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 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 therapeutic efficacy of the sequence-selective, DNA minor-groove-binding alkylating agent carzelesin was evaluated against a series of human tumor xenografts growing at the s.c. site. The model consisted of seven colon adenocarcinomas, and six pediatric rhabdomyosarcomas. In addition, carzelesin was evaluated against xenografts selected in situ for resistance to vincristine, melphalan, and topotecan. Carzelesin was given as a single i.v. injection, and tumor volumes were determined at 7-day intervals. At the highest dose [0.5 mg/kg, the dose producing 10% lethality (LD10)]), carzelesin significantly inhibited growth in four of six colon tumor lines, causing a high proportion of partial regressions in one of seven lines and complete regressions of VRC5 colon tumors. At 0.25 mg/kg, significant growth inhibition was determined in only two of seven colon tumor lines with infrequent volume regressions. Carzelesin given at the highest nonlethal dose level significantly inhibited the growth of each of six rhabdomyosarcomas, causing a high frequency of partial or complete regressions in four of six tumor lines. There was no apparent cross-resistance to carzelesin in two rhabdomyosarcomas selected for vincristine resistance (Rh12/VCR, Rh18/VCR) or in Rh28/LPAM xenografts selected for primary resistance to the bifunctional alkylating agent melphalan. Interestingly, carzelesin maintained full activity against Rh18/TOPO tumors selected in situ for resistance to topotecan, whereas the colon tumor VRC5/TOPO, selected in a similar manner, was completely resistant to this agent.
The therapeutic efficacy of the sequence-selective, DNA minor-groove-binding alkylating agent carzelesin was evaluated against a series of human tumor xenografts growing at the s.c. site. The model consisted of seven colon adenocarcinomas, and six pediatric rhabdomyosarcomas. In addition, carzelesin was evaluated against xenografts selected in situ for resistance to vincristine, melphalan, and topotecan. Carzelesin was given as a single i.v. injection, and tumor volumes were determined at 7-day intervals. At the highest dose [0.5 mg/kg, the dose producing 10% lethality (LD10)]), carzelesin significantly inhibited growth in four of six colon tumor lines, causing a high proportion of partial regressions in one of seven lines and complete regressions of VRC5 colon tumors. At 0.25 mg/kg, significant growth inhibition was determined in only two of seven colon tumor lines with infrequent volume regressions. Carzelesin given at the highest nonlethal dose level significantly inhibited the growth of each of six rhabdomyosarcomas, causing a high frequency of partial or complete regressions in four of six tumor lines. There was no apparent cross-resistance to carzelesin in two rhabdomyosarcomas selected for vincristine resistance (Rh12/VCR, Rh18/VCR) or in Rh28/LPAM xenografts selected for primary resistance to the bifunctional alkylating agent melphalan. Interestingly, carzelesin maintained full activity against Rh18/TOPO tumors selected in situ for resistance to topotecan, whereas the colon tumor VRC5/TOPO, selected in a similar manner, was completely resistant to this agent.
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