Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program
Malcolm A Smith1, John M Maris, Richard Lock
1Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland 20892, USA. smithm@ctep.nci.nih.gov
Pediatric Blood & Cancer
|March 2, 2011
Summary
PG11047, a spermine analog, inhibits cancer cell growth by lowering polyamine levels. It showed cytostatic activity in vitro and some efficacy in vivo, particularly against Ewing sarcoma xenografts.
Area of Science:
- Pharmacology
- Oncology
- Cancer Biology
Background:
- PG11047 is a novel, conformationally restricted analog of spermine.
- It reduces cellular polyamine levels and inhibits polyamine functions, leading to cancer cell growth inhibition.
Purpose of the Study:
- To evaluate the activity of PG11047 against pediatric cancer models.
- Assess its in vitro and in vivo efficacy using the Pediatric Preclinical Testing Program (PPTP) panels.
Main Methods:
- In vitro testing involved 96-hour exposure to PG11047 at concentrations from 10 nM to 100 µM.
- In vivo studies administered PG11047 at 100 mg/kg intraperitoneally weekly for 6 weeks in PPTP xenograft models.
Main Results:
- PG11047 exhibited concentration-dependent cytostatic activity with a median EC50 of 71 nM.
- Ewing sarcoma cell lines showed higher sensitivity (lower EC50) compared to neuroblastoma cell lines.
- In vivo, PG11047 demonstrated significant differences in event-free survival in 15.6% of solid tumor xenografts, with one regression in an ependymoma xenograft.
Conclusions:
- Further pediatric development requires defining target populations and identifying effective combinations for tumor-selective cytotoxicity.
- The sensitivity of Ewing sarcoma cell lines and the ependymoma xenograft regression suggest potential for further preclinical investigation.
