PURPOSE: Melanoma, the most aggressive form of skin cancer, accounts for 75% of 
all skin cancer-related deaths and current therapeutic strategies are not 
effective in advanced disease. In the current study, we have investigated the 
efficacy of orally active small-molecule antagonist targeting CXCR2/CXCR1.
EXPERIMENTAL DESIGN: Human A375SM melanoma cells were treated with SCH-479833 or 
SCH-527123, and their effect on proliferation, motility, and invasion was 
evaluated in vitro. We examined the downstream signaling events in the cells 
following treatment with antagonists. For in vivo studies, A375SM cells were 
implanted subcutaneously into athymic nude mice followed by administration of 
SCH-479833, SCH-527123, or hydroxypropyl-beta-cyclodextrin (20%) orally for 21 
days and their effect on tumor growth and angiogenesis was evaluated.
RESULTS: Our data show that SCH-479833 or SCH-527123 inhibited the melanoma cell 
proliferation, chemotaxis, and invasive potential in vitro. Treatment of 
melanoma cells with SCH-479833 or SCH-527123 also inhibited tumor growth. 
Histologic and histochemical analyses showed significant (P < 0.05) decreases in 
tumor cell proliferation and microvessel density in tumors. Moreover, we 
observed a significant increase in melanoma cell apoptosis in SCH-479833- or 
SCH-527123-treated animals compared with controls.
CONCLUSION: Together, these studies show that selectively targeting CXCR2/CXCR1 
with orally active small-molecule inhibitors is a promising therapeutic approach 
for inhibiting melanoma growth and angiogenesis.