Polyamines are ubiquitous molecules with multiple intracellular functions. Cells tightly regulate their levels through feedback mechanisms affecting synthesis, intracellular conversion, and transport. Because
polyamines have an important role in regulating cell growth, they are a target for
cancer therapeutic development. However, to effectively inhibit cell growth through
polyamine depletion one needs to inhibit both
polyamine synthesis and import. Although the mammalian
polyamine transporter has not been cloned, we have identified
ORI 1202, an N(1)-spermine-L-lysinyl
amide, as an effective
polyamine transport inhibitor.
ORI 1202 prevents the cellular accumulation of [(3)H]
spermidine over a 20-h test period.
ORI 1202 (30-100 microM) effectively inhibits cell growth when used in conjunction with the
polyamine synthesis inhibitor
alpha-difluoromethylornithine (DFMO; > or =230 microM). Human breast, prostate, and bladder
carcinoma cell lines and
melanoma cell lines show
ORI 1202 EC(50) values in the low micromolar range when tested in conjunction with DFMO. This
cytostatic effect correlates with a reduction in the intracellular levels of
putrescine and
spermidine. When
ORI 1202 (45 mg/kg, i.p., tidx5) and DFMO (1% in
drinking water) were delivered over 14 days, MDA-MB-231
breast tumor xenografts in nude mice showed 50% growth inhibition.
Polyamine depletion
therapy provides a
cytostatic therapy that could be useful against
cancer and other diseases resulting from uncontrolled cell growth.