RESUMEN
In two multicenter, placebo controlled, phase 2 studies, patients with mild-to-moderate (n=161, Study 1) or severe (n=142, Study 2) erectile dysfunction (ED) were randomized to receive placebo, 0.05, 0.1, or 0.2 mg (Study 1) or placebo, 0.1, 0.2, or 0.3 mg (Study 2) of topically applied alprostadil (containing a proprietary skin permeation enhancer). The primary efficacy end point in both studies was the change in erectile function (EF) score from baseline to final visit. The changes from baseline for EF scores were -0.8+/-1.1, 1.8+/-1.1, 0.7+/-1.2, and 3.7+/-1.2 (P<0.01; Study 1) and 2.7+/-1.3, 6.29+/-1.4, 6.49+/-1.5, and 9.44+/-1.5 (P<0.001; Study 2) for ascending dose groups in each study. Topical alprostadil was well tolerated with the most common adverse event being urogenital pain. These results suggest this topical alprostadil formulation may be a potentially useful agent for the treatment of ED.
Asunto(s)
Alprostadil/administración & dosificación , Disfunción Eréctil/tratamiento farmacológico , Vasodilatadores/administración & dosificación , Administración Tópica , Adulto , Anciano , Alprostadil/efectos adversos , Coito , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Vasodilatadores/efectos adversosRESUMEN
Long-term glucocorticoid (GC) therapy has been instrumental in decreasing morbidity and mortality in a variety of chronic inflammatory diseases, including persistent asthma. Long-term GC therapy is also widely prescribed for COPD. One of the important and often unrecognized side effects of chronic GC therapy is secondary osteoporosis. The risk of GC-induced bone loss is roughly correlated with daily dose, duration, and total cumulative lifetime dose of GC treatment. Oral prednisone increases the risk of bone loss and fracture. High doses of inhaled GCs may also increase the risk of osteopenia/osteoporosis, but the risk appears to be less than that associated with oral GCs. Hormone replacement therapy, oral and parenteral bisphosphonates, supplemental calcium and vitamin D, calcitonin, and fluoride compounds have been used, experimentally, in the management of GC-induced bone loss. Asthma and COPD specialists are key prescribers of oral and inhaled steroids and are likely to encounter patients with significant bone loss. Despite known risk factors and the availability of reliable diagnostic tools to recognize bone loss, the opportunity to slow, reverse, and treat bone loss is often missed. We present a review of the current literature regarding the incidence, treatment, and prevention of osteopenia/osteoporosis secondary to chronic GC therapy in adult asthma and COPD patients. Guidelines are presented regarding the identification of patients at risk for developing GC-induced secondary bone loss, and therapeutic alternatives are discussed.
Asunto(s)
Asma/tratamiento farmacológico , Glucocorticoides/efectos adversos , Enfermedades Pulmonares Obstructivas/tratamiento farmacológico , Osteoporosis/inducido químicamente , Administración por Inhalación , Administración Oral , Adulto , Alendronato/uso terapéutico , Asma/complicaciones , Densidad Ósea , Remodelación Ósea , Calcitonina/farmacología , Calcitonina/uso terapéutico , Ácido Clodrónico/uso terapéutico , Ácido Etidrónico/uso terapéutico , Fluoruros/uso terapéutico , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Terapia de Reemplazo de Hormonas , Humanos , Enfermedades Pulmonares Obstructivas/complicaciones , Osteoporosis/complicaciones , Osteoporosis/tratamiento farmacológico , Prednisona/efectos adversos , Factores de TiempoRESUMEN
We have recently reported the results of a 24-month, double-blind, placebo-controlled study in 359 elderly osteoporotic women who were treated with daily oral alendronate (ALN) 1, 2.5, or 5 mg or placebo (PBO). We report the results of a 12-month, open-label, extension study during which 246 patients from the original study were treated with ALN 10 mg/day. Significant increases in lumbar spine bone mineral density (BMD) were observed in patients who had previously received PBO or ALN 1 and 2.5 mg/day for 24 months. Significant gains in trochanter BMD were seen in all treatment groups. Small changes were observed in femoral neck, total body, and forearm BMD during the course of this extension study. In general, the greatest increases in BMD during the open-label extension year occurred in patients who received either PBO or the lower doses of ALN during the previous 2-year blinded study. The frequencies of all categories of upper gastrointestinal adverse experiences (AEs) were less during months 25-36 (open-label extension) than during months 0-24 (original study). In conclusion, treatment with ALN 10 mg/day for 12 months in elderly women with osteoporosis who were previously treated for 24 months with PBO or ALN 1, 2.5, or 5 mg/day increased or maintained BMD of the spine, trochanter, and forearm, and was generally safe and well tolerated, especially in the upper gastrointestinal tract.
