RESUMO
Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kg(-1) d(-1), compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Peptidomiméticos/farmacologia , Tiocarbamatos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromanos/farmacologia , Cisplatino/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Sequestradores de Radicais Livres/farmacologia , Humanos , Camundongos , Estrutura Molecular , Terapia de Alvo Molecular , Compostos Organoáuricos/administração & dosagem , Compostos Organoáuricos/química , Peptidomiméticos/administração & dosagem , Peptidomiméticos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Tiocarbamatos/administração & dosagem , Tiocarbamatos/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Medicina Baseada em Evidências , Displasia Pélvica Canina/tratamento farmacológico , Compostos Organoáuricos/administração & dosagem , Medição da Dor/veterinária , Dor/veterinária , Pontos de Acupuntura , Animais , Cães , Displasia Pélvica Canina/complicações , Microesferas , Dor/etiologia , Manejo da Dor , Medição da Dor/métodos , Resultado do TratamentoRESUMO
Seventy-eight dogs with pain due to hip dysplasia were studied in a controlled, double-blind clinical trial to evaluate gold bead implantation as a pain-relieving treatment. The dogs were randomly assigned to two groups, 36 in the gold implantation group and 42 in the placebo group. Both groups were treated equally regarding anaesthesia, hair clipping and penetration of the skin with the same type of needle. The gold implantation group had small pieces of 24 carat gold inserted through needles at five different acupuncture points and the placebo group had the skin penetrated at five non-acupuncture points so as to avoid any possible effect of stimulating the acupuncture points. A certified veterinary acupuncturist marked the points, and two surgeons performed the implantations according to a randomisation code made in advance. After 14 days, three months and six months, the owners assessed the overall effect of the treatments by answering a questionnaire, and the same veterinarian examined each dog and evaluated its degree of lameness by examining videotaped footage of it walking and trotting. The treatment was blinded for both the owners and the veterinarian. There were significantly greater improvements in mobility and greater reductions in the signs of pain in the dogs treated with gold implantation than in the placebo group. The veterinarian's and the owners' assessments corresponded well.