This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Irinotecan is a semisynthetic water soluble analog of camptothecin that differs from other camptothecin analogs, such as topotecan and 9-aminocamptothecin, in that it is a prodrug that undergoes deesterification to a much more potent topoisomerase-I inhibitor, SN-38. Similar to other camptothecin analogs, both irinotecan and its active metabolite, SN-38, undergo pH-dependent reversible hydrolysis from active lactone species to hydroxy acid (carboxylate) forms. Irinotecan itself possesses a marginal antiproliferative effect, while its metabolite SN-38 is 100-fold more active in vitro. Irinotecan has demonstrated significant preclinical as well as clinical antitumor activity. A high degree of activity including cures have been observed in a broad spectrum of murine tumors including Ehrlich carcinoma, MH134 hepatoma, S180, and meth A fibrosarcoma. Significant antitumor activity has also been reported in xenografts derived from pediatric tumors such as neuroblastoma and rhabdomyosarcoma, as well as in rhabdomyosarcoma xenografts selected in vivo for resistance to vincristine, melphalan and topotecan. In addition, significant activity against a variety of xenografts derived from adult tumors including colon adenocarcinoma Co-4, mammary carcinoma MX-1, gastric adenocarcinomas ST-15 and SC-6, squamous cell carcinoma QG-56, and lung tumor xenografts Mqnul, Msnul, and LX1 has been observed. Finally, significant objective clinical activity has recently been reported in both Phase I and Phase II clinical trials of irinotecan in adult patients. The objectives of this study are: 1) To estimate the maximum tolerated and dose-limiting toxicities of irinotecan administered over 90 min, weekly x 4, every 6 weeks in children with refractory or progressive solid tumors; 2) To determine the pharmacokinetics of irinotecan and its active metabolite SN-38 administered over 90 min, weekly x 4, every 6 weeks to children with refractory or progressive cance; and 3) To determine the pharmacokinetics of irinotecan and its active metabolite SN-38 administered weekly x 4, every 6 weeks to children with refractory or progressive cancer who are receiving concomitant anticonvulsants.
Showing the most recent 10 out of 459 publications
