br Acknowledgements This work was financially supported by

Acknowledgements This work was financially supported by the Natural Science Foundation of Jiangsu Province (BK20180857), General Program of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (17KJB150009) and China Postdoctoral Science Foundation Funded Project (2017M611704).
Strategic Paths Towards Anticancer Therapy Oncology mainly focuses on patient symptoms, treating hallmarks acquired by normal mass of cl that gradually progress to a neoplastic state, instead of fighting against a still-unknown causal entity responsible for cancer occurrence and progression [1]. Global strategies, namely chemotherapy and radiotherapy (RT), still comprise the mainstay of the treatment of solid tumors by addressing specific mechanisms involved in tumorigenesis. More targeted therapies (see Glossary), such as antiangiogenesis strategies, have been developed with various degrees of success depending on the patient pathogenesis 2, 3. A better insight into the diverse underlying processes, including causes, triggered cellular and molecular pathways, and potential related targets, would definitely help in the development of relevant and effective anticancer treatments. In contrast to the empiricism from animal models that gave rise to alkylating agents or to the rational design emanating from the targeting of pathways altered in tumors, we suggest that rethinking the use of conventional anticancer drugs could make it possible to exploit their full potential. This alternative approach relies on the optimization of an already marketed bioactive drug capable of reaching its target in effective concentrations to exert its anticancer activity while limiting adverse side effects. In this context, alkylating agents are old molecules still widely used in the frontline treatment of various solid tumors. Among them, platinum derivatives do not alkylate but rather complex with their nucleophilic targets. Although historically affiliated to alkylating agents, they should therefore rather be referred to as ‘alkylating-like’ agents. Half of cancer patients experience platinum-based drug therapy 4, 5. Thus, the clinical relevance of platinum compounds is key in daily practice. Cisplatin is the oldest platinum drug approved by the FDA. Although alternative platinum derivatives have been developed to improve its therapeutic index, cisplatin remains the leader molecule of platinum complexes and one of the most compelling anticancer drugs, with a pivotal role in the management of solid tumors 6, 7. Therefore, cisplatin will be addressed as a prototypic platinum-based anticancer agent to exemplify paradigms, mechanisms, limitations, and new directions that fall under a broader understanding of the future of alkylating agents and platinum compounds in the clinic.
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 brain 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].