Effects of alpha-difluoromethylornithine on local recurrence and pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice.
We have recently shown that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis reduces pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice. The present experiments were designed to further explore PA involvement in breast cancer metastasis, using GFP-tagged MDA-MB-435 cells that can be tracked at the single cell level. Administration of DFMO significantly reduced the number of mice with pulmonary metastasis as well as the number of metastases per mouse. Both single-cell and multicellular metastatic deposits were similarly suppressed, thus suggesting that DFMO was inhibiting lung colonization by tumor cells rather than preventing progression of single-cell deposits to overt metastasis. DFMO administration also significantly reduced local recurrences following removal of the primary tumor. Prolongation of DFMO treatment to 14 weeks did not yield a superior antimetastatic effect beyond that provided by a 10-week course of therapy. Discontinuation of DFMO, on the other hand, was associated with local regrowth of the tumors and, possibly, recurrence of pulmonary metastasis. These data provide a rationale for testing the efficacy of anti-PA treatment within the context of adjuvant therapy of breast cancer.
Manni
Andrea
A
Departments of Medicine, Pennsylvania State University College of Medicine, Pennsylvania, USA. amanni@psu.edu
Washington
Sharlene
S
Craig
Laura
L
Cloud
Michael
M
Griffith
James W
JW
Verderame
Michael F
MF
Texter
Lindsay J
LJ
Mauger
David
D
Demers
Laurence M
LM
Harms
John F
JF
Welch
Danny R
DR
D000818:Animals; D000518:Eflornithine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D065108:Ornithine Decarboxylase Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D065108:Ornithine Decarboxylase Inhibitors; D049452:Green Fluorescent Proteins; D000518:Eflornithine