The
tumor vasculature delivers nutrients,
oxygen, and therapeutic agents to
tumor cells. Unfortunately, the delivery of anticancer drugs through
tumor blood vessels is often inefficient and can constitute an important barrier for
cancer treatment. This barrier can sometimes be circumvented by antiangiogenesis-induced normalization of
tumor vasculature. However, such normalizing effects are transient; moreover, they are not always achieved, as shown here, when 9L
gliosarcoma xenografts were treated over a range of doses with the
VEGF receptor-selective
tyrosine kinase inhibitors axitinib and AG-028262. The suppression of
tumor blood perfusion by antiangiogenesis agents can be turned to therapeutic advantage, however, through their effects on
tumor drug retention. In 9L
tumors expressing the
cyclophosphamide-activating
enzyme P450 2B11, neoadjuvant
axitinib treatment combined with intratumoral
cyclophosphamide administration significantly increased
tumor retention of
cyclophosphamide and its active metabolite,
4-hydroxycyclophosphamide. Similar increases were achieved using other
angiogenesis inhibitors, indicating that increased
drug retention is a general response to antiangiogenesis. This approach can be extended to include systemic delivery of an anticancer
prodrug that is activated intratumorally, where antiangiogenesis-enhanced retention of the therapeutic metabolite counterbalances the decrease in
drug uptake from systemic circulation, as exemplified for
cyclophosphamide. Importantly, the increase in intratumoral
drug retention induced by neoadjuvant antiangiogenic
drug treatment is shown to increase
tumor cell killing and substantially enhance therapeutic activity in vivo. Thus,
antiangiogenic agents can be used to increase
tumor drug exposure and improve therapeutic activity following intratumoral
drug administration, or following systemic
drug administration in the case of a therapeutic agent that is activated intratumorally.