Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky
tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of
tumor vessels, causing extensive secondary
cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the
tumor periphery. However, comparative studies with the second generation
tubulin-binding VDA
OXi4503 indicate that the viable rim of
tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA,
combretastatin.
OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic
free radicals. To examine this possibility in situ, KHT
sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form
quinone intermediates but only the cis-isomer binds
tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive
hydroxyl groups. The results showed that the cis-isomer (
OXi4503) significantly impaired
tumor blood flow leading to secondary
tumor cell death and >95%
tumor necrosis 24h post
drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with
combretastatin increased the antitumor efficacy of the latter agent to near that of
OXi4503. These findings indicate that while the predominant in vivo effect of
OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic
free radicals likely contributes to its enhanced potency.