Cancer cells can overcome the ability of
polyamine biosynthesis inhibitors to completely deplete their internal
polyamines by the importation of
polyamines from external sources. This paper discusses the development of a group of lipophilic
polyamine analogues that potently inhibit the cellular
polyamine uptake system and greatly increase the effectiveness of
polyamine depletion when used in combination with DFMO, a well-studied
polyamine biosynthesis inhibitor. The attachment of a length-optimized C(16) lipophilic substituent to the epsilon-
nitrogen atom of an earlier lead compound, D-Lys-Spm (5), has produced an analogue, D-Lys(C(16)acyl)-Spm (11) with several orders of magnitude more potent cell growth inhibition on a variety of cultured
cancer cell types including breast (MDA-MB-231), prostate (PC-3),
melanoma (A375), and ovarian (SK-OV-3), among others. These results are discussed in the context of a possible membrane-catalyzed interaction with the extracellular
polyamine transport apparatus. The resulting novel two-
drug combination therapy targeting cellular
polyamine metabolism has shown exceptional efficacy against cutaneous
squamous cell carcinomas (SCC) in a transgenic
ornithine decarboxylase (ODC) mouse model of
skin cancer. A majority (88%) of large, aggressive SCCs exhibited complete or nearly complete remission to this combination
therapy, whereas responses to each agent alone were poor. The availability of a potent
polyamine transport inhibitor allows, for the first time, for a real test of the hypothesis that starving cells of
polyamines will lead to objective clinical response.