Oncotarget

Research Papers:

NEO412: A temozolomide analog with transdermal activity in melanoma in vitro and in vivo

Steve Swenson, Catalina Silva-Hirschberg, Weijun Wang, Anupam Singh, Florence M. Hofman, Kristen L. Chen, Axel H. Schönthal and Thomas C. Chen _

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Oncotarget. 2018; 9:37026-37041. https://doi.org/10.18632/oncotarget.26443

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Abstract

Steve Swenson1, Catalina Silva-Hirschberg2, Weijun Wang1, Anupam Singh2, Florence M. Hofman3, Kristen L. Chen4, Axel H. Schönthal2 and Thomas C. Chen1,3,5

1Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

2Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

3Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

4Medical College of Wisconsin, Milwaukee, WI, USA

5Department of Orthopedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Correspondence to:

Thomas C. Chen, email: [email protected]

Keywords: perillyl alcohol; temozolomide; transdermal; melanoma in situ; linoleic acid

Received: October 06, 2018     Accepted: November 26, 2018     Published: December 11, 2018

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.


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