aq4n and apaziquone

Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

Topics: Anthraquinones; Antineoplastic Agents; Aziridines; Cell Hypoxia; Humans; Indolequinones; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Nitrogen Mustard Compounds; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Tirapazamine; Triazines

Solid tumours contain regions of very low oxygen concentrations that are said to be hypoxic. Hypoxia is a natural phenotype of solid tumours resulting from an imperfect vascular network. There are a number of consequences associated with tumour hypoxia including: resistance to ionising radiation, resistance to chemotherapy and the magnification of mutated p53. In addition tissue hypoxia has been regarded as a key factor for tumour aggressiveness and metastasis by activation of signal transduction pathways and gene regulatory mechanisms. It is clear that hypoxia in solid tumours promotes a strong oncogenic phenotype and is a phenomenon that occurs in all solid tumours. As such this provides a significant target for drug discovery particularly for tumour-targeting agents. A range of chemical classes (N-oxides, quinones, nitro-aromatics) have been explored as bioreductive agents that target tumour hypoxia. The most advanced agent, tirapazamine, is in phase III clinical trials in combination with cis-platin. The aim of this review is to give a brief overview of the current molecules and strategies being explored for targeting tumour hypoxia.

Topics: Anthraquinones; Antineoplastic Agents; Aziridines; Benzoquinones; Cell Hypoxia; Clinical Trials, Phase III as Topic; Drug Screening Assays, Antitumor; Humans; Imidazoles; Indolequinones; Neoplasms; Prodrugs; Quinolines; Radiation-Sensitizing Agents; Tirapazamine; Triazines