The human colon
carcinoma cell line SW 707 was exposed for up to 72 h to the new
antineoplastic agent 4-amino-N-(2'-aminophenyl)benzamide (
GOE 1734,
dinaline). Thereafter, uptake measurements with fluorodeoxy-[14C]
glucose (FdGlc) were performed and cell-cycle fractions as well as
adenine nucleotide pools were determined by flow cytometry and HPLC. One day after a 24 h exposure to 20-540 microM
dinaline a 2.0-to 2.5-fold enhancement of FdGlc uptake was observed, and the values after 48-h or 72-h incubations showed a 2.5- to 3.5-fold or a 2.0-fold increase respectively. For all periods of exposure a diminished S phase (3%-71% of control) was found initially after incubation, demonstrating the antiproliferative effect of
dinaline, with total recovery after 1 day.
Adenine nucleotide pools were not diminished concomitantly. The enhanced FdGlc uptake caused by
dinaline was the basis for choosing
2-deoxyglucose (dGlc) as the combination partner, which acts as an
antimetabolite to
enzymes involved in
glucose metabolism. Several combinations of
dinaline and dGlc were analyzed for their effects on growth inhibition. Almost 50% additional decrease in cell number as compared to monotherapy with
dinaline was found after coexposure to 12 mM dGlc and 20 microM
dinaline 24 h after incubation. Similar effects were observed 2 days after incubation with the two drugs. After 3 days, the cell numbers reached monotherapy levels. Since the
cytostatic effect of
dinaline could be enhanced by dGlc although incubation with dGlc alone caused no changes in cell number, the combined effect of both agents is synergistic. These results imply that
dinaline might have applications in combination treatment in vivo.