Human solid
tumors frequently have a relatively small growth fraction,which interferes with the action of many chemotherapeutic agents that target actively cycling cells. Several
polyamine analogues are currently being developed for clinical application against human solid
tumors including
N1,N11-bis(ethyl)norspermine. Therefore, an effort was made to examine the effects of growth rate on
polyamine-analogue efficacy. Low growth fraction (LGF) cell cultures of the human
non-small cell lung cancer cell line NCI-H157 were generated to partially mimic solid
tumors with low mitotic indices. Log-phase cells were compared with LGF cells with respect to cell survival and biochemical effects after exposure to
polyamine analogues. The results demonstrate generally that LGF NCI-H157 cells were sensitive to analogue treatment. However, the dose necessary to elicit a response in LGF cells was an order of magnitude higher than the dose needed in log-phase cells. Additionally, the biochemical effects of analogues were similar between log phase and LGF cells with regard to a down-regulation of
polyamine biosynthesis as measured by
ornithine decarboxylase activity and an increase in
polyamine catabolism as indicated by an increase in
spermidine/
spermine N1-acetyltransferase activity. However, biochemical effects were less dramatic in the LGF cells than those observed in the log-phase cells. The overall results of these studies suggest that the growth status of solid
tumors can significantly affect the response to antitumor
polyamine analogues, and growth fraction must be considered in the continued development and use of the
polyamine analogues.