 was simply purified by ammonium sulfate precipitation at pH 4, followed by column chromatography on diethylaminoethyl (DEAE)cellulose (Wako Pure Chemical Industries, Ltd.), and Butyl-Toyopearl 650 C (Tosoh Manufacturing Co., Ltd.) and by gel filtration chromatography on Sephadex G-50 (Pharmacia Fine Chemicals).
Purpose: The cooverexpression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) observed in many human tumors and their synergistic interaction in the transformation of cells make these receptors important targets for the development of new targeted therapeutics. Targeting of EGFR and HER2 simultaneously has been pursued as a strategy with which to potentially increase efficiency and selectivity in therapy of certain cancers. This study was set to construct a bispecific energized fusion protein (Ec-LDP-Hr-AE) consisting of two oligopeptides against EGFR and HER2, and lidamycin, and investigate its antitumor efficacy.Experimental Design: In vitro experiments measured the binding and internalization of bispecific Ec-LDP-Hr fusion protein. The potency of energized fusion proteins was also done in which the bispecific Ec-LDP-Hr-AE was compared with lidamycin (LDM) and its monospecific counterparts, Ec-LDP-AE and LDP-Hr-AE. In vivo, Ec-LDP-Hr-AE was given i.v. to nude mice bearing human ovarian carcinoma SK-OV-3 xenografts.Results: Binding and internalization studies showed that bispecific fusion protein Ec-LDP-Hr bound to carcinoma cells specifically and then were internalized into the cytoplasm. Bispecific Ec-LDP-Hr-AE was more potent and selective in its cytotoxicity against different carcinoma cell lines than corresponding momospecific agents and LDM in vitro. In addition, Ec-LDP-Hr-AE significantly inhibited the growth of SK-OV-3 xenografts in nude mouse model. In vivo imaging study showed that FITC-labeled Ec-LDP-Hr was targeted and accumulated in the tumors.Conclusion: A ligand-based and an antibody-based oligopeptide fused to the enediyne antibiotic LDM created a new bispecific fusion protein with low molecular weight and more potent in vitro and in vivo antitumor activity (than momospecific fusion proteins). Clin Cancer Res; 16(7); 2085-94. ©2010 AACR.The ErbB family (ErbB1/EGFR, ErbB2/HER2, ErbB3/ HER3, and ErbB4/HER4) of receptor tyrosine kinases is known to drive both formation and progression of several commonly occurring cancers (1). Ligand binding to the receptors results in receptor homodimerization and heterodimerization, then initiated a series of intracellular events that ultimately promote cell growth, proliferation, differentiation, and migration (2-4). Human epidermal growth factor receptor 2 (HER2) has no identified ligand but it is the preferred binding partner for the other three family members (5). The cooverexpression of epidermal growth factor receptor (EGFR) and HER2 observed in many human tumors and their synergistic interaction in the transformation of cells make these receptors important targets for the development of new targeted therapeutics (6-8). Several monoclonal antibodies (e.g., cetuximab, trastuzumab, and pertuzumab) and tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, and lapatinib) targeting EGFR and HER2 or both have been approved by the U.S. Food and Drug Administration for therapeutic use and several more are in ...
The potent enediyne antitumor antibiotic C1027 has been previously reported to induce novel DNA interstrand cross-links and drug monoadducts under anaerobic conditions [Xu et al. (1997) J. Am. Chem. Soc. 119, 1133-1134]. In the present study, we explored the mechanism of formation of these anaerobic DNA lesions. We found that, similar to the aerobic reaction, the diradical species of the activated drug initiates anaerobic DNA damage by abstracting hydrogen atoms from the C4', C1', and C5' positions of the A1, A2, and A3 nucleotides, respectively, in the most preferred 5'GTTA1T/5'ATA2A3C binding sequence. It is proposed that the newly generated deoxyribosyl radicals, which cannot undergo oxidation, likely add back onto the nearby unsaturated ring system of the postactivated enediyne core, inducing the formation of interstrand cross-links, connecting either A1 to A2 or A1 to A3, or drug monoadducts mainly on A2 or A3. Comparative studies with other enediynes, such as neocarzinostatin and calicheamicin gamma1I under similar reaction conditions indicate that the anaerobic reaction process is a kinetically competitive one, depending on the proximity of the drug unsaturated ring system or dioxygen to the sugar radicals and their quenching by other hydrogen sources such as solvent or thiols. It was found that C1027 mainly generates interstrand cross-links, whereas most of the anaerobic lesions produced by neocarzinostatin are drug monoadducts. Calicheamicin gamma1I was found to be less efficient in producing both lesions. The anaerobic DNA lesions induced by enediyne antitumor antibiotics may have important implications for their potent cytotoxicity in the central regions of large tumors, where relative anaerobic conditions prevail.
HERG expression levels and chemosensitivity were positively correlated for vincristine, paclitaxel, and hydroxy-camptothecin. Erythromycin was active as a modulator. These results suggest that HERG may serve as a molecular marker and modulating target for individualized cancer therapy.
Previous studies have shown that dipyridamole (DP), a potent nucleoside transport inhibitor blocking the rescue effect of exogenous nucleosides, markedly potentiates the cytotoxicity of antimetabolites. However, no enhancement of the chemotherapeutic effect of antimetabolites by DP in vivo has yet been reported. This study provided evidence that the combination of DP and amphotericin B (AmB) significantly potentiated the inhibitory effect of 5-fluorouracil (FU) or methotrexate (MTX) against a panel of transplantable tumors including sarcoma 180, cervical carcinoma U14, and Lewis lung carcinoma in mice. No significant increase in toxicity was induced by this combination in treated mice. Our results indicate that the combination of DP and AmB with antimetabolites is potentially useful in cancer chemotherapy.
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