A Randomized, Double-Blind, Placebo-Controlled Phase 3 Skin Cancer Prevention Study of α-Difluoromethylornithine in Subjects with Previous History of Skin Cancer

Bailey, Howard; Kim, KyungMann; Verma, Ajit Kumar; Sielaff, Karen; Larson, Paul O.; Snow, Stephen N.; Lenaghan, Theresa; Viner, Jaye L.; Douglas, J. A.; Dreckschmidt, Nancy E.; Hamielec, Mary; Pomplun, Marcy; Sharata, Harry H.; Puchalsky, David; Berg, Eric R.; Havighurst, Thomas C.; Carbone, Paul P.

doi:10.1158/1940-6207.capr-09-0096

Cited by 100 publications

(82 citation statements)

References 26 publications

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“…Thus, the link between ODC and NMSC is indisputable, validating ODC as both a chemoprevention and chemotherapeutic target. In fact, a recent phase III chemoprevention trial demonstrated that ␣-difluoromethylornithine, a suicide inactivator of ODC, markedly reduces the incidence of new basal cell carcinoma in subjects with a history of skin cancer (18). Earlier studies showed that topical ␣-difluoromethylornithine administration reduced the incidence of actinic keratosis, a precursor of squamous cell carcinoma, in subjects at high risk for NMSC (56).…”

Section: Discussionmentioning

confidence: 99%

“…A link between neoplastic transformation and increased ODC enzyme activity, as well as increases in intracellular putrescine and spermidine, have been well documented in animal models of skin carcinogenesis and other epithelial tumors (11)(12)(13)(14)(15)(16)(17). Moreover, a link between human nonmelanoma skin cancer (NMSC), the most prevalent cancer in the United States, and elevated ODC enzyme activity levels has been described (18). The induction of ODC activity during tumor development has been attributed to both increased Odc gene transcription and translation of the ODC mRNA (9,19).…”

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confidence: 99%

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Cytoplasmic Accumulation of the RNA-binding Protein HuR Stabilizes the Ornithine Decarboxylase Transcript in a Murine Nonmelanoma Skin Cancer Model

Nowotarski

Shantz

2010

Journal of Biological Chemistry

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Ornithine decarboxylase (ODC) is the first and usually ratelimiting enzyme in the polyamine biosynthetic pathway. Under normal physiological conditions, polyamine content and ODC enzyme activity are highly regulated. However, the induction of ODC activity is an early step in neoplastic transformation. The studies described here use normal mouse keratinocytes (C5N cells), and spindle carcinoma cells (A5 cells) to explore the regulation of ODC in nonmelanoma skin cancer development. Previous results have shown that induction of ODC activity is both necessary and sufficient for the promotion of skin tumors. We see a marked increase in ODC enzyme activity in A5 cells compared with C5N keratinocytes, which correlates with a 4-fold stabilization of ODC mRNA. These data suggest that ODC is post-transcriptionally regulated in skin tumor development. Thus, we sought to investigate whether the ODC transcript interacts with the RNA-binding protein HuR, which is known to bind to and stabilize its target mRNAs. We show that HuR is able to bind to the ODC 3-UTR in A5 cells but not in C5N cells. Immunofluorescence results reveal that HuR is present in both the nucleus and cytoplasm of A5 cells, whereas C5N cells exhibit strictly nuclear localization of HuR. Knockdown experiments in A5 cells showed that when HuR is depleted, ODC RNA becomes less stable, and ODC enzyme activity decreases. Together, these data support the hypothesis that HuR plays a causative role in ODC up-regulation during nonmelanoma skin cancer development by binding to and stabilizing the ODC transcript. Ornithine decarboxylase (ODC)2 catalyzes the conversion of the amino acid ornithine to the diamine putrescine, which is subsequently converted to the higher polyamines spermidine and spermine (1, 2). Polyamines are small, ubiquitous polycations and are necessary for normal cell growth and development. Thus, the ablation of ODC is lethal in utero (3). Because of their charge, polyamines are able to bind to RNA, DNA, and proteins and thereby influence gene expression (4). Both polyamine content and ODC enzyme activity are tightly regulated in cells, and ODC is induced in response to a variety of proliferative stimuli by alterations in its transcription, translation, and protein degradation (5-10). A link between neoplastic transformation and increased ODC enzyme activity, as well as increases in intracellular putrescine and spermidine, have been well documented in animal models of skin carcinogenesis and other epithelial tumors (11-17). Moreover, a link between human nonmelanoma skin cancer (NMSC), the most prevalent cancer in the United States, and elevated ODC enzyme activity levels has been described (18). The induction of ODC activity during tumor development has been attributed to both increased Odc gene transcription and translation of the ODC mRNA (9, 19).Interestingly, changes in intracellular polyamine pools have also been shown to affect the localization of RNA-binding proteins (RBPs), which influence the stability of their target mRNA transcripts (2...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cytoplasmic Accumulation of the RNA-binding Protein HuR Stabilizes the Ornithine Decarboxylase Transcript in a Murine Nonmelanoma Skin Cancer Model

Nowotarski

Shantz

2010

Journal of Biological Chemistry

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“…130 There is also some evidence that a-difluoromethylornithine, an irreversible inhibitor of the pathway that produces polyamines in humans, may reduce the risk for BCC in those with a history of keratinocyte cancer, although treatment-associated audiometric abnormalities have been reported. 131,132 Although there is evidence that oral celecoxib makes NMSC in general, and BCC in particular, less likely in patients with previous NMSC, the potential benefits should be weighed against the significant risk for a cardiovascular event that is associated with this medication. 133,134 The dietary supplements b-carotene and selenium have also been studied, and are not recommended for reducing risk for BCC or cSCC in patients with a history of BCC.…”

Section: Follow-up and Reducing Risk For Future Skin Cancersmentioning

confidence: 99%

“…[116][117][118][119]123,[125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141] …”

Section: Follow-up and Reducing Risk For Future Skin Cancersunclassified

Guidelines of care for the management of basal cell carcinoma

Baum¹,

Bordeaux²,

Brown³

et al. 2018

Journal of the American Academy of Dermatology

328

219

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Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed. ( J Am Acad Dermatol

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“…A recent study showed that DFMO, when combined with sulindac (an NSAID), significantly reduced the risk of recurring colorectal polyps (Meyskens et al, 2008). Another controlled phase III clinical trial showed that DFMO might reduce the recurrence of basal cell carcinoma (Balley et al, 2010). In addition, DFMO is currently being researched in prevention of esophageal cancer (Sinicrope et al, 2011) and breast cancer (Izbicka et al, 2010).…”

Section: Difluoromethylornithine (Dfmo)mentioning

confidence: 99%