RESUMEN
Proteasome inhibitors are emerging as a promising class of anti-cancer therapeutic agents. The first of this new class of drugs with a clinical significance, bortezomib (PS 341, Velcade), is a modified dipeptidyl boronic acid. Bortezomib reduces the NF-kappaB translocation / transcription and blocks the drug-related signalling pathways critical to basic vital functions of myeloma cells. Bortezomib induces apoptosis by releasing cytochrome C from mitochondria and by activating caspase-9 and Jun-kinases (JNK) and the Fas-caspase-8-dependent apoptotic pathway. Bortezomib has been reported to down-regulate cytokine-induced expression of VCAM-1, a major ligand on bone marrow stromal cells for VLA-4; it inhibits the heterotypic adherence between the myeloma cells and stromal cells and blocks the signalling pathways of resistance to apoptosis. The drug has been shown experimentally to inhibit the IL-6-induced proliferation of myeloma cells; it demonstrates synergy with dexamethasone and inhibits angiogenesis. Phase II/ III clinical studies with Velcade have shown an overall therapeutic response rate of 35% in refractory, relapsed myeloma patients (Bladé criteria). These surprisingly good results, the drug's good tolerance and controllable side effects provide a solid base for further studies on bortezomib, including studies on the drug used as front line therapy.
Asunto(s)
Antineoplásicos/farmacología , Ácidos Borónicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , Pirazinas/farmacología , Bortezomib , Ensayos Clínicos como Asunto , Humanos , Estructura Molecular , Neovascularización Patológica/prevención & controlRESUMEN
Bones are among the major parts of the body that are targeted in neoplastic diseases. Bone lesions increasing in number and size and diffuse osteoporosis are found in 30-80% of cancer patients. All literature data about the pathogenetic factors of osteolytic and osteosclerotic bone lesions are classified into four groups: 1. Directly connected with the neoplastic tumour mass. 2. Humoral interaction between the tumour cells and bone cells. 3. Systemic effects and complications of the neoplastic process. 4. Extracancerous factors. We discuss here the basic pathogenetic forms of bone lesions in neoplasias: 1. Local osteolysis in the area of neoplastic infiltration. 2. Humorally activated demineralisation with hypercalcemia. 3. Light chain osteomalacia. 4. Hypophosphatemic osteomalacia. We consider the major current biochemical markers of bone remodelling and their use in diagnosing and monitoring bone disease in neoplastic conditions.