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Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program.

Publication ,  Journal Article
Houghton, PJ; Lock, R; Carol, H; Morton, CL; Gorlick, R; Anders Kolb, E; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, CA; Zhang, MX ...
Published in: Pediatr Blood Cancer
February 2012

BACKGROUND: Genz-644282 is a novel non-camptothecin topoisomerase I poison that is in clinical development. PROCEDURES: Genz-644282 was tested against the PPTP in vitro panel (0.1 nM to 1 µM), and in vivo using three times per week × 2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4 mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1 mg/kg in 3 models to assess the dose-response relationship. mRNA gene signatures predictive for Genz-644282 response in vitro were applied to select 15 tumor models that were evaluated prospectively. RESULTS: In vitro, Genz-644282 demonstrated potent cytotoxic activity with a median IC(50) of 1.2 nM (range 0.2-21.9 nM). In vivo, Genz-644282 at its MTD (4 mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2 mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1 mg/kg. Further testing at 2 mg/kg showed that Genz-644282 induced objective regressions in 7 of 17 (41%) models. There was a significant correlation between predictive response scores based on Affymetrix U133Plus2 baseline tumor expression profiles and the observed in vivo responses to Genz-644282. CONCLUSIONS: Genz-644282 was highly active within a narrow dose range (2-4 mg/kg), typical of other topoisomerase I poisons. As with other topoisomerase I poisons, how accurately these data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent.

Duke Scholars

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

February 2012

Volume

58

Issue

2

Start / End Page

200 / 209

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Tumor Burden
  • Topotecan
  • Topoisomerase I Inhibitors
  • Survival Rate
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Naphthyridines
  • Mice, SCID
 

Citation

APA
Chicago
ICMJE
MLA
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Houghton, P. J., Lock, R., Carol, H., Morton, C. L., Gorlick, R., Anders Kolb, E., … Smith, M. A. (2012). Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program. Pediatr Blood Cancer, 58(2), 200–209. https://doi.org/10.1002/pbc.23016
Houghton, Peter J., Richard Lock, Hernan Carol, Christopher L. Morton, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, et al. “Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program.Pediatr Blood Cancer 58, no. 2 (February 2012): 200–209. https://doi.org/10.1002/pbc.23016.
Houghton PJ, Lock R, Carol H, Morton CL, Gorlick R, Anders Kolb E, et al. Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):200–9.
Houghton, Peter J., et al. “Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 58, no. 2, Feb. 2012, pp. 200–09. Pubmed, doi:10.1002/pbc.23016.
Houghton PJ, Lock R, Carol H, Morton CL, Gorlick R, Anders Kolb E, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups CA, Zhang MX, Madden SL, Teicher BA, Smith MA. Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):200–209.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

February 2012

Volume

58

Issue

2

Start / End Page

200 / 209

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Tumor Burden
  • Topotecan
  • Topoisomerase I Inhibitors
  • Survival Rate
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Naphthyridines
  • Mice, SCID