Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program

Malcolm A. Smith, John M. Maris, Richard Lock, E. Anders Kolb, Richard Gorlick, Stephen T. Keir, Hernan Carol, Christopher L. Morton, C. Patrick Reynolds, Min H. Kang, Peter J Houghton

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: PG11047 is a novel conformationally restricted analog of the natural polyamine, spermine that lowers cellular endogenous polyamine levels and competitively inhibits natural polyamine functions leading to cancer cell growth inhibition. The activity of PG11047 was evaluated against the PPTP's in vitro and in vivo panels. Procedures: PG11047 was evaluated against the PPTP in vitro panel using 96hr exposure at concentrations ranging from 10nM to 100μM. It was tested against the PPTP in vivo panels at a dose of 100mg/kg administered by the intraperitoneal route weekly for 6 weeks. Results: In vitro PG11047 demonstrated a concentration-response pattern consistent with cytostatic activity. The median EC50 for PG11047 was 71nM. Cell lines of the Ewing sarcoma panel had a lower median EC50 value compared to the remaining cell lines in the panel, while cell lines of the neuroblastoma panel had a higher median EC50 value. In vivo PG11047 induced significant differences in EFS distribution compared to control in 5 of 32 (15.6%) of the evaluable solid tumor xenografts and in 0 of 7 (0%) of the evaluable ALL xenografts. The single case of tumor regression occurred in an ependymoma xenograft. Conclusions: Further pediatric development of PG11047 will require better defining a target population and identifying combinations for which there is a tumor-selective cytotoxic effect. The regression observed for an ependymoma xenograft and the exquisite sensitivity of some Ewing sarcoma cell lines to the antiproliferative effects of PG11047 provide leads for further preclinical investigations.

Original languageEnglish (US)
Pages (from-to)268-274
Number of pages7
JournalPediatric Blood and Cancer
Volume57
Issue number2
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

Fingerprint

Polyamines
Heterografts
Pediatrics
Cell Line
Ependymoma
Ewing's Sarcoma
Neoplasms
Spermine
Health Services Needs and Demand
Cytostatic Agents
Neuroblastoma
Growth
In Vitro Techniques
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine

Keywords

  • Developmental therapeutics
  • Polyamine
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program. / Smith, Malcolm A.; Maris, John M.; Lock, Richard; Kolb, E. Anders; Gorlick, Richard; Keir, Stephen T.; Carol, Hernan; Morton, Christopher L.; Reynolds, C. Patrick; Kang, Min H.; Houghton, Peter J.

In: Pediatric Blood and Cancer, Vol. 57, No. 2, 01.08.2011, p. 268-274.

Research output: Contribution to journalArticle

Smith, MA, Maris, JM, Lock, R, Kolb, EA, Gorlick, R, Keir, ST, Carol, H, Morton, CL, Reynolds, CP, Kang, MH & Houghton, PJ 2011, 'Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 57, no. 2, pp. 268-274. https://doi.org/10.1002/pbc.22797
Smith, Malcolm A. ; Maris, John M. ; Lock, Richard ; Kolb, E. Anders ; Gorlick, Richard ; Keir, Stephen T. ; Carol, Hernan ; Morton, Christopher L. ; Reynolds, C. Patrick ; Kang, Min H. ; Houghton, Peter J. / Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2011 ; Vol. 57, No. 2. pp. 268-274.
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