EFFECTIVE SCHEDULES OF EXPOSURE OF MEDULLOBLASTOMA AND RHABDOMYOSARCOMA XENOGRAFTS TO TOPOTECAN CORRELATE WITH IN-VITRO ASSAYS

Citation
Ca. Pawlik et al., EFFECTIVE SCHEDULES OF EXPOSURE OF MEDULLOBLASTOMA AND RHABDOMYOSARCOMA XENOGRAFTS TO TOPOTECAN CORRELATE WITH IN-VITRO ASSAYS, Clinical cancer research, 4(8), 1998, pp. 1995-2002
Citations number
41
Categorie Soggetti
Oncology
Journal title
ISSN journal
10780432
Volume
4
Issue
8
Year of publication
1998
Pages
1995 - 2002
Database
ISI
SICI code
1078-0432(1998)4:8<1995:ESOEOM>2.0.ZU;2-Q
Abstract
The camptothecin derivative topotecan has been postulated to mediate i ts antitumor effect through a drug-induced increase in covalent topois omerase I-DNA complexes. If this hypothesis is correct, then schedules of exposure to topotecan that maximize the number of topoisomerase I- DNA complexes should produce the greatest cytotoxicity, We identified schedules of exposure to topotecan that maximize levels of complexes i n vitro and used these schedules to postulate effective schedules of e xposure in vivo in a mouse xenograft model. Unexpectedly, K+-SDS preci pitation assays quantitating covalent topoisomerase I-DNA complexes sh owed that Daoy medulloblastoma and Rh30 rhabdomyosarcoma cells became refractory to drug-induced increases in complexes after an 8-h exposur e to 2.5 mu M topotecan, In contrast, assays using 10-50 nM topotecan showed that the cells did not become refractory, and more importantly, intermittent exposure to drug increased the level of complexes simila r to 2-fold above the maximum level observed after a single drug expos ure. The data indicate that continuous exposure to topotecan does not maximize topoisomerase I-DNA complexes and suggest that effective inte rmittent schedules of exposure to topotecan might be identified, Growt h inhibition assays confirmed this hypothesis and showed that growth i nhibition by topotecan was extremely schedule dependent in Rh30 cells but not in Daoy cells. Xenograft studies showed that schedules modeled after the in vitro experiments produced complete tumor regressions in mice. Topotecan given daily (0.6-2.2 mg/kg) or every other day (1-3.3 mg/kg) for 2 weeks, repeated every 21 days for three cycles, produced complete regressions of Daoy xenografts; however, daily exposure was required to achieve complete regressions of Rh30 xenografts, We conclu de that effective intermittent schedules of exposure to topotecan, bas ed on biochemical parameters, can be identified. The clinical utility of each schedule will depend on the relative antitumor effect compared to the toxic effect on the bone marrow, which usually limits administ ration of topotecan to patients.