Milk of Human Kindness? — HAMLET, Human Papillomavirus, and Warts
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《新英格兰医药杂志》
Cutaneous viral warts are common, benign, usually self-limited papillomas with a preference for the hands and feet. A wide range of local therapies based on destruction, keratolysis, immunostimulation, or antimitotic effects have been tried for the treatment of cutaneous warts, but most of the clinical trials of these local treatments have been of low quality.1 In a review, Gibbs et al. pointed out that simple preparations containing salicylic acid are the only topical treatments for which there is good evidence of efficacy and safety.1
In this issue of the Journal, Gustafsson et al. (pages 2663–2672) report the effects of a topically applied protein–lipid complex on cutaneous viral warts. They showed a beneficial effect of a substance purified from human milk, -lactalbumin bound to oleic acid (often referred to as human -lactalbumin made lethal to tumor cells [HAMLET]). In a randomized, placebo-controlled, double-blind study in which they measured the change in lesion volume of 166 skin papillomas in 40 patients, Gustafsson et al. found a reduction of 75 percent or more in all 20 patients in the experimental group, as compared with a response rate of 15 percent in the placebo group. No reactions were observed around the skin papillomas, but some patients reported a prickling sensation in the lesion.
The experimental treatment is a folding variant of human -lactalbumin in an active complex with oleic acid. In vitro, it induces cell death in many different types of tumor cell lines and undifferentiated cells through an apoptosis-like mechanism. Both the folding and the lipid cofactor are required for this effect. The protein–lipid complex travels through the cytoplasm to the nucleus, where it binds with high affinity to the histones and nucleosomes of transformed cells. Interaction of the complex with histones and chromatin in the nuclei of the transformed cells prevents transcription, cell replication, and chromosomal recombination and causes disruption of the chromatin structure and fragmentation of DNA. Healthy, differentiated cells, in contrast, survive challenge with -lactalbumin–oleic acid and show no apoptotic changes, making the substance rather specific for transformed cells.
Before the place of this complex in the treatment of cutaneous viral warts can be established, additional studies comparing its efficacy and side effects with those of well-established therapies, such as topical treatments containing salicylic acid or the application of liquid nitrogen, will be required. Practically speaking, -lactalbumin–oleic acid will probably never be able to compete with existing inexpensive therapies for cutaneous viral warts. The real challenge, therefore, will be to prove that it is also effective in the treatment or prevention of other conditions related to human papillomavirus (HPV).
HPV plays a key role in the development not only of cutaneous warts, but also of laryngeal papillomas, genital warts, vulvar intraepithelial neoplasia, cervical carcinoma, and possibly cutaneous squamous-cell carcinoma. To date, more than 90 types of HPV have been identified and their genomes sequenced. More than 100 additional partially sequenced isolates require further characterization.
HPVs may be classified on the basis of their tropism as either genital (mucosal) or cutaneous. Genital HPVs are subdivided into high-risk and low-risk types, according to their malignant potential and cell-transforming capacity in vitro. The cutaneous HPVs may be subdivided into the classic types associated with cutaneous viral warts such as verruca vulgaris and verruca plantaris (the lesions treated by Gustafsson et al.) and the so-called epidermodysplasia verruciformis types.
The latter types were initially found in patients with epidermodysplasia verruciformis, a rare genetic syndrome characterized by numerous warts and a high risk of squamous-cell carcinomas on sun-exposed sites. But these types of HPV are also common in healthy persons. Their prevalence increases with age. About 50 percent of healthy persons around 50 years of age are infected. This proportion increases to almost 100 percent among organ-transplant recipients who are receiving long-term immunosuppressive therapy.
Numerous hyperkeratotic skin lesions and actinic keratoses develop in organ-transplant recipients, and these lesions have a strong potential to evolve into cutaneous squamous-cell carcinoma. The cause of such carcinomas in this group of patients and in the general immunocompetent population is still under debate. One well-recognized and important risk factor is ultraviolet radiation, which causes DNA damage; if unrepaired, this damage can give rise to mutations. Recent studies also implicate HPV in the causation of cutaneous squamous-cell carcinoma, either alone or in collaboration with sun exposure.2,3,4,5
The hair follicle is a possible reservoir for the epidermodysplasia verruciformis types of HPV. Interestingly, the prevalence of DNA of these types of HPV in eyebrow hairs is significantly higher in persons with a history of cutaneous squamous-cell carcinoma than in persons without skin cancer.2 Moreover, patients with a history of squamous-cell carcinoma are more likely than controls to have antibodies against these types of HPV.3 The exact role of HPV in the development of cutaneous squamous-cell carcinoma is still enigmatic, but one thing is certain: its role in cutaneous carcinogenesis is different from its role in cervical cancer.
