Potential New Locoregional Treatments for Pre-Invasive Cervical Cancer
The anticancer drug EO9 (or Apaziquone) is an indolequinone based bioreductive drug that requires activation by cellular oxidoreductases to generate DNA damaging species. Its mechanism of action, which centres on the enzyme NQO1 reducing EO9 to reactive species, has been extensively reviewed elsewhere alongside its pre-clinical and clinical history 104,105. Briefly, EO9 failed clinical trials when administered intravenously primarily because rapid pharmacokinetic elimination prevented sufficient drug reaching the tumour to induce an anti-tumour effect. It was argued that whilst its poor pharmacokinetic properties were not suitable for systemic drug administration, they would paradoxically be ideal for the locoregional treatment of pre-invasive cancers 106. In the case of non-muscle invasive bladder cancer (NMIBC), intravesical administration would circumvent the drug delivery problem and any drug reaching the systemic circulation would be rapidly cleared thereby reducing the risk of systemic toxicity. In a phase I/II pilot study involving 12 patients with low risk NMIBC, eight complete responses were recorded107 with similar complete response rates (67%) reported in phase II studies 108. Furthermore, follow up studies reported good two-year recurrence free rates109,110 suggesting that the long-term response rates were good in comparison to standard of care treatments for NMIBC. Whilst the results of phase III clinical trials were disappointing (due largely to changes in clinical trial design from phase II to phase III105), these studies have nevertheless established the principle that compounds with poor systemic pharmacokinetic properties can have clinical efficacy when used in a loco-regional setting. In the context of pre-invasive cervical cancers, NQO1 is overexpressed in squamous cell carcinoma of the cervix and CINs compared to normal cervical epithelia 111 suggesting that EO9 would be a promising candidate for the locoregional treatment of pre-invasive cervical cancer.