RESUMEN
AZD1152 is a highly selective Aurora B kinase inhibitor currently undergoing Phase I and II clinical evaluation in patients with acute myelogenous leukemia and advanced solid malignancies. We have established two AZD1152-resistant cell lines from SW620 colon and MiaPaCa pancreatic carcinoma lines, which are >100-fold resistant to the active metabolite of AZD1152, AZD1152 HQPA and interestingly, cross-resistant to the pan-Aurora kinase inhibitor, VX-680/MK0457. Using whole-genome microarray analysis and comparative genomic hybridization, we were able to identify MDR1 and BCRP as the causative genes that underlie AZD1152 HQPA-resistance in these models. Furthermore, the upregulation of either of these genes is sufficient to render in vivo tumor growth insensitive to AZD1152. Finally, the upregulation of MDR1 or BCRP is predictive of tumor cell sensitivity to this agent, both in vitro and in vivo. The data provide a genetic basis for resistance to Aurora kinase inhibitors, which could be utilized to predict clinical response to therapy.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/genética , Antineoplásicos/farmacología , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/genética , Organofosfatos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Aurora Quinasa B , Aurora Quinasas , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Hibridación Genómica Comparativa , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica/métodos , Humanos , Concentración 50 Inhibidora , Ratones , Ratones SCID , Proteínas de Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Piperazinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Factores de Tiempo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We have developed a murine melanoma model that allows us to investigate the mechanisms by which spontaneous, immunogenic melanoma metastases escape immunological destruction in syngeneic mice. In the current study, we tested the hypothesis that loss of immunogenicity is an obligatory step in the persistence of pulmonary metastases. Fragments of syngeneic K1735-M2 tumor were implanted in the outer edge of one pinna per C3H/HeN mouse, and the growing tumors were removed 2-3 weeks later. Two weeks after removal of the tumors, the mice demonstrated effective T-cell-mediated immunity to s.c. challenge with K1735-M2 cells. However, lung metastases appeared in 23% of the immunized mice within 9-12 weeks after the initial tumor implantation. The expression of protective immunity to s.c. tumors required the presence of both CD4+ and CD8+ T cells. The immunized mice had specific CTLs capable of killing both K1735-M2 melanoma cells and the cells of nine independently derived melanoma metastases. Furthermore, K1735-M2 immunization protected these mice from s.c. tumor challenge with all nine metastatic cell lines. Our results demonstrate that the persistence of these metastases within the lung was not attributable to emergence of antigen-loss variants in immunized hosts. Our model provides an approach to investigate other mechanisms by which spontaneous metastases escape from immunological control and an opportunity to improve immunotherapy of melanoma metastases.
Asunto(s)
Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Melanoma Experimental/inmunología , Melanoma Experimental/secundario , Animales , Antígenos de Neoplasias/inmunología , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Hipersensibilidad Tardía/inmunología , Inmunidad Innata/inmunología , Inmunización , Masculino , Ratones , Ratones Endogámicos C3H , Trasplante de Neoplasias , Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
The role of ultraviolet (UV) radiation in the induction of nonmelanoma skin cancer is widely accepted, although its precise contribution to the development of primary cutaneous melanoma skin cancer requires further definition. We found that painting aloe emodin, a trihydroxyanthraquinone from Aloe barbadensis, in ethyl alcohol vehicle on the skin of mice in conjunction with exposure to UVB (280-320 nm) radiation results in the development of melanin-containing skin tumors. C3H/HeN mice were treated thrice weekly with aloe emodin in a 25% ethanol in water vehicle and exposed to 15 kJ/m2 UV radiation. Neither ethanol vehicle nor aloe emodin alone induced skin tumors in the absence of UV radiation. In two separate experiments, 20-30% of the mice treated with a combination of UV radiation and ethanol vehicle and 50-67% of the UV-irradiated animals given aloe emodin in ethanol vehicle developed primary cutaneous melanin-containing tumors. The diagnosis of melanoma was established using Fontana silver stain for melanin; these tumors were negative for vimentin and keratin. Melanin-containing melanosomes were observed by transmission electron microscopy in tumors diagnosed as melanomas. Although the mechanism of carcinogenesis in these mice is currently unknown, our findings have led to the development of the first facile murine model for the induction of primary melanoma. This model has the potential to clarify the role of UV radiation in the etiology of malignant melanoma.