Unlike cervical cancer, skin cancer related to HPV is probably caused by an interaction between the epidermodysplasia verruciformis types of HPV and ultraviolet radiation (see Figure). The early viral protein E6 of some types of HPV may impair the process of DNA repair or prevent apoptosis after exposure to ultraviolet radiation.4,5 As a result, HPV-infected, DNA-damaged cells may survive and become genomically unstable. This instability may ultimately lead to actinic keratoses and squamous-cell carcinoma. Additional studies of the possible therapeutic and preventive effects of this -lactalbumin–oleic acid complex on other HPV-related lesions seem to be warranted.
Figure. A Proposed Scheme for the Development of Actinic Keratoses and Cutaneous Squamous-Cell Carcinoma and the Possible Mechanism of Action of Topical -Lactalbumin–Oleic Acid Complex.
Skin keratinocytes are continuously exposed to genotoxic damage, induced primarily by ultraviolet (UV) radiation. As shown in the panels on the left, most cells respond to DNA damage by repairing the DNA or dying by apoptosis. As a result, damaged cells are repaired or discarded, and normal keratinocytes remain. Occasionally, as shown in the panels on the right, HPV-infected keratinocytes are damaged by ultraviolet radiation. HPV-infected cells may have impaired DNA repair and decreased sensitivity to apoptosis induced by ultraviolet radiation and may therefore survive. DNA mutations may be formed by replication of the damaged DNA. As a result, DNA-mutated keratinocytes may accumulate, and this accumulation in combination with HPV-induced cell proliferation may lead to actinic keratoses. At the later stages of this process, HPV DNA may disappear from the outgrowing mutated cells, since HPV is probably not essential for tumor-cell maintenance. Topical treatment with -lactalbumin–oleic acid complex might offer an alternative route to apoptosis and interference with the earlier stages of tumor development.
Source Information
From the Departments of Dermatology (J.N.B.B.) and Medical Microbiology, Center of Infectious Diseases (M.C.W.F.), Leiden University Medical Center, Leiden, the Netherlands.
References
Gibbs S, Harvey I, Sterling J, Stark R. Local treatments for cutaneous warts: systematic review. BMJ 2002;325:461-461.
Struijk L, Bouwes Bavinck JN, Wanningen P, et al. Presence of human papillomavirus DNA in plucked eyebrow hairs is associated with a history of cutaneous squamous cell carcinoma. J Invest Dermatol 2003;121:1531-1535.
Feltkamp MC, Broer R, di Summa FM, et al. Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer. Cancer Res 2003;63:2695-2700.
Iftner I, Elbel E, Schopp B, et al. Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1. EMBO J 2002;21:4741-4748.
Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 2000;14:3065-3073.
Related Letters:
Treatment of Warts
Garry C. E., Garry J. A., Garry R. F., Bouwes Bavinck J. N., Feltkamp M. C.W.(Jan N. Bouwes Bavinck, M.)
In this issue of the Journal, Gustafsson et al. (pages 2663–2672) report the effects of a topically applied protein–lipid complex on cutaneous viral warts. They showed a beneficial effect of a substance purified from human milk, -lactalbumin bound to oleic acid (often referred to as human -lactalbumin made lethal to tumor cells [HAMLET]). In a randomized, placebo-controlled, double-blind study in which they measured the change in lesion volume of 166 skin papillomas in 40 patients, Gustafsson et al. found a reduction of 75 percent or more in all 20 patients in the experimental group, as compared with a response rate of 15 percent in the placebo group. No reactions were observed around the skin papillomas, but some patients reported a prickling sensation in the lesion.
The experimental treatment is a folding variant of human -lactalbumin in an active complex with oleic acid. In vitro, it induces cell death in many different types of tumor cell lines and undifferentiated cells through an apoptosis-like mechanism. Both the folding and the lipid cofactor are required for this effect. The protein–lipid complex travels through the cytoplasm to the nucleus, where it binds with high affinity to the histones and nucleosomes of transformed cells. Interaction of the complex with histones and chromatin in the nuclei of the transformed cells prevents transcription, cell replication, and chromosomal recombination and causes disruption of the chromatin structure and fragmentation of DNA. Healthy, differentiated cells, in contrast, survive challenge with -lactalbumin–oleic acid and show no apoptotic changes, making the substance rather specific for transformed cells.
Before the place of this complex in the treatment of cutaneous viral warts can be established, additional studies comparing its efficacy and side effects with those of well-established therapies, such as topical treatments containing salicylic acid or the application of liquid nitrogen, will be required. Practically speaking, -lactalbumin–oleic acid will probably never be able to compete with existing inexpensive therapies for cutaneous viral warts. The real challenge, therefore, will be to prove that it is also effective in the treatment or prevention of other conditions related to human papillomavirus (HPV).
HPV plays a key role in the development not only of cutaneous warts, but also of laryngeal papillomas, genital warts, vulvar intraepithelial neoplasia, cervical carcinoma, and possibly cutaneous squamous-cell carcinoma. To date, more than 90 types of HPV have been identified and their genomes sequenced. More than 100 additional partially sequenced isolates require further characterization.
