title: Lipophilic lysine-spermine conjugates are potent polyamine transport inhibitors for use in combination with a polyamine biosynthesis inhibitor.
abstract: 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.
authors.affiliation: MediQuest Therapeutics, Inc, Bothell, Washington 98021, USA. markburns@aminextherapeutics.com
authors.forename: Mark R
authors.initials: MR
authors.lastname: Burns
authors.forename: Gerard F
authors.initials: GF
authors.lastname: Graminski
authors.forename: Reitha S
authors.initials: RS
authors.lastname: Weeks
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Thomas G
authors.initials: TG
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D000518:Eflornithine / Q000008:administration & dosage; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009955:Ornithine Decarboxylase / Q000235:genetics; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D011073:Polyamines; C540184:lysyl-epsilon-palmitoyl-N1-spermine; D013096:Spermine; D009955:Ornithine Decarboxylase; D008239:Lysine; D000518:Eflornithine