Asunto(s)
Carcinógenos/toxicidad , Emodina/toxicidad , Etanol/toxicidad , Melanoma/etiología , Neoplasias Inducidas por Radiación , Neoplasias Cutáneas/etiología , Animales , Antraquinonas , Femenino , Melanoma/inducido químicamente , Ratones , Ratones Endogámicos C3H , Neoplasias Cutáneas/inducido químicamenteRESUMEN
We determined whether cutaneous angiogenesis induced by exposure of mice to ultraviolet-B (UVB) radiation is associated with an imbalance between positive and negative angiogenesis-regulating molecules. Unshaved C3H/HeN mice were exposed to a single dose (15 kJ per m2) of UVB. At various times, the mice were killed, and their external ears were processed for routine histology and immunohistochemistry. Antibodies against proliferating cell nuclear antigen and bromodeoxyuridine identified dividing cells. Antibodies against CD31/ PECAM-1 identified endothelial cells, and antibodies against basic fibroblast growth factor (bFGF), vascular endothelial growth factor/vascular permeability factor, and interferon-beta (IFN-beta) identified angiogenesis-regulating molecules. Epidermal hyperplasia was documented by 48 h and reached a maximum on day 7 after exposure to UVB. The expression of bFGF increased by 24 h, whereas the expression of IFN-beta decreased by 72 h after exposure to UVB. The expression of vascular endothelial growth factor/vascular permeability factor increased slightly after irradiation. The altered balance between bFGF and IFN-beta was associated with increased endothelial cell proliferation (bromodeoxyuridine + CD31 + cells) within existing blood vessels, leading to telangiectasia and new blood vessels. UV-induced epidermal hyperplasia and cutaneous angiogenesis were highest in IFN-alpha/beta receptor knockout mice. These results demonstrate that in response to UVB radiation, dividing keratinocytes produce a positive angiogenic molecule (bFGF) but not a negative angiogenic molecule (IFN-beta), and that this altered balance is associated with enhanced cutaneous angiogenesis.
Asunto(s)
Neovascularización Patológica/etiología , Piel/irrigación sanguínea , Rayos Ultravioleta , Animales , División Celular/efectos de la radiación , Factores de Crecimiento Endotelial/análisis , Femenino , Factor 2 de Crecimiento de Fibroblastos/análisis , Hiperplasia/etiología , Hiperplasia/metabolismo , Interferón-alfa/análisis , Interferón beta/análisis , Queratinocitos/citología , Cinética , Linfocinas/análisis , Ratones , Ratones Endogámicos C3H , Neovascularización Patológica/metabolismo , Piel/patología , Piel/efectos de la radiación , Coloración y Etiquetado , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Our objective was to determine the clinical activity, toxicity, and immunological effects of active immunotherapy using UVB-irradiated (UVR) autologous tumor (AT) cells plus adjuvant DETOX in metastatic melanoma patients. Eligibility included nonanergic patients fully recovered after resection of 5 or more grams of metastatic melanoma. Treatment consisted of intradermal injections of 10(7) UVR-AT plus 0.25 ml of DETOX every 2 weeks x 6, then monthly. Peripheral blood mononuclear cells (PBMCs) were harvested for cytotoxicity assays, and skin testing was performed for delayed-type hypersensitivity (DTH) determinations before the first, fourth, seventh, and subsequent treatments. Forty-two patients were treated, 18 in the adjuvant setting and 24 with measurable disease. Among the latter group, there were two durable responses in soft-tissue sites and in a bone metastasis. Treatment was well tolerated. Thirty-five patients were assessable for immunological parameters; 10 of these patients, including the 2 responders, demonstrated early induction of PBMC cytotoxicity against AT cells that persisted up to 10 months on treatment before falling to background levels. In five of seven patients, the fall-off heralded progressive disease. Late induction of a weak DTH reaction to AT cells was observed in eight patients. Active immunotherapy with UVR-AT + DETOX had modest but definite clinical activity in advanced melanoma. The induction of both PBMC cytotoxicity and DTH reactivity to AT cells supported a specific systemic immune effect of treatment, although the former more closely followed disease course in this study.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Vacunas contra el Cáncer , Proteínas del Citoesqueleto/uso terapéutico , Inmunoterapia , Lípido A/análogos & derivados , Melanoma/inmunología , Melanoma/terapia , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Rayos Ultravioleta , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/sangre , Neoplasias Óseas/inmunología , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Citotoxicidad Inmunológica , Combinación de Medicamentos , Femenino , Humanos , Hipersensibilidad Tardía , Inmunidad Activa , Inmunoglobulina G/sangre , Lípido A/uso terapéutico , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias de los Tejidos Blandos/inmunología , Neoplasias de los Tejidos Blandos/terapia , Tasa de Supervivencia , Factores de TiempoRESUMEN
