Abstract
Despite new treatments introduced over the past several years, metastatic melanoma remains difficult to cure. Although melanoma in situ (MIS) has better prognosis, it relies heavily on thorough surgical excision, where ill-defined margins can pose a challenge to successful removal, potentially leading to invasive melanoma. As well, MIS in the head and neck area can create serious aesthetic concerns with regard to the surgical defect and substantial scar formation. Toward improved treatment of localized melanoma, including the targeting of unrecognized invasive components, we have been studying a novel agent, NEO412, designed for transdermal application. NEO412 is a tripartite agent that was created by covalent conjugation of three bioactive agents: temozolomide (TMZ, an alkylating agent), perillyl alcohol (POH, a naturally occurring monoterpene with anticancer properties), and linoleic acid (LA, an omega-6 essential fatty acid). We investigated the anti-melanoma potency of NEO412 in vitro and in mouse models in vivo. The in vitro results showed that NEO412 effectively killed melanoma cells, including TMZ-resistant and BRAF mutant ones, through DNA alkylation and subsequent apoptosis. in vivo, NEO412 inhibited tumor growth when applied topically to the skin of tumor-bearing animals, and this effect involved a combination of increased tumor cell death with decreased blood vessel development. At the same time, drug-treated mice continued to thrive, and there was no apparent damage to normal skin in response to daily drug applications. Combined, our results present NEO412 as a potentially promising new treatment for cutaneous melanoma, in particular MIS, deserving of further study.
Highlights
Melanoma is the most dangerous type of skin cancer
We used colony-formation assays (CFAs), which determine the ability of cells to maintain their proliferative potency and spawn colonies of descendants
To further characterize the in vivo anti-tumor activity of NEO412, we investigated its impact on blood vessel formation in tumor tissues from those animals described in Figure 6, where implanted A2058 or M24 melanoma cells had been subjected to transdermal treatment with NEO412 or vehicle only
Summary
Melanoma is the most dangerous type of skin cancer. It is estimated that there will be over 91,270 newly diagnosed cases in 2018 and an estimated 9,320 deaths [1]. Treatment of melanoma generally involves surgical removal of the tumors, and in advanced cases, biopsy of lymph nodes is performed as well [2]. Systemic chemotherapy and immunotherapy are some of the standard treatment options in late stage disease, but www.oncotarget.com the toxic side effects and recurrence secondary to chemoand immunoresistance hinder its clinical usefulness [4]. In addition to targeting BRAF, several immunotherapies are in, or moving toward, the clinic focusing on immune checkpoint inhibitor antibodies [6]. While some of the older chemotherapeutic treatments for melanoma are considered outdated in light of the immunotherapies and BRAF checkpoint inhibitors, the body of evidence shows that the older therapies do have value [8]
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