Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo.
OBJECTIVE
In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo.


METHODS
The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice.


RESULTS
The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF.


CONCLUSIONS
Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.
Lev
Dina Chelouche
DC
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Unit 0173, 7777 Knight Rd, Houston, TX 77054, USA.
Onn
Amir
A
Melinkova
Vladislava O
VO
Miller
Claudia
C
Stone
Valerie
V
Ruiz
Maribelis
M
McGary
Eric C
EC
Ananthaswamy
Honnavara N
HN
Price
Janet E
JE
Bar-Eli
Menashe
M
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000009:adverse effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D003606:Dacarbazine