We have developed a model for studying the role of local immunologic mechanisms in tumor development, in which injection of K1735 melanoma cells into the UV-irradiated ears of C3H mice results in a significantly higher incidence of tumors than injection into unirradiated ears. This effect of UV irradiation is immunologically mediated. We hypothesized that UV blocks the efferent arm of the immune response, thereby facilitating tumor development within the irradiated site. We demonstrate that elicitation of a delayed type hypersensitivity response to alloantigen is diminished in UV-irradiated ears. in addition, tumor rejection is impaired in melanoma-immune mice challenged in UV-irradiated ears, even though such mice exhibit systemic immunity when challenged in a nonirradiated site. The ability of immune lymphoid cells to inhibit melanoma growth when mixed with tumor cells and injected into the ears was inhibited by prior UV irradiation of the ears, indicating that the activity of immune effector cells is abrogated in the UV-irradiated microenvironment. Analysis of lymphoid cells in growing tumors indicated that the number of CD8+ T lymphocytes was reduced in the UV-irradiated site. We conclude that efferent immune responses are impaired in UV-irradiated tissue and suggest that the impairment may involve reductions in both the number and the activity of immune effector cells. These studies illustrate that conditions in the local microenvironment during the early stages of tumor growth may profoundly influence the outcome of the host-tumor interaction.
Asunto(s)
Melanoma/inmunología , Melanoma/patología , Neoplasias Inducidas por Radiación/inmunología , Neoplasias Inducidas por Radiación/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Rayos Ultravioleta/efectos adversos , Animales , División Celular/inmunología , División Celular/efectos de la radiación , Movimiento Celular/efectos de la radiación , Femenino , Rechazo de Injerto/etiología , Rechazo de Injerto/inmunología , Hipersensibilidad Tardía/inmunología , Inmunidad Celular/efectos de la radiación , Isoantígenos/inmunología , Ratones , Ratones Endogámicos C3H , Piel/inmunología , Piel/efectos de la radiación , Neoplasias Cutáneas/etiologíaRESUMEN
The immune system plays an important role in ultraviolet (UV) carcinogenesis by contributing to host resistance against skin cancer development. UV radiation, however, circumvents immune surveillance against skin cancers by modulating the immune response in a way that favors tumor development. Studies addressing the cellular mechanisms by which UV radiation modifies immune function are summarized. These studies demonstrate that UV irradiation of the skin produces both local, nonspecific immune suppression that inhibits immune effector functions within irradiated skin, as well as systemic, specific immune suppression against antigens introduced at a critical time after exposure to UV radiation. Evidence is presented suggesting that the production of cytokines by epidermal cells in response to UV-induced DNA damage is an important component of UV-induced specific immune suppression.
Asunto(s)
Sistema Inmunológico/efectos de la radiación , Neoplasias Inducidas por Radiación/inmunología , Neoplasias Cutáneas/inmunología , Rayos Ultravioleta/efectos adversos , Animales , Daño del ADN , Humanos , Tolerancia InmunológicaRESUMEN
This paper reviews the current epidemiologic and experimental evidence regarding the effect of sunburns on cutaneous malignant melanoma and the possible effectiveness of sunscreens in preventing those effects. Although there is growing agreement that sunlight exposure, particularly the ultraviolet wavelengths in solar radiation, contributes to the etiology of cutaneous malignant melanoma, there are at present insufficient data on the effective ultraviolet waveband and whether the use of sunscreens may be useful in preventing melanoma. The main obstacle in answering this question is that the exact role of sunlight in the pathogenesis of melanoma still remains undefined. However, new experimental animal models are now available that will assist in determining and defining the mechanism of initiation and promotion of melanoma by sunlight and, particularly, ultraviolet radiation in sunlight. While we await more definitive data, it is reasonable to recommend an overall "safe sun strategy" in which the use of sunscreens certainly must be accompanied by other protective measures of overall reduction of sunlight exposure.
