Antiangiogenic effects of the novel camptothecin ST1481 (gimatecan) in human tumor xenografts.
ST1481 (gimatecan) is a novel lipophilic camptothecin with a promising preclinical pharmacological profile. On the basis of its high antitumor efficacy when delivered by the oral route, the compound is suitable for prolonged administration. This schedule of treatment has been reported as the most appropriate to exploit the antiangiogenic effects of cytotoxic drugs. The aim of the study was to investigate the antiangiogenic and antitumor effects of oral ST1481 in human tumor xenografts. In spite of a marginal drug effect against the s.c. growing A549 lung carcinoma following administration with an intermittent schedule (q4dx4 times, maximum tolerated dose: 2 mg/kg), tumor growth was strongly inhibited by a daily low-dose (0.5 mg/kg) prolonged administration. Immunohistochemical analysis showed a reduced number of microvessels in tumors of both treated groups versus controls and a significantly higher reduction in the daily versus the q4dx4-treated tumors (P < 0.0001, by Student's t test). In our experimental model, the relation between microvessel density and tumor size (r = 0.738, by the Spearman rank test) suggests a role of inhibition of tumor vasculature in tumor response. Significant inhibition of tumor angiogenesis (P < 0.0001 versus control tumors) was observed even with a very low drug dose (0.06 mg/kg) in the orthotopically implanted (i.d.) MeWo melanoma, under conditions causing minimal tumor growth inhibition. Additional evidences of the antiangiogenic activity of ST1481 were provided by antimotility effects on endothelial cells, in vivo inhibition of vascularization in the Matrigel assay, and down-regulation of the expression of the proangiogenic basic fibroblast growth factor in A549 tumor cells associated with inhibition of the pathway involving Akt. In conclusion, the available results support the possibility that the antiangiogenic properties of ST1481 contribute to its antitumor potential and that this effect might be enhanced by the continuous low-dose treatment.
Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
Giovanna
G
Petrangolini
Graziella
G
Pratesi
Michelandrea
M
De Cesare
Rosanna
R
Supino
Claudio
C
Pisano
Marcella
M
Marcellini
Vincenzo
V
Giordano
Diletta
D
Laccabue
Cinzia
C
Lanzi
Franco
F
Zunino
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C433984:ST 1481; D002166:Camptothecin