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 carcinoma cell line 253J B-V growing orthotopically within the bladder of athymic nude mice were treated with the anti-epidermal growth factor receptor monoclonal antibody C225, angiogenesis was inhibited, resulting in regression of the primary tumor and inhibition of metastasis. In this study, we evaluated 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 (range, 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 significantly differ from results after the use of C225 alone. Treatment with paclitaxel and C225 down-regulated the expression of basic fibroblast growth factor, vascular endothelial cell growth factor, interleukin-8, and matrix metalloproteinase type 9 and inhibited tumor-induced neovascularity compared with untreated controls (P < 0.005). Moreover, the combination of C225 and paclitaxel enhanced apoptosis in tumor and endothelial cells compared with either agent alone (P < 0.005). These studies indicate that therapy with paclitaxel increases the ability of C225 to inhibit tumorigenicity and metastasis. This effect is mediated by inhibition of angiogenesis and induction of apoptosis.
Inoue
K
K
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Slaton
J W
JW
Perrotte
P
P
Davis
D W
DW
Bruns
C J
CJ
Hicklin
D J
DJ
McConkey
D J
DJ
Sweeney
P
P
Radinsky
R
R
Dinney
C P
CP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000276:immunology* / Q000628:therapy*; D002455:Cell Division; D000068818:Cetuximab; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004727:Endothelium / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D016209:Interleukin-8 / Q000096:biosynthesis; D008207:Lymphatic Metastasis; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009929:Organ Size / Q000187:drug effects; D017239:Paclitaxel / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; D017239:Paclitaxel; D000068818:Cetuximab