The promising but still limited efficacy of
angiogenesis inhibitors as monotherapies for
cancer treatment indicates a need to integrate these agents into existing therapeutic regimens. Presently, we investigate the antitumor activity of the small-molecule
angiogenesis inhibitor axitinib (AG-013736) and its potential for combination with metronomic
cyclophosphamide.
Axitinib significantly inhibited angiogenesis in rat 9L
tumors grown s.c. in scid mice but only moderately delayed
tumor growth. Combination of
axitinib with metronomic
cyclophosphamide fully blocked 9L
tumor growth on initiation of drug treatment. In contrast, metronomic
cyclophosphamide alone required multiple treatment cycles to halt
tumor growth. However, in contrast to the substantial
tumor regression that is ultimately induced by metronomic
cyclophosphamide, the
axitinib/
cyclophosphamide combination was
tumor growth static.
Axitinib did not inhibit hepatic activation of
cyclophosphamide or export of its activated metabolite, 4-hydroxy-cyclophosphamide (4-OH-CPA), to extrahepatic tissues; rather,
axitinib selectively decreased 9L
tumor uptake of 4-OH-CPA by 30% to 40%. The reduced
tumor penetration of 4-OH-CPA was associated with a decrease in
cyclophosphamide-induced
tumor cell apoptosis and a block in the induction of the endogenous
angiogenesis inhibitor thrombospondin-1 in
tumor-associated host cells, which may contribute to the absence of
tumor regression with the
axitinib/
cyclophosphamide combination. Finally,
axitinib transiently increased 9L
tumor cell apoptosis, indicating that its effects are not limited to the endothelial cell population. These findings highlight the multiple effects that may characterize
antiangiogenic agent/metronomic
chemotherapy combinations and suggest that careful optimization of drug scheduling and dosages will be required to maximize antitumor responses.