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. 2011 Aug;57(2):268-74.
doi: 10.1002/pbc.22797. Epub 2011 Feb 25.

Initial Testing (Stage 1) of the Polyamine Analog PG11047 by the Pediatric Preclinical Testing Program

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Free PMC article

Initial Testing (Stage 1) of the Polyamine Analog PG11047 by the Pediatric Preclinical Testing Program

Malcolm A Smith et al. Pediatr Blood Cancer. .
Free PMC article

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 96 hr exposure at concentrations ranging from 10 nM to 100 µM. It was tested against the PPTP in vivo panels at a dose of 100 mg/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 EC(50) for PG11047 was 71 nM. Cell lines of the Ewing sarcoma panel had a lower median EC(50) value compared to the remaining cell lines in the panel, while cell lines of the neuroblastoma panel had a higher median EC(50) 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.

Conflict of interest statement

CONFLICT OF INTEREST STATEMENT: The authors consider that there are no actual or perceived conflicts of interest.

Figures

Figure 1
Figure 1
PG11047 in vitro activity. Top panel: The median relative IC50 (EC50) ratio graph shows the relationship between the relative IC50 values for the cell lines of the PPTP in vitro panel. Each bar represents the ratio of the median relative IC50 for the entire cell line panel to the relative IC50 value of the indicated cell line. Bars to the right represent cell lines with higher sensitivity, while bars to the left indicate cell lines with lesser sensitivity. Bottom panel: Representative dose response curve for the NALM-6 (ALL) cell line.
Figure 2
Figure 2
PG11047 activity against individual solid tumor xenografts. Kaplan-Meier curves for EFS, median relative tumor volume graphs, and individual tumor volume graphs are shown for selected lines: CHLA-258, BT-36, NB-1771, and OS-1. Controls (gray lines); Treated (black lines).
Figure 3
Figure 3
PG11047 in vivo objective response activity, left: The colored heat map depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥ 2 but < 6, and low activity by a score of < 2. Right: representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.

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