Novel lysine-spermine conjugate inhibits polyamine transport and inhibits cell growth when given with DFMO.
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.
Weeks
R S
RS
Oridigm Corporation, 4010 Stone Way North, No. 220, Seattle, Washington 98103, USA. weeksrs@oridigm.com
Vanderwerf
S M
SM
Carlson
C L
CL
Burns
M R
MR
O'Day
C L
CL
Cai
F
F
Devens
B H
BH
Webb
H K
HK
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects*; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008545:Melanoma; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011073:Polyamines / Q000378:metabolism*; D011471:Prostatic Neoplasms; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; C417042:ORI 1202; D011073:Polyamines; D013096:Spermine; D008239:Lysine; D013095:Spermidine; D000518:Eflornithine