Metastasis of hormone-independent breast cancer to lung and bone is decreased by α-difluoromethylornithine treatment

Monica M. Richert, Pushkar A. Phadke, Gail Matters, Douglas J. DiGirolamo, Sharlene Washington, Laurence Demers, Judith S. Bond, Andrea Manni, Danny R. Welch

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Introduction: 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. α-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). Conclusion: 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.

Original languageEnglish (US)
Article numberR819
JournalBreast Cancer Research
Volume7
Issue number5
DOIs
StatePublished - Aug 9 2005

Fingerprint

Eflornithine
Bone Neoplasms
Lung Neoplasms
Hormones
Breast Neoplasms
Neoplasm Metastasis
Injections
Neoplasms
Lung
Incidence
Therapeutics
Growth
Ornithine Decarboxylase
Polyamines
Nude Mice
Heart Ventricles
Bone and Bones
Ornithine
Putrescine
Green Fluorescent Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Richert, Monica M. ; Phadke, Pushkar A. ; Matters, Gail ; DiGirolamo, Douglas J. ; Washington, Sharlene ; Demers, Laurence ; Bond, Judith S. ; Manni, Andrea ; Welch, Danny R. / Metastasis of hormone-independent breast cancer to lung and bone is decreased by α-difluoromethylornithine treatment. In: Breast Cancer Research. 2005 ; Vol. 7, No. 5.
@article{cd6bf2556dd946598858c39c2074eefb,
title = "Metastasis of hormone-independent breast cancer to lung and bone is decreased by α-difluoromethylornithine treatment",
abstract = "Introduction: 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. α-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). Conclusion: 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.",
author = "Richert, {Monica M.} and Phadke, {Pushkar A.} and Gail Matters and DiGirolamo, {Douglas J.} and Sharlene Washington and Laurence Demers and Bond, {Judith S.} and Andrea Manni and Welch, {Danny R.}",
year = "2005",
month = "8",
day = "9",
doi = "10.1186/bcr1292",
language = "English (US)",
volume = "7",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "5",

}

Metastasis of hormone-independent breast cancer to lung and bone is decreased by α-difluoromethylornithine treatment. / Richert, Monica M.; Phadke, Pushkar A.; Matters, Gail; DiGirolamo, Douglas J.; Washington, Sharlene; Demers, Laurence; Bond, Judith S.; Manni, Andrea; Welch, Danny R.

In: Breast Cancer Research, Vol. 7, No. 5, R819, 09.08.2005.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metastasis of hormone-independent breast cancer to lung and bone is decreased by α-difluoromethylornithine treatment

AU - Richert, Monica M.

AU - Phadke, Pushkar A.

AU - Matters, Gail

AU - DiGirolamo, Douglas J.

AU - Washington, Sharlene

AU - Demers, Laurence

AU - Bond, Judith S.

AU - Manni, Andrea

AU - Welch, Danny R.

PY - 2005/8/9

Y1 - 2005/8/9

N2 - Introduction: 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. α-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). Conclusion: 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.

AB - Introduction: 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. α-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). Conclusion: 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.

UR - http://www.scopus.com/inward/record.url?scp=33644877724&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33644877724&partnerID=8YFLogxK

U2 - 10.1186/bcr1292

DO - 10.1186/bcr1292

M3 - Article

VL - 7

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 5

M1 - R819

ER -