Combination of dacarbazine and dimethylfumarate efficiently reduces melanoma lymph node metastasis.
Dimethylfumarate (DMF) has been shown to reduce melanoma growth and metastasis in animal models. We addressed the question of whether DMF is as effective in its antitumor activity as the US Food and Drug Administration-approved alkylating agent dacarbazine (DTIC). We also tested the possibility of an improved antitumoral effect when both therapeutics were used together. Using our severe combined immunodeficiency (SCID) mouse model, in which xenografted human melanoma cells metastasize from primary skin sites to sentinel nodes, we show that these treatments, alone or in combination, reduce tumor growth at primary sites. Our main finding was that metastasis to sentinel nodes is significantly delayed only in mice treated with a combination of DTIC and DMF. Subsequent experiments were able to show that a combination of DTIC/DMF significantly reduced lymph vessel density in primary tumors as examined by real-time PCR and immunohistochemistry. In addition, DTIC/DMF treatment significantly impaired melanoma cell migration in vitro. In vivo, DTIC/DMF therapy significantly reduced mRNA expression and protein concentration of the promigratory chemokines CXCL2 and CXCL11. In addition, our data suggest that this xenotransplantation model is suitable for preclinical testing of various combinations of antimelanoma agents.
Valero
Teresa
T
Skin and Endothelial Research Division, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Steele
Silvia
S
Neumüller
Karin
K
Bracher
Andreas
A
Niederleithner
Heide
H
Pehamberger
Hubert
H
Petzelbauer
Peter
P
Loewe
Robert
R
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054371:Chemokine CXCL11 / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D003606:Dacarbazine / Q000494:pharmacology*; D003879:Dermatologic Agents / Q000494:pharmacology*; D000069462:Dimethyl Fumarate; D004359:Drug Therapy, Combination; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000378:metabolism; D021701:Sentinel Lymph Node Biopsy; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D054371:Chemokine CXCL11; D054426:Chemokine CXCL2; C515203:Cxcl11 protein, mouse; C404915:Cxcl2 protein, mouse; D003879:Dermatologic Agents; D005650:Fumarates; D012333:RNA, Messenger; D003606:Dacarbazine; D000069462:Dimethyl Fumarate