Asunto(s)
Alendronato/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Absorciometría de Fotón , Administración Oral , Anciano , Anciano de 80 o más Años , Alendronato/administración & dosificación , Alendronato/efectos adversos , Densidad Ósea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Fémur/diagnóstico por imagen , Fémur/efectos de los fármacos , Cuello Femoral/diagnóstico por imagen , Cuello Femoral/efectos de los fármacos , Fracturas Espontáneas/prevención & control , Gastritis/inducido químicamente , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/efectos de los fármacos , Persona de Mediana Edad , Radio (Anatomía)/diagnóstico por imagen , Radio (Anatomía)/efectos de los fármacos , Resultado del Tratamiento , Cúbito/diagnóstico por imagen , Cúbito/efectos de los fármacosRESUMEN
The leukocyte integrins are cell adhesion molecules which play pivotal roles in the development of a variety of immune responses including T-cell-mediated cytotoxicity, lymphocyte proliferation, macrophage presentation of antigen, and adhesion of leukocytes to vascular endothelium. The relevance of lymphocyte function-associated antigen-1 (LFA-1) to leukocyte malignancies is currently under examination in a number of laboratories. Here, we present evidence demonstrating that LFA-1 plays a role during the in vitro invasion of human endothelium by JY lymphoma cells and during in vivo metastasis of two distinct models of murine leukemia: P815 mastocytoma and EL4 lymphoma. When assayed in vitro, a murine anti-human LFA-1 (alpha subunit) monoclonal antibody (mAb) inhibits up to 80% of JY lymphoma cell invasion. When assayed in vivo, a rat anti-LFA-1 (alpha subunit) mAb significantly inhibited the development of experimental metastases, when administered concomitantly with either P815 or EL4 tumor cells. The leukocyte integrins, particularly LFA-1, may represent useful targets for the therapeutic modulation of metastasis.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Antígeno-1 Asociado a Función de Linfocito/fisiología , Linfoma/patología , Animales , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular , Células Cultivadas , Humanos , Molécula 1 de Adhesión Intercelular , Neoplasias Hepáticas/secundario , Antígeno-1 Asociado a Función de Linfocito/inmunología , Linfocitos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Invasividad Neoplásica , Factores de TiempoRESUMEN
Cell adhesion molecules are surface proteins important for cell migration and adhesion and are strongly expressed in eyes with inflammation. We studied the expression of two cell adhesion molecules: intercellular adhesion molecule-1 (ICAM-1, CD54) and lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) in mice with experimental autoimmune uveitis. B10.A mice were immunized with interphotoreceptor retinoid-binding protein and eyes were serially examined for expression of cell adhesion molecules using immunohistochemical staining. ICAM-1 was expressed on the vascular endothelium of the ciliary body and retina by 7 days after immunization, and LFA-1 was first expressed on some infiltrating inflammatory cells 9 days after immunization. Clear histologic evidence of ocular inflammation did not occur until 11 days after immunization. We then studied the effect of monoclonal antibodies against ICAM-1 and LFA-1 on the development of experimental autoimmune uveitis. Three groups of mice were immunized and treated for 21 days with daily intraperitoneal injections of rat monoclonal antibody against murine ICAM-1 or LFA-1 or with rat IgG as control. Ocular inflammation, graded clinically by examination of the fundus 14 and 21 days after immunization, was significantly decreased in animals treated with anti-ICAM-1 (P < 0.01 at Days 14 and 21) and with anti-LFA-1 antibody (P < 0.01 at Days 14 and 21). The intraocular inflammation graded histologically was also decreased in mice treated with anti-ICAM-1 and anti-LFA-1 antibody. This difference in the histologic grade of inflammation was statistically significant (P < 0.02) between mice treated with anti-ICAM-1 antibody and control mice and approached statistical significance (P < 0.10) in mice treated with anti-LFA-1 antibody compared to the control mice. Proliferative responses to lipopolysaccharide, PPD, and interphotoreceptor binding protein of lymphocytes obtained from the draining lymph nodes of mice treated with the antibodies were lower than those from the control mice, suggesting that cell-cell binding was impaired in treated mice. These data show that ICAM-1 is expressed in the eye before histologic evidence of inflammation, and that monoclonal antibodies against ICAM-1 and LFA-1 are effective in inhibiting experimental autoimmune uveitis in mice.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/prevención & control , Moléculas de Adhesión Celular/inmunología , Antígeno-1 Asociado a Función de Linfocito/inmunología , Uveítis/prevención & control , Animales , Enfermedades Autoinmunes/inmunología , Moléculas de Adhesión Celular/análisis , Femenino , Molécula 1 de Adhesión Intercelular , Activación de Linfocitos , Antígeno-1 Asociado a Función de Linfocito/análisis , Ratones , Uveítis/inmunologíaRESUMEN
