RESUMO
Pet dogs with naturally occurring cancers play an important role in studies of cancer biology and drug development. We assessed tolerability, efficacy, and pharmacokinetic/pharmacodynamic relationships with a first-in-class small molecule inhibitor of valosin-containing protein (VCP/p97), CB-5339, administered to 24 tumor-bearing pet dogs. Tumor types assessed included solid malignancies, lymphomas, and multiple myeloma. Through a stepwise dose and schedule escalation schema, we determined the maximum tolerated dose to be 7.5 mg/kg when administered orally on a 4 days on, 3 days off schedule per week for 3 consecutive weeks. Adverse events were minimal and mainly related to the gastrointestinal system. Pharmacokinetic/pharmacodynamic data suggest a relationship between exposure and modulation of targets related to induction of the unfolded protein response, but not to tolerability of the agent. An efficacy signal was detected in 33% (2/6) of dogs with multiple myeloma, consistent with a mechanism of action relating to induction of proteotoxic stress in a tumor type with abundant protein production. Clinical trials of CB-5339 in humans with acute myelogenous leukemia and multiple myeloma are ongoing.
Assuntos
Antineoplásicos , Linfoma , Mieloma Múltiplo , Proteína com Valosina , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cães , Inibidores Enzimáticos/uso terapêutico , Linfoma/tratamento farmacológico , Linfoma/patologia , Linfoma/veterinária , Dose Máxima Tolerável , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/veterinária , Resposta a Proteínas não Dobradas , Proteína com Valosina/antagonistas & inibidoresRESUMO
Veterinarians are gaining interest in and access to Position Emission Tomography (PET and PET/CT) imaging for both clinical and research applications. This manuscript provides an overview of how veterinarians may approach the use of off-site PET and PET/CT scanners already in use for human medical imaging in order to gain access to this technology without direct investment in costly equipment and infrastructure. An overview of general procedures, animal transport, and radiation safety considerations is offered along with references to key regulatory statutes that may apply to the operation of PET imaging facilities in individual states.