RESUMEN
Cancer literature has consistently described autocrine loops involving growth factors to be important mechanisms for cellular transformation and proliferation in preclinical cancer models. Finally, convincing clinical data exist to implicate autocrine loops as central to the pathogenesis of a malignant condition, largely as a result of the recent development of inhibitors of protein tyrosine kinases important in cell signaling and growth. Although a rare condition, the study of patients with dermatofibrosarcoma protuberans (DFSP) is enriched by data demonstrating strong scientific rationale for its pathogenesis and susceptibility to molecular-based therapies. DFSP is a low-grade sarcoma that responds to treatment with imatinib, an inhibitor of the PDGF receptor tyrosine kinase. This treatment response illustrates the importance of autocrine/paracrine loops involving PDGF and its receptor as the key molecular target in DFSP. New insight into this fundamental biological mechanism sets the scene for the further development of molecular-targeted therapeutic options for cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Comunicación Autocrina/efectos de los fármacos , Dermatofibrosarcoma/tratamiento farmacológico , Dermatofibrosarcoma/fisiopatología , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Antineoplásicos/farmacología , Benzamidas , Factor de Crecimiento Epidérmico/fisiología , Receptores ErbB/fisiología , Humanos , Mesilato de Imatinib , Factor I del Crecimiento Similar a la Insulina/fisiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Piperazinas/farmacología , Factor de Crecimiento Derivado de Plaquetas/fisiología , Pirimidinas/farmacología , Receptor IGF Tipo 1/fisiología , Receptores de Factores de Crecimiento/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
AIMS: Cyclophosphamide was widely used as a single agent prior to the advent of platinum-based regimens for epithelial ovarian cancer, and, in combination with platinum, prior to the adoption of platinum and paclitaxel as standard first-line therapy. As cyclophosphamide currently has no defined role in ovarian cancer we aimed to assess its activity in women with recurrent disease. METHODS: A retrospective review was conducted of patients from three centers in Melbourne, Australia who had received oral cyclophosphamide treatment for recurrent ovarian cancer. The primary end-point was response rate to oral cyclophosphamide (150 mg p.o. day 1-14) based on Gynecologic Cancer InterGroup (GCIG) CA125 and/or Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary end-points included overall and progression-free survival and toxicity. RESULTS: In all, 26 patients were identified and 23 patients were evaluable for response. The median number of prior chemotherapy regimens was three (range 1-6). The response rate to oral cyclophosphamide was 44% with 10 of the 23 patients achieving a partial response (PR) based on GCIG (CA125) criteria. The median number of cycles received was three (range 1-16). Cyclophosphamide showed activity both in patients with platinum-sensitive (seven of 13 PR) and resistant or refractory disease (three of 10 PR). There was no grade 3 or 4 toxicity but two patients ceased cyclophosphamide due to less severe non-hematological toxicity. CONCLUSION: Single agent oral cyclophosphamide is active and well tolerated in recurrent ovarian cancer. Further investigation of oral cyclophosphamide in patients with platinum-sensitive and platinum-resistant disease is warranted.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Ciclofosfamida/administración & dosificación , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antineoplásicos Alquilantes/efectos adversos , Australia , Carcinoma Epitelial de Ovario , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Ováricas/mortalidad , Estudios RetrospectivosRESUMEN
In melanoma, mutations in KIT are most frequent in acral and mucosal subtypes and rarely reported in cutaneous melanomas particularly those associated with intermittent UV exposure. Conversely melanomas arising within chronic sun damaged skin are considered to harbour KIT mutations at higher rates. To characterize the frequency of KIT mutations in a representative melanoma population, 261 patients from two Australian melanoma centres were prospectively screened for mutations in exons 11, 13 and 17 of the KIT gene. A total of 257 patients had cutaneous melanoma arising from non-acral sites and four were acral melanomas. No mucosal or ocular melanomas were analysed. KIT mutations were identified in five tumours (2% of the entire cohort) including two acral melanomas. Two of the three non-acral melanomas with KIT mutations were associated with markers of chronic sun damage as assessed by the degree of skin elastosis. In the remaining cohort, 43% had chronically sun damaged skin. This report confirms that within an Australian population, KIT mutations are infrequent in cutaneous melanomas associated with both intermittent and chronic sun exposed skin.