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  • br Rationale and Conventional Use of Alkylating Agents

    2020-05-12


    Rationale and Conventional Use of Alkylating Agents and Platinum Derivatives in Clinical Practice After the attack on Bari Harbor in 1943 revealed the effects of mustard gas on bone marrow depletion and the first therapeutic outcomes in lymphoma, alkylating agents gradually became a gold standard as first-line treatment for various cancer indications. The DrugBank database reports all FDA-approved alkylating agents and affiliated compounds in worldwide use, their initial indications, delivery type, and administration route (Table 1) [8]. Other alkylating agents (e.g., mitolactol, which has been granted orphan drug designation from the FDA for the treatment of invasive carcinoma of the uterine cervix and as adjuvant therapy in the treatment of primary molarity by dilution tumors) and platinum complexes [lobaplatin for inoperable metastatic breast cancer, chronic myelogenous leukemia, and small cell lung cancer in China, heptaplatin for gastric cancer in Korea, and nedaplatin for non-small cell lung cancer, esophageal cancer, and head and neck cancer and miriplatin for hepatocellular carcinoma in Japan] are also currently in use in humans [5].
    Optimization of the Use of Alkylating Agents and Platinum Derivatives
    Concluding Remarks Owing to their broad anticancer spectrum, alkylating agents and platinum derivatives are key in the management of solid tumors. Still, they suffer from acute systemic toxicity, suboptimal treatment schedules, intrinsic or acquired resistance, and inadequate routing at both the tissue and the cellular level. In this context, this review envisions promising alternatives to the conventional use of alkylating agents and platinum derivatives in clinical practice, including their administration by appropriate routes depending on the tumor location, optimized subcellular rerouting, synergistic strategies, and the development of an arsenal of smart nanocarriers. Driven by the necessity to rethink their use through rather simple potentiating therapeutic strategies relevant to daily needs and clinical practice – instead of developing new drugs that would quickly face the same issues in terms of limited therapeutic index (see Outstanding Questions) – we do believe that these old molecules have great promise for future applications in the management of solid tumors.
    Acknowledgments This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by the University of Angers (Angers, France), by the University of Liege (Liege, Belgium), and by the ‘Fonds de la Recherche Scientifique’ (F.R.S.-FNRS). P.L. is Research Associate in Belgium. It is also related to LabEx IRON ‘Innovative Radiopharmaceuticals in Oncology and Neurology’ as part of the French Government’s Investissements d’Avenir program, to the Institut National du Cancer (INCa) MARENGO consortium ‘MicroRNA Agonist and Antagonist Nanomedicines for GliOblastoma Treatment: From Molecular Programmation to Preclinical Validation’ through the PL-BIO 2014-2020 grant, and to the MuMoFRaT project ‘Multi-scale Modeling & Simulation of the Response to Hypo-fractionated Radiotherapy or Repeated Molecular Radiation Therapies’ supported by La Région Pays-de-la-Loire and by Cancéropôle Grand-Ouest (tumor targeting and radiotherapy network). H.L. was a PhD student involved in the Erasmus Mundus Joint Doctorate Program for Nanomedicine and Pharmaceutical Innovation (EMJD NanoFar) and received a fellowship from La Région Pays-de-la-Loire.
    Introduction DNA damage poses a challenge to cells due to the possibilities that DNA lesions can lead to mutations or cell death [1]. DNA damage can form spontaneously or upon environmental exposures, for example to UV radiation and alkylating agents [1]. Alkylating agents are potentially genotoxic due to their ability to react at nucleophilic centers on DNA, forming adducts that can be cytotoxic or mutagenic, causing heritable mutations to occur in DNA, which can lead to cancer [1]. In this work, we probe the cellular effects of the alkylating agents chloroacetaldehyde (CAA) and styrene oxide (SO) in E. coli as a model system. We chose CAA and SO for our assays since they are direct-acting, share a common mechanism (alkylation), have been studied for their genotoxic properties, are readily available, and are important industrially [[2], [3], [4], [5], [6], [7]].