Vascular endothelial growth factor expression is closely related to irinotecan-mediated inhibition of tumor growth and angiogenesis in neuroblastoma xenografts.
In the present study, irinotecan (CPT-11) was highly effective not only against the chemosensitive neuroblastoma (NB) xenografts SK-N-ASnu and TNB9, but also against the multidrug-resistant NB xenograft TS-N-2nu. SK-N-ASnu and TNB9 were significantly more responsive to low-dose daily CPT-11 treatment than to intermittent administration of one-third of the median lethal dose. For TS-N-2nu, there was no significant difference in tumor growth inhibition between the two treatment schedules. Treatment with CPT-11 alone could not completely abolish tumor growth in mice. For TNB9, tumor regrowth seemed to result from an inability to regress host vessels in the stroma during treatment and an inability to suppress host-derived vascular endothelial growth factor (VEGF) expression throughout therapy. In the multidrug-resistant TS-N-2nu, VEGF was not suppressed by low-dose therapy with CPT-11, and neurofilament-positive tumor cells escaped from apoptosis and were growth arrested at G(0)/G(1) phase. These findings suggest a mechanism for the incomplete responsiveness of TS-N-2nu to CPT-11. Our data demonstrate that diminished VEGF gene and protein expression is closely correlated with tumor growth inhibition and inhibition of angiogenesis by CPT-11 in NB xenografts. Our results further suggest that a persistent blocker of stroma-derived VEGF will need to be combined with CPT-11 to completely inhibit the growth of chemosensitive NB, and that administration of CPT-11 at higher doses will be required to inhibit the growth of multidrug-resistant NB.
Kaneko
Setsuko
S
Department of Pediatric Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. mkaneko@md.tsukuba.ac.jp
Ishibashi
Makiko
M
Kaneko
Michio
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007223:Infant; D000077146:Irinotecan; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D009447:Neuroblastoma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077146:Irinotecan; D002166:Camptothecin