We have shown earlier that
polyamine biosynthesis inhibition is accompanied by cell cycle alterations that can be utilized to enhance the efficacy of herpes simplex virus
thymidine kinase -
ganciclovir (HSV-TK/GCV) cancer gene
therapy. In the present study, we asked 1) can the activated
polyamine catabolism instead of biosynthesis inhibition be utilized to enhance the efficacy of HSV-TK/GCV gene therapy, and 2) can other known cell cycle inhibitors be used to make
tumor cells more sensitive to this form of gene therapy? We show, using rat (9L) and human (U251-MG)
glioma cell populations with 15% of HSV-TK-positive cells that
DENSPM-induced activation of
polyamine catabolism caused a profound
polyamine deprivation in U251-MG cells, but there were no associated cell cycle effects in these cells. Consequently, we did not see any enhancement of the HSV-TK/GCV system.
Aphidicolin,
hydroxyurea,
mimosine and
resveratrol, but not
lovastatin induced an apparent cell cycle arrest, followed by an intense but transient increase of the S phase cells after removal of the
drug. This effect was shown to potentiate the HSV-TK/GCV cytotoxicity to some extent, especially in 9L cells and when the GCV treatment was started 0-24 h before the
drug treatment. However, the enhancement was weaker than observed earlier with DFMO-induced cell cycle arrest and a considerable degree of the effect appeared to result from the growth-inhibitory actions of the drugs. In summary, we demonstrate that
polyamine deprivation via
DENSPM action is not associated with cell cycle effects and is not sufficient to cause enhancement of the HSV-TK/GCV system. Also, drugs with a rapid effect to the cell cycle are weak boosters of the HSVTK/GCV gene therapy, thus being less useful than DFMO for enhancement of this gene therapy form in animal studies and clinical trials.