Asunto(s)
Melanoma/etiología , Neoplasias Cutáneas/etiología , Quemadura Solar/complicaciones , Protectores Solares/uso terapéutico , Carcinoma Basocelular/etiología , Carcinoma de Células Escamosas/etiología , Humanos , Melanoma/epidemiología , Factores de Riesgo , Estaciones del Año , Neoplasias Cutáneas/epidemiología , Quemadura Solar/prevención & controlRESUMEN
Previously we reported that exposure of mice to UV radiation increases the incidence of melanomas arising from injection of syngeneic melanoma cells into the UV-irradiated ears. In this study, we investigated the UV dose-response characteristics, duration, waveband dependence, and role of inflammation in this effect of UV irradiation. The optimal conditions consisted of short term (3-4 weeks), intermittent (twice weekly) exposures to a moderate dose (4.8 kJ/m2) of UVB (280-320 nm) radiation from FS40 sunlamps and the effect lasted only for 3 days after the final UV irradiation. Removal of wavelengths below 315 nm with a Mylar filter abrogated the effect. The UV dose response and the time course of UV-induced inflammation, assessed by ear swelling and microscopic evaluation, did not correlate with that for enhanced melanoma outgrowth, nor did the treatment of the ears with the inflammatory agents turpentine and 12-o-tetradecanoyl phorbol-13-acetate mimic the UV effects on melanoma development. These results indicate that enhancement of melanoma development in UV-irradiated skin is probably unrelated to the inflammatory effects of UV irradiation.
Asunto(s)
Dermatitis/etiología , Dermatitis/fisiopatología , Melanoma Experimental/etiología , Neoplasias Inducidas por Radiación/etiología , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Ratones , Ratones Endogámicos C3H , Trasplante de NeoplasiasRESUMEN
BACKGROUND: Epidemiologic evidence suggests that exposure to UV radiation plays a significant role in the development of melanoma skin cancers. As early surgical removal of the melanoma is the only effective therapy, current strategies for reducing mortality from melanoma focus on prevention of the disease. Chemical sunscreens protect mice from development of skin cancers that resemble sunlight-induced human squamous cell cancers, but there appears to be a complex relationship between UV radiation exposure and development of melanoma. PURPOSE: We asked whether common sunscreens would protect mice against UV radiation-induced enhancement of melanoma incidence. METHODS: C3H mice were exposed to 4.8 kJ/m2 UVB from FS40 sunlamps twice a week for 3 weeks. Sunscreens containing 7.5% 2-ethylhexyl-p-methoxycinnamate, 8% octyl-N-dimethyl-p-aminobenzoate, 6% benzophenone-3, or the oil-in-water vehicle alone were applied to the ears and tails of the mice 20 minutes before irradiation. At various times during and after exposure, we determined UV radiation-induced inflammation by measuring ear swelling. We also examined the ears histologically for UV radiation-induced alterations. One day after the final irradiation, 2.5 x 10(4) syngeneic K1735 melanoma cells were injected into the external ears. Mice were examined weekly for tumor growth for 5-8 weeks after tumor cell injection. Control mice were treated in the identical way except for exposure to UV radiation. RESULTS: The incidence of melanomas was significantly higher in the UV-irradiated mice. All three sunscreens protected against UV radiation-induced ear swelling and clearly diminished histopathologic alterations, including sunburn cell formation, epidermal hyperplasia, and mononuclear cell infiltrate in the dermis. However, the sunscreens failed to protect against UV radiation-induced increase in melanoma incidence. The sunscreens or vehicle alone did not significantly alter tumor growth. CONCLUSIONS: Protection against sunburn does not necessarily imply protection against other possible UV radiation effects, such as enhanced melanoma growth. IMPLICATIONS: Sunscreen protection against UV radiation-induced inflammation may encourage prolonged exposure to UV radiation and thus may actually increase the risk of melanoma development. These findings suggest that further research on the ability of sunscreens to prevent melanoma is urgently needed.
