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

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.

journal_name

Pediatr Blood Cancer

journal_title

Pediatric blood & cancer

authors

Smith MA,Maris JM,Lock R,Kolb EA,Gorlick R,Keir ST,Carol H,Morton CL,Reynolds CP,Kang MH,Houghton PJ

doi

10.1002/pbc.22797

subject

Has Abstract

pub_date

2011-08-01 00:00:00

pages

268-74

issue

2

eissn

1545-5009

issn

1545-5017

journal_volume

57

pub_type

杂志文章

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