Tumor growth requires angiogenesis, which in turn requires an imbalance in the presence of angiogenic and angiostatic factors. We have shown that the
CXC chemokine family, consisting of members that are either angiogenic or angiostatic, is a major determinant of
tumor-derived angiogenesis in
non-small-cell lung cancer (NSCLC). Intratumor injection of
interferon-inducible protein 10 (IP-10, or CXCL10), an angiostatic
CXC chemokine, led to reduced
tumor growth in a SCID mouse model of NSCLC. In this study, we hypothesized that treatment with CXCL10 would, by restoring the angiostatic balance, improve long-term survival in NSCLC-bearing SCID mice. To test this hypothesis, A549 NSCLC cells were injected in the subcutis of the flank, followed by intratumor
injections with CXCL10 continuously (group I), or for ten weeks (group II), or a control group (
human serum albumin). Median survival was 169, 130, and 86 days respectively (P<0.0001). We extended these studies to examine the mechanism of prolonged survival in CXCL10-treated mice. CXCL10 treatment inhibited lung
metastases, but was dependent upon continued treatment, and was associated with an increased rate of apoptosis in the primary
tumor, with no direct effect on the proliferation of the NSCLC cells. Furthermore, the inhibition of lung
metastases was due to the angiostatic effect of CXCL10 on the primary
tumor, since the rate of apoptosis within lung
metastases was unaffected. These data suggest that anti-angiogenic
therapy of human
lung cancer should be continued indefinitely to realize persistent benefit, and confirms the anti-metastatic capacity of localized angiostatic
therapy.