Asunto(s)
Melanoma/patología , Melanoma/prevención & control , Neoplasias Inducidas por Radiación/patología , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/prevención & control , Protectores Solares/farmacología , Rayos Ultravioleta/efectos adversos , Ácido 4-Aminobenzoico/farmacología , Animales , Benzofenonas/farmacología , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , Cinamatos/farmacología , Femenino , Inflamación/patología , Ratones , Ratones Endogámicos C3HRESUMEN
We investigated the capacity of three sunscreen compounds to protect mice from the inflammatory and immunosuppressive effects of ultraviolet radiation (UVR). The sunscreen preparations contained 7.5% 2-ethylhexyl-p-methoxycinnamate, 8% octyl-N-dimethyl-p-aminobenzoate, or 6% benzophenone-3 in an oil-in-water emulsion. Skin swelling was used as the measure of their effect on UVR-induced inflammation, and immunosuppression was assessed by contact sensitization with 2,4-dinitrofluorobenzene applied to UV-irradiated skin (local suppression) or a distant site (systemic suppression). The sunscreens were applied to the shaved dorsal skin of C3H mice, which were then given a single dose of UVR ranging from 2 to 32 kJ/m2 within the UVB (280-320 nm) region. All three sunscreens gave complete protection against local suppression of contact hypersensitivity caused by a dose of 2 kJ/m2 UVB. They also protected against both inflammation and systemic immunosuppression caused by UVR; however, protection was highly dependent on the UVR dose. Furthermore, the sunscreens were less effective in protecting against systemic immunosuppression than against inflammation. These results indicate that immunosuppression is less sensitive to the protective effects of the sunscreens than inflammation and that protection against UVR-induced inflammation does not necessarily imply prevention of immunologic alterations. In addition, these studies suggest that UVR-induced immunosuppression and inflammation may involve different mechanisms.
Asunto(s)
Dermatitis por Contacto/prevención & control , Dermatitis/inmunología , Piel/efectos de la radiación , Protectores Solares/farmacología , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Tolerancia Inmunológica/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Análisis Espectral , Rayos UltravioletaRESUMEN
Primary cutaneous melanomas can be induced in inbred mice by applying a dose of dimethylbenz[a]anthracene to the skin of 4-day-old mice, and then applying repeated doses of a tumor promoter to the same site over a long period of time. Preliminary experiments suggest that the final incidence of melanomas is strongly influenced by the age at which the initiating dose of carcinogen is applied. Melanomas induced by this method in C3H mice are immunogenic and exhibit a high degree of cross-reactivity when tested by immunization and challenge in vivo. Exposing the mice to ultraviolet (UV) radiation during carcinogenesis dramatically accelerates the appearance of melanoma. We are attempting to determine how UV radiation potentiates melanoma induction by studying the growth of melanoma cells transplanted into UV-irradiated skin. Our studies suggest that UV irradiation accelerates the outgrowth of melanoma cells by means of a local, immunosuppressive effect on the skin. However, this effect is distinct from the ability of UV irradiation to alter epidermal Langerhans cells and interfere with the induction of contact hypersensitivity responses. We postulate that UV irradiation augments melanoma development by interfering with the efferent arm of the immune response in the UV-irradiated site.
Asunto(s)
Melanoma/inmunología , Neoplasias Cutáneas/inmunología , 9,10-Dimetil-1,2-benzantraceno , Factores de Edad , Animales , Melanoma/etiología , Ratones , Ratones Endogámicos C3H , Ésteres del Forbol , Neoplasias Cutáneas/etiología , Rayos UltravioletaRESUMEN
Injection of melanoma cells into the UV-irradiated ear skin of syngeneic mice results in an increased incidence of melanomas compared with that in nonirradiated ear skin. This effect of UV is localized to the site of irradiation and appears to be immunologically mediated. In these studies we test the hypothesis that the effect of UV irradiation on melanoma development is related to its ability to alter epidermal Langerhans cells and impair the induction of contact hypersensitivity. A regimen of UV irradiation that altered epidermal immune cells and interfered with the generation of contact hypersensitivity was tested for its ability to increase the incidence of melanoma. Conversely, the ear skin of C3H mice treated with a regimen of UV radiation that enhanced melanoma development was examined for the number of appearance of ATPase+ and Thy-1+ dendritic epidermal cells and tested for the ability to initiate a contact hypersensitivity response. No correlation between these effects of UV irradiation could be detected. Furthermore, implantation of melanoma cells into UV-irradiated ear skin resulted in the generation of systemic immunity against subsequent tumor challenge. Therefore, we conclude that the ability of UV irradiation to modify melanoma development is unrelated to its effects on the afferent arm of the contact hypersensitivity response and that enhanced melanoma development is not due to an impairment in the induction of tumor immunity.
