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.