RESUMO
Pancreatic adenocarcinomas are aggressive and frequently develop resistance to all current therapies. Replication-selective adenoviruses can overcome resistance to chemotherapeutics through their sensitizing effects on drug-induced cell killing. We previously found that adenovirus deleted in the anti-apoptotic E1B19K gene enhanced gemcitabine-induced apoptotis. Here we demonstrate that our engineered double-deleted AdΔΔ mutant (deleted in the pRb-binding E1ACR2 region and E1B19K) selectively replicates and enhances cell killing in combination with DNA-damaging cytotoxic drugs in pancreatic cancer cells. Combinations of AdΔΔ with gemcitabine, irinotecan or cisplatin resulted in two- to fourfold decreases in EC(50) (half maximal effective concentration) values and was more efficent than similar combinations with wild-type virus, the dl1520 (ONYX-015) and dl922-947 mutants. AdΔΔ replication was impaired in normal bronchial human epithelial cells and did not sensitize the cells to drugs. Gemcitabine-insensitive AsPC-1, BxPC-3 and PANC-1 cells were efficiently killed by irinotecan in combination with AdΔΔ. Suboptimal doses of AdΔΔ and gemcitabine significantly prolonged time to tumor progression in two human pancreatic tumor xenograft in vivo models, PT45 and SUIT-2. We conclude that AdΔΔ has low toxicity to normal cells while potently sensitizing pancreatic cancer cells to DNA-damaging drugs, and holds promise as an improved therapeutic strategy for pancreatic cancer.
Assuntos
Adenocarcinoma/terapia , Adenoviridae/genética , Antineoplásicos/administração & dosagem , Vírus Oncolíticos/genética , Neoplasias Pancreáticas/terapia , Animais , Apoptose , Linhagem Celular Tumoral , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Vetores Genéticos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Vacinas Virais , Replicação Viral , Eliminação de Partículas Virais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Much excitement surrounds the possibility that strontium ruthenate exhibits chiral p-wave superconducting order. Such order would be a solid state analogue of the A phase of He-3, with the potential for leading to exotic physics relevant to quantum computing. We take a critical look at the evidence for such time reversal symmetry breaking order. The possible superconducting order parameter symmetries and the evidence for and against chiral p-wave order are reviewed, with an emphasis on the most recent theoretical predictions and experimental observations. In particular, attempts to reconcile experimental observations and theoretical predictions for the spontaneous supercurrents expected at sample edges and domain walls of a chiral p-wave superconductor and for the polar Kerr effect, a key signature of broken time reversal symmetry, are discussed.
