Immunomodulators for skin cancer

Therapeutic interventions to augment tumor antigenicity or increase the host's immune response against cancer cells include recombinant cytokines, immune modulators, vaccination with tumor antigens, T cell-based immunotherapy, and gene therapy. We describe the current role of the immunomodulators (up-regulators of the immune response) in the therapy of skin cancer (non melanoma skin cancer, melanoma, lymphoma, Kaposi sarcoma, and extramammary Paget's disease).     

Polyamines and nonmelanoma skin cancer

Elevated levels of polyamines have long been associated with skin tumorigenesis. Tightly regulated metabolism of polyamines is critical for cell survival and normal skin homeostasis, and these controls are dysregulated in skin tumorigenesis. A key enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) is upregulated in skin tumors compared to normal skin. Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. The formation of skin tumors in these transgenic mice is dependent upon polyamine biosynthesis, especially putrescine, since treatment with inhibitors of ODC activity blocks the formation of skin tumors and causes the rapid regression of existing tumors. Although the mechanism by which polyamines promote skin tumorigenesis are not well understood, elevated levels of polyamines have been shown to stimulate epidermal proliferation, alter keratinocyte differentiation status, increase neovascularization, and increase synthesis of extracellular matrix proteins in a manner similar to that seen in wound healing. It is becoming increasingly apparent that elevated polyamine levels activate not only epidermal cells but also underlying stromal cells in the skin to promote the development and progression of skin tumors. The inhibition of polyamine biosynthesis has potential to be an effective chemoprevention strategy for nonmelanoma skin cancer.     

Trends in nonmelanoma skin cancer mortality

Nonmelanoma skin cancer mortality rates for recent decades show a biphasic pattern: from 1950-65 rates decreased; from 1966-86 rates increased. Age standardised mortality rates for 35-74 year old males increased from 1.6 (95% CI, 1.3-1.9) deaths per 100,000 person years in 1966-72 to 2.3 (95% CI, 2.0-2.5) deaths per 100,000 person years in 1980-86. Rates in women were lower but showed a similar percentage increase (46%), between these periods, to that observed for men (44%). The increased mortality from 1966 was presumably a result of increased ultraviolet exposure.     

Xeroderma pigmentosum: beyond skin cancer

Xeroderma pigmentosum (XP) is a rare, autosomal-recessive inherited disease that is found worldwide at a frequency of approximately 1:250,000. XP is caused by a deficiency in either nucleotide excision repair (NER) or postreplication repair (PRR), and is characterized by severe actinic changes leading to early onset of skin cancers, various ocular manifestations, and occasional neurological abnormalities. Diagnosis is usually made clinically and can be confirmed by unscheduled DNA synthesis. Early preventative care is the most important treatment modality. We present a review of the history, clinical manifestations, pathogenesis, diagnosis, and treatment of XP.     

Resiquimod,a topical drug for viral skin lesions and skin cancer

Introduction: Resiquimod is an immune response modifier which stimulates cells through a toll-like receptors (TLR) 7 and 8 dependent pathway resulting in activation of immune responses that are effective against viral and tumor lesions.

Areas covered: Studies on genital herpes, hepatitis C and actinic keratosis (AK) as well as papers of molecular activities of resiquimod were identified by a PubMed search. Although effective against genital HSV-2 in animal models, development of topical resiquimod for the treatment of recurrent genital herpes in humans was stopped due to inconsistent results in clinical trials. Reduction of HCV viral load was achieved by oral application but was associated with unacceptable side effects. Topical treatment of AK was well tolerated and effective with clearance rates higher compared to imiquimod. The molecular mode of action underlying the clinical efficacy primarily depends on cytokine induction in TLR7/8 expressing dendritic cells in the skin.

Expert opinion: Topical resiquimod was shown to be a safe and effective treatment option for AK and appears to have potential as a treatment modality for patients with extended skin areas affected with AK (field cancerization). Resiquimod may also have potential for the therapy or prevention of epithelial viral infections.     