Hereditary tubulointerstitial nephritis is a prominent cause of renal failure in humans. A variety of animal models utilizing immunologically induced nephritis have been developed. The kdkd congenic variant of the CBA/Ca mouse has normal kidneys at birth but develops progressive, lethal autoimmune nephritis beginning at approximately Week 8. The destruction of renal tubular epithelium in mediated by a population of antigen-specific, H-2Kk-restricted, Lyt-2+, L3T4- T cells. The present experiments demonstrate that systemic treatment with anti-ICAM-1 monoclonal antibody reduces kidney disease in kdkd mice. Anti-ICAM-1 mab localizes to inflammatory sites in the kidney and effects a significant reduction in leukocyte infiltration. Concomitantly, urine protein levels of anti-ICAM-1-treated mice are significantly reduced. The use of anti-adhesion molecule monoclonal antibodies that alter leukocyte activity and/or trafficking may be useful therapies for certain autoimmune disorders.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Enfermedades Autoinmunes/terapia , Moléculas de Adhesión Celular/inmunología , Nefritis Intersticial/terapia , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Molécula 1 de Adhesión Intercelular , Riñón/química , Riñón/inmunología , Ratones , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Nefritis Intersticial/inmunología , Nefritis Intersticial/patología , Proteinuria/inmunología , Proteinuria/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis TumoralRESUMEN
Patients with vitiligo have circulating antibodies to pigment cells. To characterize this response further and to identify the antigens defined by vitiligo antibodies, sera of 23 patients with vitiligo and 22 patients with unrelated conditions were analyzed by immunoprecipitation and SDS-PAGE analysis of 125I-labeled cell antigens on pigment and control cells. Antibodies to pigment cell antigens were present in 18 (78%) of the patients with vitiligo but in only three (14%) of the control patients (p less than 0.05). The antibodies were directed to one or more antigens with molecular weight (MW) in kilodaltons (kD) of approximately 35, 40-45, 75, 90, or 150. The responses were most commonly directed to the 40-45-kD, 75-kD, and 90-kD antigens. Antibodies to these antigens were present in 74%, 57%, and 35% of vitiligo patients versus in 14%, 9%, and 0% of control individuals. The 35-kD and 90-kD antigens were preferentially expressed on human pigment cells, whereas the 40-45-, 75-, and 150-kD antigens were expressed on both pigment and control cells. These antigens were labeled by the lactoperoxidase technique, suggesting that they are cell surface antigens. These results confirm that antibodies to pigment cells are associated with vitiligo. These antibodies are directed to several cell surface antigens, some of which are preferentially expressed on pigment cells.
Asunto(s)
Antígenos/análisis , Melanocitos/inmunología , Vitíligo/inmunología , Anticuerpos , Células Cultivadas , Medios de Cultivo , Electroforesis en Gel de Poliacrilamida , Epítopos , Humanos , Pruebas de Precipitina , Dodecil Sulfato de Sodio , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Patients with vitiligo often have antibodies to pigment cells. To examine whether there is a relation between the presence of such antibodies and disease activity, sera of 24 patients with vitiligo (10 with active and 14 with inactive disease) and 19 normal individuals were tested for antibodies to pigment cell surface antigens using a live cell enzyme-linked immunoabsorbent assay. IgG pigment cell antibodies were present in 80% (eight of 10) of patients with active vitiligo but in none of those with inactive disease or in normal individuals. The antibody level of patients with active vitiligo (mean binding index [BI] 3.3 +/- 0.59) was significantly higher than in patients with inactive disease (BI 0.96 +/- 0.04) or normal individuals (BI 1.0 +/- 0.04, p less than 0.001). Antibodies present in eight patients with high titers of pigment cell antibodies reacted to three of four pigment cells but to only one of six unrelated cells. These findings indicate that a correlation exists between the incidence and level of pigment cell antibodies and the activity of vitiligo, and support the hypothesis that vitiligo is an autoimmune disease mediated by an immune reaction to pigment cells.
