Thalidomide enhances the anti-tumor activity of standard chemotherapy in a human melanoma xenotransplatation model.
It has been demonstrated that thalidomide's anti-angiogenic properties result in clear anti-tumor activity in a number of human malignancies. We studied thalidomide in a human melanoma severe combined immunodeficiency mouse xenotransplantation model. Thalidomide as a single agent showed a significant tumor reduction of 46% compared with the control group. Thalidomide combined with dacarbazine treatment markedly enhanced the anti-tumor effect of chemotherapy and showed a significant tumor reduction relative to the dacarbazine-only group (61%) and even more tumor reduction (74%) compared with the control group. We also measured clearly reduced levels of tumor necrosis factor-alpha in the thalidomide-treated group. A significantly lower microvessel density was encountered in the thalidomide treatment groups (thalidomide alone or combined with DTIC), underscoring the anti-angiogenic effect of thalidomide as a single agent as well as in combination with chemotherapy in this model. In line with these results, we observed a nearly 3-fold increase of apoptosis for the combination of thalidomide and DTIC compared with the rate of apoptotic cells in DTIC-only-treated melanoma xenotransplants. These data underline the rationale for combining dacarbazine--a cytotoxic agent--and thalidomide--an anti-angiogenic cytostatic agent--as a promising strategy for the treatment of melanoma.
Heere-Ress
Elisabeth
E
Department of Dermatology, Division of General Dermatology, Medical University of Vienna, Austria. Elisabeth.Heere-Rees@akh-wien.ac.at
Boehm
Johannes
J
Thallinger
Christiane
C
Hoeller
Christoph
C
Wacheck
Volker
V
Birner
Peter
P
Wolff
Klaus
K
Pehamberger
Hubert
H
Jansen
Burkhard
B
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D003606:Dacarbazine / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy*; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D003606:Dacarbazine