Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma

Previously we reported that when cells from the human transitional cell car cinoma cell line 253J B-V growing orthotopically within the bladder of athy mic nude mice were treated with the anti-epidermal growth factor receptor m onoclonal antibody C225, angiogenesis was inhibited, resulting in regressio n of the primary tumor and inhibition of metastasis, In this study, we eval uated whether paclitaxel enhanced this therapeutic effect of C225. In vitro , the proliferation of 253J B-V cells was inhibited more by the combination of C225 and paclitaxel than with either agent alone. In vivo therapy with C225 and paclitaxel resulted in significantly greater regression of tumors compared with either agent alone. Median bladder tumor weight was 85 mg (ra nge, 69-133 mg) compared with 168 mg (range, 72-288 mg) after C225 alone (P < 0.05), and 273 mg (range, 83-563 mg) after paclitaxel alone (P < 0.005). The incidence of spontaneous lymph node metastasis was also reduced by the combination of C225 with paclitaxel, although this result did not signific antly differ from results after the use of C225 alone. Treatment with pacli taxel and C225 down-regulated the expression of basic fibroblast growth fac tor, vascular endothelial cell growth factor, interleukin-8, and matrix met alloproteinase type 9 and inhibited tumor-induced neovascularity compared w ith untreated controls (P < 0.005). Moreover, the combination of C225 and p aclitaxel enhanced apoptosis in tumor and endothelial cells compared with e ither agent alone (P < 0.005). These studies indicate that therapy with pac litaxel increases the ability of C225 to inhibit tumorigenicity and metasta sis. This effect is mediated by inhibition of angiogenesis and induction of apoptosis.