AQ4N (Banoxantrone) is a novel agent with broad potential in treating a variety of cancers. Considered a first-in-class hypoxic cell-activated anti-tumor therapy, AQ4N represents a new approach to cancer treatment. AQ4N is a water-soluble compound administered intravenously.
Targets Hypoxic Tumor Cells
Because AQ4N is a potent hypoxic cell cytotoxin, it targets hypoxic regions of tumors. Essentially all tumors greater than 2 mm in size have hypoxic fractions and disordered vasculature. It is widely accepted by researchers that hypoxic fractions of tumors are less responsive to radiotherapy and chemotherapy. In vitro data indicate that the level of response is just one third that of normally oxygenated (oxic) cells. This lower response can be attributed to the fact that hypoxic cells are less active than oxic cells; they are not replicating and are thus less vulnerable to cell killing through DNA damage. These cells are often referred to as quiescent.
AQ4N is selectively and irreversibly converted to AQ4, its cytotoxic form, in hypoxic tumor cells, which are its targeted site of action. It is hypothesized that when the surrounding oxygenated cells are killed by radiotherapy or chemotherapy, the AQ4-containing cells become reoxygenated. When these previously quiescent cells resume replication, it is believed that they are killed by AQ4's potent action as an inhibitor of topoisomerase II. Thus, AQ4N therapy holds the potential to target these hypoxic tumor cells and improve disease remission.
The bioreduction of AQ4N to AQ4 is strongly inhibited by oxygen and enhanced in the absence of oxygen. Because AQ4N is not cytotoxic when administered and is only converted into its active cytotoxic form once it reaches hypoxic tumor cells, potential systemic toxicity is reduced.
AQ4N Chemical Structure
AQ4 Chemical Structure
Enhances Tumor Clearance
Preclinical data demonstrate that AQ4N has anti-tumor activity as monotherapy and markedly enhances the tumor eradication effects of radiation and chemotherapy when administered in combination with either treatment.
Clinical Program for AQ4N
AQ4N is currently being evaluated in a multicenter Phase1b/2a open-label clinical trial – in combination with radiotherapy and temozolomide – to evaluate for safety, tolerability, and activity in patients with newly diagnosed glioblastoma multiforme (GBM). This trial consists of the following two parts: the primary objective of the first part is to evaluate safety and tolerability of three dose levels (200 mg/m2, 450 mg/m2, and 750 mg/m2); the second part will further evaluate safety and tolerability as well as efficacy of the highest safe and tolerated dose of AQ4N as determined in part one. We expect to enroll approximately 60 patients in the trial.
Click here for information on the current clinical trial for AQ4N.
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