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
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.