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. 2009 Dec 15;53(7):1255-63.
doi: 10.1002/pbc.22056.

Initial Testing (Stage 1) of the Kinesin Spindle Protein Inhibitor Ispinesib by the Pediatric Preclinical Testing Program

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Free PMC article

Initial Testing (Stage 1) of the Kinesin Spindle Protein Inhibitor Ispinesib by the Pediatric Preclinical Testing Program

Hernan Carol et al. Pediatr Blood Cancer. .
Free PMC article

Abstract

Background: Ispinesib is a highly specific inhibitor of kinesin spindle protein (KSP, HsEg5), a mitotic kinesin required for separation of the spindle poles. Here we report the activity of ispinesib against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP).

Procedures: Ispinesib was tested against the PPTP in vitro panel cell lines at concentrations from 0.1 nM to 1 microM and against the in vivo tumor panel xenografts by intraperitoneal administration (5 or 10 mg/kg) every 4 days for 3 doses repeated at day 21.

Results: Ispinesib was highly potent against the PPTP's in vitro cell lines with a median IC(50) of 4.1 nM. Ispinesib (10 mg/kg) induced unexplained toxicity in mice bearing osteosarcoma xenografts and exceeded the MTD in 12 of 40 non-osteosarcoma xenografts. Ispinesib induced significant tumor growth delay in 88% (23/26) of evaluable xenografts. Using a time to event measure of efficacy, ispinesib had intermediate and high levels of activity against 4 (21%) and 5 (26%) of the 19 evaluable solid tumor xenografts, respectively. Ispinesib induced maintained complete responses (CR) in a rhabdoid tumor, a Wilms tumor and a Ewing sarcoma xenograft. Ispinesib (5 mg/kg) produced 2 complete and 2 partial responses among 6 evaluable xenografts in the ALL panel. The in vivo pattern of activity was distinctive from that previously reported for vincristine.

Conclusions: Ispinesib demonstrated broad in vivo antitumor activity, including maintained complete responses for several xenografts, although with high toxicity rates at the doses studied.

Figures

Figure 1
Figure 1. Ispinesib in vitro activity
The figures illustrate typical cytotoxicity/growth inhibition dose-response curves for cell lines with T/C% values at 1 μM approaching 0% (TC-71) and for cell lines with T/C% values at 1 μM indicating a plateau agent effect of 10% or greater (Rh30). Error bars represent standard deviations for each concentration tested.
Figure 2
Figure 2. Ispinesib activity against individual solid tumor xenografts
Kaplan-Meier curves for EFS, median relative tumor volume graphs, and individual tumor volume graphs are shown for selected lines: (A) SK-NEP-1 (B) KT-11, (C) KT-16, and (D) Rh30. Controls (gray lines); Treated (black lines).
Figure 3
Figure 3. Ispinesib activity against individual ALL xenografts
Kaplan-Meier curves for EFS, median %hCD45 graphs, and individual %hCD45 graphs are shown for selected lines: (A) ALL-2, (B) ALL-3, and (C) ALL-16. Controls (gray lines); Treated (black lines).
Figure 4
Figure 4. Ispinesib in vivo objective response activity
Left: The colored ‘heat map’ depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥ 2 but < 6, and low activity by a score of < 2. Right: representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive and that achieve regression as a best response. Bars to the left are tumor models that are less sensitive and that achieve tumor progression with growth delay or no treatment effect as their best response. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.
Figure 5
Figure 5. Gene expression for KSP (KIF11) and genes with correlated expression patterns
Relative expression of KSP (KIF11) based on Affymetrix U133 Plus 2.0 expression profiles for PPTP xenografts (left panel) and cell lines (right panel), as visualized using GeneSifter software (VizX Labs, Seattle, WA). Gray indicates an absent call from Affymetrix quality control. The expression profiles for genes whose expression is highly correlated with that of KSP are also shown.

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