Asunto(s)
Dermatitis por Contacto/inmunología , Melanoma Experimental/etiología , Melanoma Experimental/inmunología , Rayos Ultravioleta/efectos adversos , Adenosina Trifosfatasas/metabolismo , Animales , Antígenos de Superficie/metabolismo , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Células de Langerhans/enzimología , Células de Langerhans/inmunología , Células de Langerhans/efectos de la radiación , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C3H , Trasplante de Neoplasias , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/inmunología , Antígenos Thy-1 , Trasplante IsogénicoAsunto(s)
Melanoma/inmunología , Neoplasias Cutáneas/inmunología , Animales , Anticuerpos Antineoplásicos/biosíntesis , Antígenos de Neoplasias/inmunología , Modelos Animales de Enfermedad , Humanos , Tolerancia Inmunológica , Inmunoterapia , Melanoma/etiología , Melanoma/terapia , Neoplasias Inducidas por Radiación , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/terapia , Rayos Ultravioleta/efectos adversosRESUMEN
Exposure of murine skin to UVB (280-320 nm) radiation accelerates the outgrowth of melanoma cells implanted into the irradiated site. Because many of the biological effects of psoralen plus UVA (320-400 nm) radiation (PUVA) resemble those of UVB radiation and because PUVA therapy is used extensively in the treatment of cutaneous diseases in humans, we determined the effect of PUVA on the growth of transplanted murine melanoma cells. Unshaved C3H/HeN(MTV-) mice were treated twice each week for 3 weeks with 0.4 mg 8-methoxypsoralen i.p. plus 4.25 kJ/m2 UVA radiation; syngeneic K1735 melanoma cells were then injected s.c. into the external ear. This treatment stimulated the outgrowth of the melanomas compared to that in untreated mice and mice treated with 8-methoxypsoralen or UVA alone. The use of a nonphototoxic, monofunctional psoralen plus UVA was equally effective, indicating that neither phototoxicity nor the ability to form DNA crosslinks was required for this effect. In vitro treatment of a murine keratinocyte cell line PAM 212 with PUVA caused the release of soluble factors that, when mixed with K1735 melanoma cells prior to injection, stimulated their outgrowth in vivo. These studies demonstrate that PUVA treatment can contribute to the pathogenesis of melanoma by exerting a stimulatory effect on the outgrowth of melanoma cells. Furthermore, they suggest that this effect may result from the ability of PUVA to cause the release of stimulatory factors from keratinocytes.
Asunto(s)
Furocumarinas/uso terapéutico , Queratinocitos/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Metoxaleno/uso terapéutico , Terapia PUVA , Animales , División Celular , Línea Celular , Femenino , Furocumarinas/farmacología , Queratinocitos/efectos de la radiación , Melanoma Experimental/patología , Metoxaleno/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Rayos UltravioletaRESUMEN
We had reported previously that the outgrowth of melanoma is enhanced when melanoma cells are injected into UV-irradiated skin of syngeneic mice. To determine whether this effect was specific for melanomas, we compared the growth of 13 different tumor cell lines (3 melanomas, 6 fibrosarcomas, 2 undifferentiated skin tumors, a squamous cell carcinoma, and a spontaneous hepatocarcinoma) in UV-irradiated and nonirradiated syngeneic mice. C3H/HeN(MTV-) mice were exposed to 4.8 kJ/m2 UV-B (280-320 nm) radiation twice a week for 3 weeks; the tumor cells were injected into the UV-irradiated pinna 24 h after the final UV irradiation. The growth of all the melanomas and 4 of the fibrosarcomas was enhanced in UV-irradiated mice, indicating that the effect of UV radiation was not specific for melanomas or tumors of a particular etiology. Using an in vivo immunization and challenge assay, we found that the 7 tumors exhibiting enhanced development in UV-irradiated skin were highly immunogenic, whereas the remaining 6 tumors were not. This suggested that enhanced tumor outgrowth resulted from an immunosuppressive effect of the UV radiation. When tested further, we found that UV-B radiation had no effect on melanoma outgrowth in congenitally athymic mice, sublethally X-irradiated mice, or mice depleted of Thy1+ cells in vivo. These results indicate that immunological mechanisms play a role in the effect of UV radiation on the growth of murine melanomas.
