Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program.

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.

journal_name

Pediatr Blood Cancer

journal_title

Pediatric blood & cancer

authors

Carol H,Lock R,Houghton PJ,Morton CL,Kolb EA,Gorlick R,Reynolds CP,Maris JM,Keir ST,Billups CA,Smith MA

doi

10.1002/pbc.22056

subject

Has Abstract

pub_date

2009-12-15 00:00:00

pages

1255-63

issue

7

eissn

1545-5009

issn

1545-5017

journal_volume

53

pub_type

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