As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [ 14 C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.
The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (irinotecan; CPT-11) were evaluated against a panel of 21 human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas, representing an intrinsically chemorefractory malignancy, six lines derived from childhood rhabdomyosarcoma (three embryonal, three alveolar) representing a chemoresponsive histiotype, sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine and melphalan, and three pediatric brain tumors. All tumors were grown at the subcutaneous site. Topotecan was administered by oral gavage 5 days per week for 12 consecutive weeks. The maximum tolerated dose (MTD) was 1.5 mg/kg per dose. Irinotecan was given by i.v. administration daily for 5 days each week for 2 weeks [(d x 5)2](one cycle of therapy), repeated every 21 days. The MTD for three cycles was 10 mg/kg per dose. Treatment was started against advanced tumors. Topotecan caused a high frequency of objective regressions in one of eight colon tumor lines, whereas irinotecan caused complete regressions (CR) of all tumors in three colon lines and a high frequency of CRs in three additional lines. Both drugs demonstrated similar activity against rhabdomyosarcoma xenografts. Topotecan caused CR of all tumors in four of six lines, and irinotecan in five of six lines evaluated. Both agents retained full activity against tumors selected for primary resistance to vincristine, but only irinotecan retained activity against a tumor selected for primary resistance to melphalan. Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing CR in two of three lines and topotecan inducing CR in one of three lines. Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.
The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4dx4)] or daily p.o. or i.p. administration 5 days per week for up to 20 courses. On a q4dx4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in approximately 5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18-21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being < 0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (> or = 84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh12 and VRC5 colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13-20 weeks (1.0-1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC5 tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines.(ABSTRACT TRUNCATED AT 400 WORDS)
Neuroblastoma xenografts are highly sensitive to topotecan therapy, and responses in mice are achieved at systemic exposures similar to those that are clinically effective and tolerable in children. These results support the concept of deriving preclinical data relating systemic exposure to antitumor activity in xenograft models. Such data may be valuable in making informed decisions regarding the clinical development of new agents.
The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (irinotecan; CPT-11) were evaluated against a panel of 21 human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas, representing an intrinsically chemorefractory malignancy, six lines derived from childhood rhabdomyosarcoma (three embryonal, three alveolar) representing a chemoresponsive histiotype, sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine and melphalan, and three pediatric brain tumors. All tumors were grown at the subcutaneous site. Topotecan was administered by oral gavage 5 days per week for 12 consecutive weeks. The maximum tolerated dose (MTD) was 1.5 mg/kg per dose. Irinotecan was given by i.v. administration daily for 5 days each week for 2 weeks [(d x 5)2](one cycle of therapy), repeated every 21 days. The MTD for three cycles was 10 mg/kg per dose. Treatment was started against advanced tumors. Topotecan caused a high frequency of objective regressions in one of eight colon tumor lines, whereas irinotecan caused complete regressions (CR) of all tumors in three colon lines and a high frequency of CRs in three additional lines. Both drugs demonstrated similar activity against rhabdomyosarcoma xenografts. Topotecan caused CR of all tumors in four of six lines, and irinotecan in five of six lines evaluated. Both agents retained full activity against tumors selected for primary resistance to vincristine, but only irinotecan retained activity against a tumor selected for primary resistance to melphalan. Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing CR in two of three lines and topotecan inducing CR in one of three lines. Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.