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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Neocarzinostatin (Figure 5.57) is a macromolecular enediyne antibiotic produced by Streptomyces macromomyceticus. It consists of two components, a labile chromophore (i.e., the bicyclic dienediyne structure) and an associated 113 amino acid apoprotein to which the chromophore is tightly but non-covalently bound (i.e., Kd = approx 10−10 M). The chromophore is a very labile and potent DNA-cleaving agent, and the role of the apoprotein is to protect it and then release it to the target DNA. As with the other agents in the enediyne family, opening of the epoxide moiety under reductive conditions in cells allows Bergman cyclization to occur, leading to a di-radical intermediate and double-stranded DNA cleavage. Sequence-selectivity studies have shown that neocarzinostatin has an order of preference for interaction and cleavage of DNA bases of T > A > C > G. Other members of the neocarzinostatin group of antibiotics include maduropeptin, kedarcidin, actinoxanthin, and macromomycin.
Total-Body Hyperthermia and Chemotherapy
Published in Leopold J. Anghileri, Jacques Robert, Hyperthermia in Cancer Treatment, 2019
Experimentally, many drugs (adriamycin [ADM], bleomycin [BLM], ACNU, BCNU, mitomycin C [MMC], and cis-diamminedichloroplatinum [cis-DDP]) have been pointed out for their synergistic anticancer effects with hyperthermia.13–17 However, in combined anticancer chemotherapy during TBH, the drug should be selected carefully, because some agents show decreased anticancer activity at heating temperatures. We examined the effect of heating on anticancer activities of some drugs by in vitro bioassay. The results are shown in Figure 2, indicating decreased activity in neocarzinostatin (NCS) and ACNU. Based on these results, as combined anticancer chemotherapy we have used mainly MMC and 5-fluorouracil (5-FU) for gastrointestinal cancer, i.e., patients received an i.v. drip infusion of 5-FU (10 to 20 mg/kg, total doses 500 to 1000 mg) with or without cyclophosphamide (EDX) (6 mg/kg, total doses 300 mg) during TBH, and an i.v. injection of MMC (0.2 to 0.4 mg/kg, total doses 10 to 20 mg) at the midpoint of the heating time. However, clinically, the synergistic anticancer effect of combined chemotherapy with TBH is not demonstrated. This needs to be studied under the combined hyperthermia-chemotherapy protocol to verify this combination as clinically effective.
Direct ionizing radiation and bystander effect in mouse mesenchymal stem cells
Published in International Journal of Radiation Biology, 2022
Amanda Nogueira-Pedro, Helena Regina Comodo Segreto, Kathryn D. Held, Antonio Francisco Gentil Ferreira Junior, Carolina Carvalho Dias, Araceli Aparecida Hastreiter, Edson Naoto Makiyama, Edgar Julian Paredes-Gamero, Primavera Borelli, Ricardo Ambrósio Fock
Much of the biological effects of radiation occurs by the formation of ROS, such as hydroxyl radicals which are instantaneously generated, but also secondary ROS that can be generated at mitochondria due to physiological processes after irradiation (Yoshino and Kashiwakura 2017). Persistent (Leach et al. 2001) and time-dependent ROS induction (Schmitt 2007) as well as transient ROS or reactive nitrogen species (Leach et al. 2001) production in mammalian cells by X-radiation have been previously shown. In this work, ROS measurement in MSCs was performed for different radiation doses but at a fixed time point of 24 h after stimuli. Radiation-induced an increase of ROS content in MSCs at the higher doses but did not involve NO· generation. Since the increase of ROS and γ-H2AX were observed in this work, it is possible that ROS induction could have been mediated by H2AX phosphorylation, as H2AX upregulates DNA-damage-induced ROS in a mechanism involving Nox1 and Rac1 in some cancer cell lineages upon neocarzinostatin or doxorubicin treatment (Kang et al. 2012).
Factors affecting the dynamics and heterogeneity of the EPR effect: pathophysiological and pathoanatomic features, drug formulations and physicochemical factors
Published in Expert Opinion on Drug Delivery, 2022
Rayhanul Islam, Hiroshi Maeda, Jun Fang
Maeda et al. [22,45,46] achieved improved tumor-targeted delivery of SMANCS in advanced-stage solid tumors by using artificially induced hypertension, e.g. from 110 to 150 mmHg, together with slow i.v. infusion of angiotensin II (AT-II) during arterial infusion of SMANCS (styrene maleic acid copolymer-conjugated neocarzinostatin) dissolved in Lipiodol®, a lipid contrast agent. The rationale for this method is that the tumor vasculature does not respond to AT-II because of the lack of a smooth muscle layer, which is a critical difference compared with the anatomy of normal blood vessels. By raising the systolic blood pressure, one can effectively increase blood flow into the tumor. Fenestrations in the dilated tumor vessels will open and the vessels will become increasingly leaky, the result being greater selective accumulation of nanomedicines such as SMANCS in Lipiodol® in tumor tissues [45]. In contrast to tumor blood vessels, normal blood vessels will constrict, endothelial cell gaps will tighten, and drugs will accumulate less in normal tissues.
Responsive polymer conjugates for drug delivery applications: recent advances in bioconjugation methodologies
Published in Journal of Drug Targeting, 2019
Daniel Cristian Ferreira Soares, Caroline Mari Ramos Oda, Liziane Oliveira Fonseca Monteiro, Andre Luis Branco de Barros, Marli Luiza Tebaldi
Neocarzinostatin (NCS) is a protein with high anti-tumour activity and can inhibit tumour cell growth at the nanomolar range. However, the major limitation of NCS clinical use is its severe toxicity and very short half-life of about 1.9 min in mice [37–40]. Matsumura and Maeda developed a conjugate of chromoprotein NCS by covalent coupling with a polystyrene-maleimide copolymer and proved that the conjugate increased the circulation times in vivo relative to the native protein [41]. Since then, interest in research about polymer–protein conjugation for therapeutic use has been increased. In this way, Maeda et al. [42] reported increased bio-circulation of a covalently coupled conjugate of chromoprotein-NCS and a polystyrene-maleimide copolymer (SMANCS) (Figure 2). This conjugate was approved in Japan by the Ministry of Health and Welfare (MHW) for treatment of hepatocellular cancer.