Electrochemotherapy for primary skin cancer and skin metastasis related to other malignancies

Electrochemotherapy is an effective local tumor ablation modality in the treatment of solid cancers. Its use combines the administration of nonpermeable or poorly permeable highly intrinsic cytotoxic drugs with the application of short and intense electric pulses to the tumors to facilitate the drug delivery into the cancer cells. After several preclinical and clinical studies using different and nonhomogenous protocols, the results of the multicenter European Standard Operating Procedure of Electrochemotherapy (ESOPE) project provided clinical procedures for a standardized, efficient, and safe electric pulse and drug administration protocol for the local treatment of any type of skin tumor nodules. Additional studies using the the multicenter European Standard Operating Procedure of Electrochemotherapy standard operating procedures confirmed the overall clinical results obtained. Currently, the tumors most frequently treated with ECT are melanoma and breast cancer metastasis, but also head and neck cancer, primary tumors of the skin, and Kaposi sarcoma. This review is intended as an update on the therapy and as an indication of possible future developments.     

Non-melanoma skin cancer in mouse and man

As a frontier organ, skin is exposed to different environmental and/or occupational chemicals which cause cutaneous cancers in experimental animals. In mice, 7,12-dimethylbenz[a]anthrancene (DMBA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are frequently used as skin model tumor initiator and promoter, respectively. The sequential administration of DMBA and TPA leads to the appearance of a large number of benign papillomas, of which some convert later into invasive squamous cell carcinomas (SCC). At the molecular level, initiation of carcinogenesis in mouse skin consists in the mutational activation of the Ha-ras oncoprotein. HA-RAS mutations are rare in human SCC, but HA-RAS-mutated tumors appear in melanoma patients treated with B-raf inhibitors, indicating that initiated, HA-RAS-mutated stem cells also reside in human skin. Similarly, UV-induced human SCC show footprint mutations in the tumor suppressor gene TP53 which are also observed in UV-induced mouse SCC. Strong species differences exist with respect to phorbol ester-mediated tumor promotion. While certain mouse strains are very susceptible, other rodent species are much less sensitive. Likewise, humans appear to be much more resistant to phorbol ester-mediated skin toxicity. Papilloma formation as a result of a chemical insult is uncommon in men, questioning the relevance of this preneoplastic lesion for humans. However, skin tumorigenesis in the experimental situation and in humans appears to follow common molecular mechanisms, even though there are species differences in the morphological correlates to the preneoplastic state. Therefore, we recommend not simply labeling them as irrelevant for human risk assessment.     

Peplomycin therapy for skin cancer in Japan

Peplomycin was given in a dose of 5 mg daily, divided into two equal parts for intramuscular administration each morning and evening. This schedule not only augments the antitumour effect but also reduces adverse reactions to the drug. Peplomycin-mitomycin C (P-M) therapy improves the response rates in T3 and T4 cases of skin cancer, and is also effective in some N1, N3 and M1 cases. Continuous intra-arterial infusion of peplomycin, though requiring somewhat complicated procedures, is very effective against squamous cell carcinoma of the head, neck and extremities. Multidisciplinary therapy incorporating peplomycin has given a considerably higher five-year survival rate than that found in historical controls.     

Pharmacologic treatment options for advanced epithelial skin cancer

Introduction: Epithelial skin cancers (ESCs), namely basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), are considered common skin malignancies, with rising incidence rates over the past few decades. A subgroup of patients with ESC present with advanced and ‘difficult’-to-treat tumours, including locally advanced and metastatic tumours. Currently, there is no widely accepted staging system for locally advanced ESCs, while metastatic BCCs and SCCs share a staging system. Therefore, selecting an appropriate therapeutic regimen for these patients may be difficult.

Areas covered: The purpose of this review is to highlight the pharmacologic treatment options for advanced ESCs. These include ‘conventional’ chemotherapeutic regimens such as 5-fluorouracil, cisplatin, vincristine, bleomycin and doxorubicin and newer, more ‘targeted’ therapies.

Expert opinion: Vismodegib, a Hedgehog (Hh) inhibitor, was recently approved for the treatment of advanced BCC showing a good efficacy rate and a relatively well-tolerated safety profile in clinical studies. In addition, a number of hedgehog inhibitors are now in Phase I and II trials of advanced BCC demonstrating encouraging results. Phase II studies with epithelial growth factor receptor inhibitors, such as cetuximab, gefitinib, panitimumab and erlotinib have been conducted in patients with advanced SCCs, used either as monotherapy or in combination with chemotherapy. However, there is still much knowledge to be gained about the treatment efficacies, optimal treatment durations, mechanisms of drug tolerance, adverse events and the ways in which these therapies influence patient outcomes and quality of life.     