Asunto(s)
Anticuerpos/análisis , Melanocitos/inmunología , Vitíligo/inmunología , Humanos , Vitíligo/fisiopatologíaRESUMEN
Bone marrow transplantation is a therapeutic treatment for many life-threatening hematologic disorders, especially leukemia and certain immune deficiency diseases. However, acute graft-versus-host disease is often associated with bone marrow transplantation. In mice, allogeneic GVHD appears to be mediated by both host natural killer cells and donor T cells. In vitro and in vivo experiments demonstrate that treatment with either YN1/1.7 or M17/4.2 mabs is immunomodulatory and inhibits both the mixed lymphocyte reaction and natural killer cell activity. In addition, utilizing an allogeneic model of acute, lethal GVHD with C57B1/6 mice as donors and sublethally irradiated BDF1 mice as recipients, treatment of host mice with anti-LFA-1 alpha (M17/4.2) or anti-MALA-2 (YN1/1.7) mabs at a dose of 10 mg/kg/day for 10 days significantly reduced GVHD and enhanced survival. Mabs to lymphocyte adhesion molecules such as LFA-1 alpha and MALA-2 may provide a useful therapy for the treatment of GVHD.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/inmunología , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Antígeno-1 Asociado a Función de Linfocito/inmunología , Animales , Pruebas Inmunológicas de Citotoxicidad , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Células Asesinas Naturales/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis TumoralRESUMEN
Current reports have suggested a role for intracellular adhesion molecule 1 (ICAM-1) in the progression of human malignant melanoma and other cancers. Stage I, II, and III patients with histologically diagnosed malignant melanoma had significantly increased serum levels of circulating ICAM-1 (cICAM-1) and a striking increase in the incidence of positive sera. In Stage II and III patients, the level of cICAM-1 was inversely correlated with survival. Patients with elevated levels of serum cICAM-1 (greater than 2 SD units above control mean) had a significantly shorter mean survival. We suggest that elevated levels of serum cICAM-1 may be of diagnostic and prognostic importance in patients with malignant cutaneous melanoma.
Asunto(s)
Moléculas de Adhesión Celular/sangre , Melanoma/sangre , Adulto , Femenino , Humanos , Molécula 1 de Adhesión Intercelular , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , PronósticoRESUMEN
In earlier work, we demonstrated that in vivo derived B16F10 tumor cells metastasize aggressively from intracameral (ic) and subcutanous (sc) sites, colonizing the lungs and lymph nodes. Natural killer (NK) cells play an important role in metastasis from ocular tumors. Treatment of mice with MoAb PK136, a highly specific anti-NK antibody, altered the pattern of metastasis; metastases appeared in the lungs, adrenal glands, liver, and spleen. Treatment with cyclophosphamide (Cy) did not affect survival or metastasis, but combined treatment with the immunomodulator Linomide (LS2616) and Cy decreased metastasis and increased survival. In the present study, we examine the role played by NK cells in regulating metastasis of sc tumors. Treatment of mice with LS2616 enhanced NK cell activity and decreased metastasis. Treatment with MoAb PK136 decreased survival and increased metastasis, but did not affect the pattern of metastasis. Treatment with 25 mg/kg Cy alone resulted in a decrease in growth of the primary tumor, increased survival, and decreased metastasis. Combined treatment with LS2616 and Cy was very effective in decreasing metastasis, increasing survival, and affecting cures (30%). In summary, our experiments demonstrate the importance of NK cells in regulating metastasis from sc tumors of in vivo derived B16F10 melanoma and demonstrate the effectiveness of LS2616 and low doses of Cy on metastasis and survival. In combination with earlier work, the present experiments demonstrate: 1) that modulation of NK activity differentially affects metastasis from sc and ic compartments, and 2) that regional differences in the location of the primary tumor may determine the effectiveness of treatment with Cy.
Asunto(s)
Células Asesinas Naturales/inmunología , Melanoma Experimental/secundario , Metástasis de la Neoplasia/inmunología , Animales , Cámara Anterior , Anticuerpos Monoclonales/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carragenina/uso terapéutico , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Femenino , Rayos gamma , Hidroxiquinolinas/administración & dosificación , Hidroxiquinolinas/uso terapéutico , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Inyecciones Subcutáneas , Células Asesinas Naturales/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Masculino , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL/inmunología , Ratones Mutantes/inmunología , Trasplante de Neoplasias/métodos , Dióxido de Silicio/uso terapéutico , Análisis de SupervivenciaRESUMEN
In the current study we examine parameters affecting the metastasis of ocular tumors of in vivo derived B16F10 melanoma. In C57BL/6J beige (bg/bg) mice, with low NK activity, metastasis to the lungs was increased and survival time decreased. In C57BL/6J normal (+/+) mice treatment with PK136, a highly specific monoclonal anti-NK antibody (Ab), caused a depletion of NK cytotoxic activity, as demonstrated using a standard 51Cr release assay. In animals bearing ocular tumors, treatment with PK136 Ab resulted in significantly increased pulmonary metastasis and an altered pattern of metastasis. The effect of combined treatment protocols using LS2616 (linomide) and cyclophosphamide (Cy) was examined in enucleated and unenucleated animals. Treatment with LS2616 and Cy resulted in a significant decrease in mean pulmonary metastases (MPM), a decreased frequency of metastasis to the submandibular lymph nodes and an increase in mean survival time. In enucleated mice this combined treatment protocol resulted in apparent cures, the lowest MPM and the longest survival time observed. When tumor-bearing mice were treated with either silica, carrageenan or sublethal gamma irradiation, no effect on metastasis or survival was observed. This study demonstrates the importance of the NK cell as a primary effector cell for the control of metastasis from in vivo derived ocular B16F10 melanoma.
