The effect of DFMO induced uptake of [3H] putrescine on human glioma cells

Polyamine synthesis inhibitors, such as a-difluoromethylornithine (DFMO), inhibit tumor cell growth in vitro and in vivo. However, upon cessation of treatment, tumor growth resumes. We hypothesized that incorporation of radioactive polyamines might kill the growth-arrested cells. This hypothesis was...

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Bibliographic Details
Published in:	Journal of neuro-oncology Vol. 55; no. 2; pp. 71 - 80
Main Authors:	REDGATE, Edward S, ALEXANDER, Dominic, MAGRA, T. Ryan, HENRETTY, Joseph S, PATRENE, Kenneth D, BOGGS, Sallie S
Format:	Journal Article
Language:	English
Published:	Dordrecht Springer 01-11-2001 Springer Nature B.V
Subjects:	Biological and medical sciences Biological Transport - drug effects Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Adhesion Cell Division Colony-Forming Units Assay Eflornithine - pharmacology Enzyme Inhibitors - pharmacology Glioma - metabolism Glioma - pathology Humans Medical sciences Neurology Ornithine Decarboxylase Inhibitors Putrescine - pharmacokinetics Tritium Tumor Cells, Cultured Tumors of the nervous system. Phacomatoses Human Cell culture Nervous system diseases Polyamine Malignant tumor Putrescine Glioblastoma multiforme In vitro Malignant glioma Chemotherapy Glioma Central nervous system disease Tumor Combined treatment
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Summary:	Polyamine synthesis inhibitors, such as a-difluoromethylornithine (DFMO), inhibit tumor cell growth in vitro and in vivo. However, upon cessation of treatment, tumor growth resumes. We hypothesized that incorporation of radioactive polyamines might kill the growth-arrested cells. This hypothesis was previously tested in rat 9L brain tumor cells in which DFMO increased both the uptake and the retention of [3H] putrescine. In these rat cells, DFMO-induced retention of high-specific-activity [3H] putrescine for 20 days resulted in several logs killing. In the present studies all of the 5 different human glioma cell lines tested with DFMO treatment also showed enhanced uptake of exogenous [3H] putrescine, reduced cell counts and enhanced killing of colony forming cells (CSF). Extending the time of DFMO treatment of cells that had taken up high-specific-activity (80 Ci/mmol) [3H] putrescine further increased the killing. A 10-day extension resulted in a 10,000-fold reduction in cumulative cell growth. A 5-day extension resulted in a 2-3 log decrease in numbers of surviving CFC. These data further support the hypothesis and suggest that DFMO-induced cell cycle arrest enhances cellular retention of [3H] putrescine, increasing the effective internal radiation dose enough to cause proliferative death. In a clinical setting, the short (approximately 1 microm) path-length of the tritium beta particle should limit effects to the tumor cells and spare adjacent normal cells. These results support the concept that treatment with the combination of polyamine inhibitors and radioactive polyamines might be a useful adjunct to current therapies for glioblastoma multiforme.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0167-594X 1573-7373
DOI:	10.1023/A:1013348227892