Asunto(s)
Fibrosarcoma/patología , Terapia de Inmunosupresión , Activación de Linfocitos , Depleción Linfocítica , Melanoma Experimental/patología , Sarcoma Experimental/patología , Neoplasias Cutáneas/patología , Piel/efectos de la radiación , Linfocitos T/inmunología , Rayos Ultravioleta , Animales , Anticuerpos Monoclonales/administración & dosificación , Antígenos de Superficie/inmunología , Carcinoma/inmunología , Carcinoma/patología , División Celular/efectos de la radiación , Línea Celular , Fibrosarcoma/inmunología , Neoplasias Hepáticas Experimentales/inmunología , Neoplasias Hepáticas Experimentales/patología , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos C3H , Sarcoma Experimental/inmunología , Neoplasias Cutáneas/inmunología , Antígenos Thy-1RESUMEN
Increases in the incidence of cutaneous melanoma during the past few decades has drawn attention to the possible causes of this cancer. Although sunlight exposure has long been suspected of being a contributing factor, direct evidence of its participation has been difficult to obtain using epidemiological approaches. We have used murine models to investigate the possible contributions of UV radiation to the induction and pathogenesis of melanoma. Our studies demonstrate that UV radiation contributes to the induction of melanoma in a variety of ways, including an indirect, local effect on the skin. Recent evidence suggests that this indirect effect is immunologically mediated.
Asunto(s)
Melanoma Experimental/etiología , Melanoma Experimental/inmunología , Neoplasias Inducidas por Radiación , Rayos Ultravioleta/efectos adversos , Animales , Humanos , Neoplasias Inducidas por Radiación/inmunología , Piel/inmunología , Piel/efectos de la radiaciónRESUMEN
Non-melanoma skin cancers induced in mice by chemical carcinogens or ultraviolet radiation are often antigenic but rarely induce cross-protective immunity when tested by in vivo transplantation methods. We wished to determine whether melanocytic skin tumors behave similarly or whether they exhibit cross-reactive antigens in vivo. Three melanomas induced in C3H/HeNCr(MTV-) mice by initiation with ultraviolet radiation and promotion with croton oil or initiation with 7,12-dimethyl-benz[a]anthracene and promotion with 12-O-tetradecanoyl-phorbol-13-acetate or croton oil plus ultraviolet radiation were tested for immunogenicity and cross-reactivity in vivo. The three melanomas were highly immunogenic, and all induced some degree of protection against the other melanomas. Non-melanoma skin cancers induced by the same carcinogens were less immunogenic and did not immunize against the melanomas. We conclude that unlike other skin cancers, melanocytic tumors induced by chemical carcinogens and ultraviolet radiation are highly cross-reactive in vivo and thus represent a unique subset of murine skin cancers.
Asunto(s)
Carcinoma de Células Escamosas/inmunología , Fibrosarcoma/inmunología , Melanoma Experimental/inmunología , Neoplasias Cutáneas/inmunología , 9,10-Dimetil-1,2-benzantraceno , Animales , Carcinoma de Células Escamosas/inducido químicamente , Reacciones Cruzadas , Aceite de Crotón , Femenino , Fibrosarcoma/inducido químicamente , Melanoma Experimental/inducido químicamente , Ratones , Trasplante de Neoplasias , Neoplasias Inducidas por Radiación/inmunología , Neoplasias Cutáneas/inducido químicamente , Organismos Libres de Patógenos EspecíficosRESUMEN
The role of UV radiation in the development of malignant melanoma has yet to be clearly defined. The purpose of these studies was to determine whether UV irradiation of mice produces local or systemic alterations that increase the in vivo growth of transplanted melanoma cells. K-1735 melanoma cells were injected into the external ears of syngeneic C3H mice. UV irradiation of the mice before or at the time of injection of the melanoma cells accelerated the appearance of the tumors. The effect was observed when melanoma cells were transplanted directly into the site of UV irradiation, but not when they were injected into an unirradiated site. The initial survival of radiolabeled melanoma cells at the site of inoculation was not altered by UV irradiation of the host, suggesting that the accelerated appearance of tumors was due to an increase in the clonogenic potential of cells injected into UV-irradiated skin. The effect of UV irradiation on the development of other syngeneic tumors was also investigated. The outgrowth of a second melanoma was also accelerated in UV-irradiated mice, whereas the growth of a UV-induced fibrosarcoma, a methylcholanthrene-induced fibrosarcoma, and a spontaneous hepatocarcinoma was not affected. These results suggest that, in addition to its carcinogenic activity, UV radiation may contribute to the incidence of cutaneous melanoma because of a local effect on the skin that stimulates melanoma development.