Antitumor activity and pharmacokinetics of oral gimatecan on pediatric cancer xenografts

Abstract

Purpose This study compared the antitumor activity and the pharmacological proWle of gimatecan given orally and irinotecan (CPT-11) on pediatric tumor xenografts. Experimental design Gimatecan was tested in two neuroblastoma cell lines (SK-N-DZ and SK-N-(BE)2c) and on TE-671 rhabdomyosarcoma cells using two diVerent schedules. We characterized its pharmacokinetic proWle in nude mice bearing human SK-N-DZ and TE-671 cell lines. Results Gimatecan appears to have high plasma disposition. The drug was present in plasma almost completely as the intact lactone form and showed substantial activity in all tumor models. Prolonged daily treatment with low doses of gimatecan produced signiWcant tumor regression in all tumor xenografts. Conclusion The antitumor activity and the promising pharmacological proWle indicate gimatecan as an excellent candidate for clinical treatment of pediatric tumors.

Molecular profiling of childhood cancer: Biomarkers and novel therapies

“…As described for Ewing sarcoma ( Section 2.4.1.5 ), namitecan produced RD/TE-671 RMS xenograft regression at low doses and additive effects with the antiangiogenic agents bevacizumab and sunitinib [252] , while Genz-644282 induced complete responses in Rh18 and Rh28 ARMS and Rh30 ERMS xenografts [216] . Prolonged daily treatment with low doses of gimatecan also produced significant tumor regression in RD/TE-671 RMS tumor xenografts [148] .…”

“…Similarly, the combination of topotecan with vincristine and doxorubicin induced objective responses in a small cohort of 6 patients with refractory or recurrent RMS, and was well tolerated [282] . More recent in vivo studies also indicated that namitecan, Genz-644282 and gimatecan were highly active in a number of RMS xenograft models [148] , [216] , [252] . As described for Ewing sarcoma ( Section 2.4.1.5 ), namitecan produced RD/TE-671 RMS xenograft regression at low doses and additive effects with the antiangiogenic agents bevacizumab and sunitinib [252] , while Genz-644282 induced complete responses in Rh18 and Rh28 ARMS and Rh30 ERMS xenografts [216] .…”

“…In a more recent trial, topotecan in combination with cyclophosphamide produced significantly better progression-free survival than topotecan as a single regimen [145] . Etoposide has also been employed in numerous trials for refractory and relapsed neuroblastoma, with encouraging results [146] , while preclinical studies have examined other TOP1 and TOP2 inhibitors including namitecan, gimatecan and the investigational drugs EZN-2208, and (R +)XK469 [147] , [148] , [149] , [150] , [151] . Namitecan demonstrated antitumor activity in SK-N-AS neuroblastoma xenografts, inducing apoptosis and tumor shrinkage, and a significant enhancement of platinum agent activity [147] , whereas gimatecan produced significant regression of SK-N-DZ neuroblastoma xenografts in vivo [148] .…”

“…Etoposide has also been employed in numerous trials for refractory and relapsed neuroblastoma, with encouraging results [146] , while preclinical studies have examined other TOP1 and TOP2 inhibitors including namitecan, gimatecan and the investigational drugs EZN-2208, and (R +)XK469 [147] , [148] , [149] , [150] , [151] . Namitecan demonstrated antitumor activity in SK-N-AS neuroblastoma xenografts, inducing apoptosis and tumor shrinkage, and a significant enhancement of platinum agent activity [147] , whereas gimatecan produced significant regression of SK-N-DZ neuroblastoma xenografts in vivo [148] . This latter result supported the superior activity of gimatecan versus irinotecan and topotecan, in terms of producing growth arrest in 5 human neuroblastoma cell lines (SK-NDZ, BE(2)M17, LAN-1, RNGA, SK-N-BE(2)c) [149] .…”