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


METHODS
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.
Carol
Hernan
H
Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
Lock
Richard
R
Houghton
Peter J
PJ
Morton
Christopher L
CL
Kolb
E Anders
EA
Gorlick
Richard
R
Reynolds
C Patrick
CP
Maris
John M
JM
Keir
Stephen T
ST
Billups
Catherine A
CA
Smith
Malcolm A
MA
D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007274:Injections, Intraperitoneal; D016547:Kinesins / Q000037:antagonists & inhibitors*; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D018335:Rhabdoid Tumor / Q000188:drug therapy / Q000473:pathology; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000473:pathology; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000473:pathology; D016037:Single-Blind Method; D008941:Spindle Apparatus / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D009396:Wilms Tumor / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D001549:Benzamides; D011799:Quinazolines; C508757:ispinesib; D016547:Kinesins