ABSTRACT
Physiologic deoxynucleotides are required for an error-proof DNA replication, repair and synthesis. Any inaccuracy in this process results in a block in DNA synthesis until the error is corrected. If the cell enzymes are unable to correct the error, a signal for apoptosis is generated. This mechanism is the main target for anticancer nucleoside analogs. They also interact with the metabolism of physiological nucleosides, and consequently, have a large number of intracellular targets to induce cytotoxicity. In addition, it is now reported that some analogs may interfere directly with RNA synthesis. A great deal of synthesized nucleoside analogs provide the opportunity to understand the structure-based differences in their metabolism and mechanisms of action as well as to identify the specific intracellular targets and diseases, in which each of these newer nucleoside analogs acts most efficiently. This paper summarizes developments in the area of new nucleoside analogs undergoing clinical evaluation for the treatment of solid tumors, namely tezacitabine, troxacitabine, DMDC, CNDAC, ECyD, clofarabine, and decitabine.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Azacitidine/analogs & derivatives , Cytarabine/analogs & derivatives , Cytidine/analogs & derivatives , Cytosine/analogs & derivatives , Deoxycytidine/analogs & derivatives , Neoplasms/drug therapy , Nucleosides/chemistry , Nucleosides/therapeutic use , Adenine Nucleotides , Animals , Antineoplastic Agents/pharmacology , Arabinonucleosides/chemistry , Arabinonucleosides/pharmacology , Arabinonucleosides/therapeutic use , Azacitidine/chemistry , Azacitidine/pharmacology , Azacitidine/therapeutic use , Clinical Trials as Topic , Clofarabine , Cytarabine/chemistry , Cytarabine/pharmacology , Cytarabine/therapeutic use , Cytidine/chemistry , Cytidine/pharmacology , Cytidine/therapeutic use , Cytosine/chemistry , Cytosine/pharmacology , Cytosine/therapeutic use , Decitabine , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Dioxolanes/chemistry , Dioxolanes/pharmacology , Dioxolanes/therapeutic use , Humans , Nucleosides/pharmacologyABSTRACT
Cytotoxic nucleoside analogs have a broad clinical use. They were among the first chemotherapeutic agents used in the treatment of malignant diseases. The anticancer nucleosides include analogs of physiologic pyrimidine and purine nucleosides. They are used in oncology in the treatment of both, solid tumors and hematological malignancies. These agents have many intracellular targets, e.g. they act as antimetabolites, competing with natural nucleosides during DNA or RNA synthesis and as inhibitors of key cell enzymes. Understanding of the mechanisms of action of these compounds and synthesis of new analogs provides the possibility to further expand the spectrum of their clinical use and enhance their antitumor activity. In this paper we describe mechanisms of action and possible clinical use in the treatment of hematological malignancies of these nucleoside analogs, which are now in different stages of clinical trials, namely tezacitabine, troxacitabine, clofarabine, nelarabine, decitabine, CNDAC and ECyD.
