It has been suggested that
chemotherapy and
radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three
therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple
therapy combination consisting of
SU11657 (a multitargeted small molecule inhibitor of
vascular endothelial growth factor and
platelet-derived growth factor receptor tyrosine kinases),
Pemetrexed (a multitargeted
folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and
tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and
caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and
chemotherapy induced endothelial cell Akt phosphorylation, but
SU11657 could attenuate this process in vitro and in vivo in A431 human
tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple
therapy further decreased
tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater
tumor growth delay versus all other
therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431
tumor, we found that the regimen with
radiotherapy (7.5 Gy single dose), given after the institution of
SU11657 treatment, was more effective than
radiotherapy preceding
SU11657 treatment. Accordingly, we found that
SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral
edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with
SU11657 may result in: (a) normalization of
tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/
chemotherapy, and (b) direct resensitization of endothelial cells to radio/
chemotherapy. We conclude that trimodal
cancer therapy combining antiangiogenesis,
chemotherapy, and
radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.