p53 and the pathogenesis of skin cancer

The p53 tumor suppressor gene and gene product are among the most diverse and complex molecules involved in cellular functions. Genetic alterations within the p53 gene have been shown to have a direct correlation with cancer development and have been shown to occur in nearly 50% of all cancers. p53 mutations are particularly common in skin cancers and UV irradiation has been shown to be a primary cause of specific 'signature' mutations that can result in oncogenic transformation. There are certain 'hot-spots' in the p53 gene where mutations are commonly found that result in a mutated dipyrimidine site. This review discusses the role of p53 from normal function and its dysfunction in pre-cancerous lesions and non-melanoma skin cancers. Additionally, special situations are explored, such as Li-Fraumeni syndrome in which there is an inherited p53 mutation, and the consequences of immune suppression on p53 mutations and the resulting increase in non-melanoma skin cancer in these patients.     

Systemic retinoids in chemoprevention of non-melanoma skin cancer

Background: The incidence of non-melanoma skin cancer is increasing worldwide. Systemic retinoids are useful for the chemoprophylaxis of non-melanoma skin cancers. Retinoids have pleiotropic effects, but their exact cancer chemopreventive mechanism is still not clear. Objective: The aim of this study was to review published literature evaluating the use of oral retinoids in the chemoprevention of non-melanoma skin cancers. Methods: The study reviewed all relevant papers found through a search of the electronic databases MEDLINE (from 1966 to January 2008) and Embase (from 1974 to January 2008). Results/conclusion: General and specific indications for retinoid chemoprophylaxis are defined. The pharmacokinetics and dose regimens of the two most commonly used oral retinoids (isotretinoin and acitretin) in the chemoprevention of non-melanoma skin cancers are presented. The use of oral retinoids is associated with adverse effects, which are discussed in detail. The future of retinoid cancer chemoprevention depends on the development and research of novel retinoids with improved bioavailability and minimized toxicity.     

The role of skin painting in predicting lung cancer

The mouse skin cancer model provides an important system for studying mechanisms involved in the various stages of carcinogenesis and for bioassaying tobacco smoke constituents and additives for carcinogenic/cocarcinogenic and tumor-promoting properties as well as for identifying compounds that may inhibit tumor formation and malignant conversion. In addition, it is an excellent model for studying the formation of precancerous lesions as well as squamous cell carcinomas. It relates very well to other squamous cell carcinoma models and contributes to better understanding of the human epithelial cancers including lung cancer. The SENCAR mouse is an established model system demonstrated to be more sensitive than the B6C3F1 or Swiss CD-1 strains in the initiation/promotion skin-painting test method. Although the relationship between mouse skin tumors and any manifestation of the toxicity of tobacco smoke and other complex environmental mixtures in humans is unknown, the skin-painting model is the only assay that provides a practical method of obtaining a tumorigenic end point with cigarette smoke condensates and other complex mixtures. This assay provides a rapid response with relative ease of quantification of various parameters of tumorigenic response including tumor incidence, latency, multiplicity, and malignancy.     

The causes of skin cancer: a comprehensive review

Skin cancer is the most common type of cancer in fair-skinned populations around the world. The incidence and mortality rates of skin cancers are dramatically increasing and thus pose a threat to public health. Understanding the etiology and pathogenesis of skin cancer remains a goal for healthcare systems. A clearer understanding of causative factors is an essential step in the prevention of skin cancer. This article comprehensively reviews the causative agents which play a role in the development of skin cancer. Ultraviolet radiation (UV) from sun exposure is the most important cause of skin cancer. Sunburns and excessive exposures cause cumulative damage which induces immunosuppression and skin cancers. Ozone depletion, the level of UV light, elevation, latitude, altitude and weather conditions influence the emission of UV radiation reaching the earth's surface. Organ transplant recipients and AIDS patients have an increased incidence of skin cancers. Some treatment modalities, including radiation therapy, phototherapy and psoralen and long-wave ultraviolet radiation (PUVA) can also predispose to skin cancers. Viral infections such as the human papilloma virus can cause squamous cell carcinomas. Individuals with familial genetic syndromes are susceptible to specific types of skin cancers. Ionizing radiation, environmental pollutants, chemical carcinogens and work-related exposures have been associated with skin cancers. Exposure to artificial UV radiation (tanning beds and lamps), aging, skin color, diet and smoking are attributable risks. Skin cancers have been found in dermatoses and various types of keratoses, chronically injured or nonhealing wounds, and scars. This article provides a comprehensive and thorough overview of skin cancer, with an emphasis on understanding its epidemiology, incidence, etiology and related risk factors.