Bioreductive Drugs: from Concept to Clinic

In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts

“…This is due to direct effects, such as the well-characterized requirement for oxygen to generate the DNA-damaging cytotoxic free radicals during radiation treatment, and indirect mechanisms, such as the limited penetration of drugs into hypoxic regions remote from the vasculature (2,3). One approach to overcoming these resistance mechanisms is to use bioreductive agents designed to target the hypoxic regions directly, and a number of agents from this promising class of anticancer treatments are now under examination in the clinic (4). One of these agents, AQ4N (banoxantrone), is a well-tolerated prodrug that was designed to be activated into a cytotoxic agent in hypoxic regions to target this treatment-resistant fraction (5).…”

Glucose transporter Glut-1 is detectable in peri-necrotic regions in many human tumor types but not normal tissues: Study using tissue microarrays

“…This change in tumor behaviour includes increased vascularity, adaptation to low tumour pH (Potter and Harris, 2003) and increased rate of anaerobic glycolysis (Seagroves et al, 2001). The use of intrinsic hypoxia markers, which may be detected by traditional immunohistochemical techniques in biopsy or surgical specimens, may prove useful in the rational selection of patients to receive hypoxia-linked therapies such as hypoxia-dependent bioreductive drugs such as EO9 and AQ4N (McKeown et al, 2007); and ARCON (accelerated radiotherapy with carbogen and nicotinamide) (Hoskin et al, 2003). Glut-1 has been used as an intrinsic marker of hypoxia in patients being treated for carcinoma of the cervix (Airley et al, 2001.…”

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

“…It has been suggested that hypoxic environment in tumor tissues could be used as an advantage to target cancer cells with prodrugs that are metabolized into toxic metabolites only in hypoxic areas (McKeown et al, 2007). These drugs, also named bioreductive agents, are divided into 4 groups: quinones, nitroaromatics or nitro-heterocyclic, aliphatic N-oxides and heteroaromatic N-oxides.…”

“…Moreover, hypoxia might modulate expression of enzymes directly involved in metabolism of chemotherapeutic drugs, thereby limiting the toxic effects of these drugs on cancer cells. On the other hand, new therapeutic strategies aim at using bioreductive drugs that are selectively toxic to hypoxic cells (McKeown et al, 2007).…”