Asunto(s)
Neoplasias del Ojo/inmunología , Células Asesinas Naturales/fisiología , Neoplasias Pulmonares/inmunología , Melanoma/inmunología , Adyuvantes Inmunológicos/farmacología , Animales , Anticuerpos Monoclonales , Ciclofosfamida/farmacología , Enucleación del Ojo , Neoplasias del Ojo/mortalidad , Neoplasias del Ojo/cirugía , Femenino , Hidroxiquinolinas/farmacología , Células Asesinas Naturales/efectos de los fármacos , Neoplasias Pulmonares/secundario , Masculino , Melanoma/mortalidad , Melanoma/secundario , Melanoma/cirugía , Ratones , Ratones Endogámicos C57BLRESUMEN
In experiments using cultured cells, LS2616 has been shown to decrease growth of primary tumors and pulmonary metastasis of murine melanoma. In the current study, we examine the efficacy of LS2616 for the prophylactic and therapeutic treatment of metastases from ocular and flank inoculations of the highly aggressive in vivo derived B16F10 melanoma in C57BL/6J mice. Experimental animals were treated with 160 mg/kg/day of this drug in drinking water, until they became moribund or died. When mice were pretreated for 7 days and inoculated subcutaneously (sc) or intracamerally (ic) with 10(5) in vivo derived B16F10 tumor cells, the mean number of pulmonary metastases was significantly reduced, and the incidence of pulmonary metastases decreased. In ocular experiments, when pretreatment with drug was combined with enucleation at day 7, the mean number of lung nodules was significantly reduced, the incidence of metastasis to the lung and lymph nodes decreased and survival increased. An apparent cure rate of 31% was observed. Treatment beginning on the day of enucleation (day 7) resulted in a reduction of pulmonary metastases, a decrease in metastasis to the lungs and lymph nodes and no change in survival. LS2616 did not alter tumorigenicity of either sc or ic inoculations. In an in vivo neutralization assay, spleen cells of mice treated for 7 days with LS2616 demonstrated an increase in cytostatic or cytotoxic activity when incubated with B16F10 melanoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Neoplasias del Ojo/tratamiento farmacológico , Hidroxiquinolinas/uso terapéutico , Melanoma/tratamiento farmacológico , Animales , Enucleación del Ojo , Neoplasias del Ojo/fisiopatología , Neoplasias del Ojo/cirugía , Femenino , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Masculino , Melanoma/fisiopatología , Melanoma/secundario , Ratones , Neoplasias Cutáneas/tratamiento farmacológico , Bazo/citología , Bazo/fisiología , Células Tumorales Cultivadas/fisiologíaRESUMEN
We examine ocular metastasis of syngeneic murine melanoma in C57Bl/6J mice and compare the metastatic capability of B16F10 tumor cells maintained in vivo with those maintained in culture. We demonstrate that as long as the tumor cells are derived from an in vivo source, intraocular tumor readily metastasizes to the lungs. When in vivo derived tumor is introduced as an intracameral (ic) cell suspension, or as a solid fragment implanted on the iris, 100% of the animals die with extensive pulmonary metastasis 5-6 weeks later. In contrast, when B16F10 cells are passaged five times in culture and inoculated ic, a marked decrease in the frequency and extent of metastasis, and an increase in survival is seen. These studies demonstrate an alteration in the ability of cultured B16F10 cells to metastasize from the eye. When metastasis of in vivo derived tumor from the eye was compared with metastasis from an extraocular location, the extent and frequency of pulmonary metastasis and survival of hosts was the same. The effect of enucleation on the metastasis of B16F10 from the eye has only previously been examined using cultured cells. In this paper, we demonstrate that the efficacy of enucleation depends upon whether B16F10 melanoma cells have been passaged in vivo or in vitro.