HPVs may be classified on the basis of their tropism as either genital (mucosal) or cutaneous. Genital HPVs are subdivided into high-risk and low-risk types, according to their malignant potential and cell-transforming capacity in vitro. The cutaneous HPVs may be subdivided into the classic types associated with cutaneous viral warts such as verruca vulgaris and verruca plantaris (the lesions treated by Gustafsson et al.) and the so-called epidermodysplasia verruciformis types.
The latter types were initially found in patients with epidermodysplasia verruciformis, a rare genetic syndrome characterized by numerous warts and a high risk of squamous-cell carcinomas on sun-exposed sites. But these types of HPV are also common in healthy persons. Their prevalence increases with age. About 50 percent of healthy persons around 50 years of age are infected. This proportion increases to almost 100 percent among organ-transplant recipients who are receiving long-term immunosuppressive therapy.
Numerous hyperkeratotic skin lesions and actinic keratoses develop in organ-transplant recipients, and these lesions have a strong potential to evolve into cutaneous squamous-cell carcinoma. The cause of such carcinomas in this group of patients and in the general immunocompetent population is still under debate. One well-recognized and important risk factor is ultraviolet radiation, which causes DNA damage; if unrepaired, this damage can give rise to mutations. Recent studies also implicate HPV in the causation of cutaneous squamous-cell carcinoma, either alone or in collaboration with sun exposure.2,3,4,5
The hair follicle is a possible reservoir for the epidermodysplasia verruciformis types of HPV. Interestingly, the prevalence of DNA of these types of HPV in eyebrow hairs is significantly higher in persons with a history of cutaneous squamous-cell carcinoma than in persons without skin cancer.2 Moreover, patients with a history of squamous-cell carcinoma are more likely than controls to have antibodies against these types of HPV.3 The exact role of HPV in the development of cutaneous squamous-cell carcinoma is still enigmatic, but one thing is certain: its role in cutaneous carcinogenesis is different from its role in cervical cancer.
Unlike cervical cancer, skin cancer related to HPV is probably caused by an interaction between the epidermodysplasia verruciformis types of HPV and ultraviolet radiation (see Figure). The early viral protein E6 of some types of HPV may impair the process of DNA repair or prevent apoptosis after exposure to ultraviolet radiation.4,5 As a result, HPV-infected, DNA-damaged cells may survive and become genomically unstable. This instability may ultimately lead to actinic keratoses and squamous-cell carcinoma. Additional studies of the possible therapeutic and preventive effects of this -lactalbumin–oleic acid complex on other HPV-related lesions seem to be warranted.
Figure. A Proposed Scheme for the Development of Actinic Keratoses and Cutaneous Squamous-Cell Carcinoma and the Possible Mechanism of Action of Topical -Lactalbumin–Oleic Acid Complex.
Skin keratinocytes are continuously exposed to genotoxic damage, induced primarily by ultraviolet (UV) radiation. As shown in the panels on the left, most cells respond to DNA damage by repairing the DNA or dying by apoptosis. As a result, damaged cells are repaired or discarded, and normal keratinocytes remain. Occasionally, as shown in the panels on the right, HPV-infected keratinocytes are damaged by ultraviolet radiation. HPV-infected cells may have impaired DNA repair and decreased sensitivity to apoptosis induced by ultraviolet radiation and may therefore survive. DNA mutations may be formed by replication of the damaged DNA. As a result, DNA-mutated keratinocytes may accumulate, and this accumulation in combination with HPV-induced cell proliferation may lead to actinic keratoses. At the later stages of this process, HPV DNA may disappear from the outgrowing mutated cells, since HPV is probably not essential for tumor-cell maintenance. Topical treatment with -lactalbumin–oleic acid complex might offer an alternative route to apoptosis and interference with the earlier stages of tumor development.
Source Information
From the Departments of Dermatology (J.N.B.B.) and Medical Microbiology, Center of Infectious Diseases (M.C.W.F.), Leiden University Medical Center, Leiden, the Netherlands.
References
Gibbs S, Harvey I, Sterling J, Stark R. Local treatments for cutaneous warts: systematic review. BMJ 2002;325:461-461.
Struijk L, Bouwes Bavinck JN, Wanningen P, et al. Presence of human papillomavirus DNA in plucked eyebrow hairs is associated with a history of cutaneous squamous cell carcinoma. J Invest Dermatol 2003;121:1531-1535.
Feltkamp MC, Broer R, di Summa FM, et al. Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer. Cancer Res 2003;63:2695-2700.
Iftner I, Elbel E, Schopp B, et al. Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1. EMBO J 2002;21:4741-4748.
Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 2000;14:3065-3073.
Related Letters:
Treatment of Warts
Garry C. E., Garry J. A., Garry R. F., Bouwes Bavinck J. N., Feltkamp M. C.W.(Jan N. Bouwes Bavinck, M.)