RT Journal Article
SR Electronic
T1 Development of a Preclinical Model of Spontaneous Human Melanoma Central Nervous System Metastasis
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 4500
OP 4505
DO 10.1158/0008-5472.CAN-08-0041
VO 68
IS 12
A1 Cruz-Munoz, William
A1 Man, Shan
A1 Xu, Ping
A1 Kerbel, Robert S.
YR 2008
UL http://cancerres.aacrjournals.org/content/68/12/4500.abstract
AB Metastatic spread of melanoma to the central nervous system (CNS) is associated with dismal prognosis. Preclinical testing of novel therapeutic approaches would be aided by the development of appropriate models of spontaneous CNS metastasis arising from primary tumors. A highly metastatic variant of the WM239A human melanoma cell line, designated 113/6-4L, was generated and used to test the efficacy of long-term, low-dose metronomic cyclophosphamide and vinblastine chemotherapy on advanced established metastatic disease in sites such as liver, lungs, and lymph node. This treatment resulted in control of advanced, systemic disease and prolongation of survival. Among long-term surviving mice, 20% showed the presence of spontaneous brain metastases. Two cell lines (131/4-5B1 and 131/4-5B2) were generated from such metastases, which were found to spontaneously metastasize to brain parenchyma with occasional localization to leptomeninges, after orthotopic transplantation and removal of the primary tumor. The cell lines were found to have increased ability to proliferate in brain-conditioned medium and displayed enhanced adhesion to lung and brain endothelial cells. These findings represent the first report of spontaneous CNS metastases generated from primary tumors of any human cancer in mice, which heritably maintains this phenotype, and as such, the variant cell lines generated should aid studies in the biology and treatment of CNS metastases, especially of melanoma origin. [Cancer Res 2008;68(12):4500–5] ©2008 American Association for Cancer Research.