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.
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Authors | Hernan Carol, Richard Lock, Peter J Houghton, Christopher L Morton, E Anders Kolb, Richard Gorlick, C Patrick Reynolds, John M Maris, Stephen T Keir, Catherine A Billups, Malcolm A Smith |
Journal | Pediatric blood & cancer
(Pediatr Blood Cancer)
Vol. 53
Issue 7
Pg. 1255-63
(Dec 15 2009)
ISSN: 1545-5017 [Electronic] United States |
PMID | 19554570
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | (c) 2009 Wiley-Liss, Inc. |
Chemical References |
- Antimitotic Agents
- Antineoplastic Agents
- Benzamides
- Quinazolines
- ispinesib
- Kinesins
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Topics |
- Animals
- Antimitotic Agents
(pharmacology, therapeutic use)
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Benzamides
(pharmacology, therapeutic use)
- Cell Line, Tumor
(drug effects)
- Female
- Glioblastoma
(drug therapy, pathology)
- Humans
- Injections, Intraperitoneal
- Kinesins
(antagonists & inhibitors)
- Leukemia, Experimental
(drug therapy)
- Mice
- Mice, Inbred BALB C
- Mice, SCID
- Osteosarcoma
(drug therapy, pathology)
- Quinazolines
(pharmacology, therapeutic use)
- Rhabdoid Tumor
(drug therapy, pathology)
- Rhabdomyosarcoma
(drug therapy, pathology)
- Sarcoma, Ewing
(drug therapy, pathology)
- Single-Blind Method
- Spindle Apparatus
(drug effects)
- Tumor Stem Cell Assay
- Wilms Tumor
(drug therapy, pathology)
- Xenograft Model Antitumor Assays
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