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

Publication ,  Journal Article
Carol, H; Lock, R; Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Reynolds, CP; Maris, JM; Keir, ST; Billups, CA; Smith, MA
Published in: Pediatr Blood Cancer
December 15, 2009

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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Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

December 15, 2009

Volume

53

Issue

7

Start / End Page

1255 / 1263

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Wilms Tumor
  • Tumor Stem Cell Assay
  • Spindle Apparatus
  • Single-Blind Method
  • Sarcoma, Ewing
  • Rhabdomyosarcoma
  • Rhabdoid Tumor
  • Quinazolines
  • Osteosarcoma
 

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Carol, H., Lock, R., Houghton, P. J., Morton, C. L., Kolb, E. A., Gorlick, R., … Smith, M. A. (2009). Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood Cancer, 53(7), 1255–1263. https://doi.org/10.1002/pbc.22056
Carol, Hernan, Richard Lock, Peter J. Houghton, Christopher L. Morton, E Anders Kolb, Richard Gorlick, C Patrick Reynolds, et al. “Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program.Pediatr Blood Cancer 53, no. 7 (December 15, 2009): 1255–63. https://doi.org/10.1002/pbc.22056.
Carol H, Lock R, Houghton PJ, Morton CL, Kolb EA, Gorlick R, et al. Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2009 Dec 15;53(7):1255–63.
Carol, Hernan, et al. “Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 53, no. 7, Dec. 2009, pp. 1255–63. Pubmed, doi:10.1002/pbc.22056.
Carol H, Lock R, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA. Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2009 Dec 15;53(7):1255–1263.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

December 15, 2009

Volume

53

Issue

7

Start / End Page

1255 / 1263

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Wilms Tumor
  • Tumor Stem Cell Assay
  • Spindle Apparatus
  • Single-Blind Method
  • Sarcoma, Ewing
  • Rhabdomyosarcoma
  • Rhabdoid Tumor
  • Quinazolines
  • Osteosarcoma