Metastasis of hormone-independent breast cancer to lung and bone is decreased by alpha-difluoromethylornithine treatment.
BACKGROUND
Polyamines affect proliferation, differentiation, migration and apoptosis of cells, indicating their potential as a target for cancer chemotherapy. Ornithine decarboxylase converts ornithine to putrescine and is the rate-limiting step in polyamine synthesis.alpha-Difluoromethylornithine (DFMO) irreversibly inhibits ornithine decarboxylase and MDA-MB-435 human breast cancer metastasis to the lung without blocking orthotopic tumor growth. This study tested the effects of DFMO on orthotopic tumor growth and lung colonization of another breast cancer cell line (MDA-MB-231) and the effects on bone metastasis of MDA-MB-435 cells.


METHODS
MDA-MB-231 cells were injected into the mammary fat pad of athymic mice. DFMO treatment (2% per orally) began at the day of tumor cell injection or 21 days post injection. Tumor growth was measured weekly. MDA-MB-231 cells were injected into the tail vein of athymic mice. DFMO treatment began 7 days prior to injection, or 7 or 14 days post injection. The number and incidence of lung metastases were determined. Green fluorescent protein-tagged MDA-MB-435 cells were injected into the left cardiac ventricle in order to assess the incidence and extent of metastasis to the femur. DFMO treatment began 7 days prior to injection.


RESULTS
DFMO treatment delayed MDA-MB-231 orthotopic tumor growth to a greater extent than growth of MDA-MB-435 tumors. The most substantial effect on lung colonization by MDA-MB-231 cells occurred when DFMO treatment began 7 days before intravenous injection of tumor cells (incidence decreased 28% and number of metastases per lung decreased 35-40%). When DFMO treatment began 7 days post injection, the incidence and number of metastases decreased less than 10%. Surprisingly, treatment initiated 14 days after tumor cell inoculation resulted in a nearly 50% reduction in the number of lung metastases without diminishing the incidence. After intracardiac injection, DFMO treatment decreased the incidence of bone metastases (55% vs 87%) and the area occupied by the tumor (1.66 mm2 vs 4.51 mm2, P < 0.05).


CONCLUSIONS
Taken together, these data demonstrate that DFMO exerts an anti-metastatic effect in more than one hormone-independent breast cancer, for which no standard form of biologically-based treatment exists. Importantly, the data show that DFMO is effective against metastasis to multiple sites and that treatment is generally more effective when administered early.
Richert
Monica M
MM
Department of Pathology, Comprehensive Cancer Center, National Foundation for Cancer Research-Center for Metastasis Research, University of Alabama at Birmingham, Alabama, USA. mrichert@path.uab.edu
Phadke
Pushkar A
PA
Matters
Gail
G
DiGirolamo
Douglas J
DJ
Washington
Sharlene
S
Demers
Laurence M
LM
Bond
Judith S
JS
Manni
Andrea
A
Welch
Danny R
DR
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D000518:Eflornithine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D000518:Eflornithine