ABSTRACT
Most patients with advanced breast cancer develop osteolytic bone metastases, which have numerous complications. Because current therapies are not curative, new treatments are needed. Conditionally replicating adenoviruses (CRAds) are anticancer agents designed to infect and lyse tumor cells. However, in spite of their promise as selective cancer therapeutics, replicating adenoviruses have shown limited efficacy in the clinical setting. We hypothesized that a CRAd armed with osteoprotegerin (OPG) would eradicate bone metastases of breast cancer both directly, by oncolysis, and indirectly, by inhibiting osteoclastic bone resorption, and thus reducing the tumor burden. We constructed an armed CRAd (Ad5-Δ24-sOPG-Fc-RGD) by replacing viral E3B genes with a fusion of the ligand-binding domains of OPG and the Fc portion of human IgG1. Conditional replication was conferred by a 24-base pair deletion within E1A (Δ24), which prevents the binding of E1A to the retinoblastoma tumor suppressor/cell cycle regulator protein and limits replication in normal cells. Enhanced infection of cells expressing low levels of the primary Ad5 receptor was conferred by incorporating an arginine-glycine-aspartic acid (RGD) peptide sequence into the fiber knob to mediate binding to α(v) integrins. After characterization of the armed CRAd, we demonstrated that infection of breast cancer cells by Ad5-Δ24-sOPG-Fc-RGD both killed the infected cells by oncolysis and inhibited the formation of osteoclasts in an in vitro co-culture model. In a murine model of osteolytic bone metastases of breast cancer, the CRAd armed with shortened OPG (sOPG)-Fc reduced tumor burden in the bone and inhibited osteoclast formation more effectively than an unarmed CRAd.
Subject(s)
Adenoviridae/genetics , Bone Neoplasms/secondary , Breast Neoplasms/therapy , Osteoprotegerin/genetics , Animals , Bone Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , Female , Humans , Mice , Osteoprotegerin/metabolism , Tumor Burden/genetics , Virus ReplicationABSTRACT
Conditionally replicating adenoviruses (CRAds) have many advantages as agents for cancer virotherapy and have been safely used in human clinical trials. However, replicating adenoviruses have been limited in their ability to eliminate tumors by oncolysis. Thus, the efficacy of these agents must be improved. To this end, CRAds have been engineered to express therapeutic transgenes that exert antitumor effects independent of direct viral oncolysis. These transgenes can be expressed under native gene control elements, in which case placement within the genome determines the expression profile, or they can be controlled by exogenous promoters. The therapeutic transgenes used to arm replicating adenoviruses can be broadly classified into three groups. There are those that mediate killing of the infected cell, those that modulate the tumor microenvironment and those with immunomodulatory functions. Overall, the studies to date in animal models have shown that arming a CRAd with a rationally chosen therapeutic transgene can improve its antitumor efficacy over that of an unarmed CRAd. However, a number of obstacles must be overcome before the full potential of armed CRAds can be realized in the human clinical context. Hence, strategies are being developed to permit intravenous delivery to disseminated cancer cells, overcome the immune response and enable in vivo monitoring of the biodistribution and activity of armed CRAds.
Subject(s)
Adenoviridae/genetics , Neoplasms/therapy , Oncolytic Virotherapy , Oncolytic Viruses/genetics , Virus Replication/genetics , Animals , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , Models, Genetic , Transgenes/geneticsABSTRACT
The PIC profiles of 175 children over a wide age range were factor analyzed in order to determine the underlying personality dimensions measured by the instrument. The subjects were referred to an interdisciplinary university clinic for a variety of learning, cognitive, and emotional problems. A principal components analysis with oblique rotation yielded three major factors: Internalized Personality Disturbance, Cognitive Development, and Externalized Behavior Disorder. A small fourth factor that involved mainly the Somatic Concern scale was revealed also. Implications of the factors for the interpretation and clinical use of the PIC profiles are discussed.
Subject(s)
Personality Disorders/diagnosis , Personality Inventory , Referral and Consultation , Child , Child Behavior Disorders/diagnosis , Cognition Disorders/diagnosis , Female , Humans , Learning Disabilities/diagnosis , Male , Personality Development , PsychometricsABSTRACT
Compared the performance of learning-disabled and behavior-disordered children (N = 60) on the recently published Personality Inventory of Children (PIC) to investigate the discriminant validity of the instrument. The data were analyzed by profile analysis and stepwise discriminant analysis. Results showed that learning-disabled and behavior-disordered children could be differentiated clearly on subtests that comprise the Cognitive Development and Conduct Disorder factors. However, less differentiation was found on the Internalization factor. Further examination indicated a possible diagnosis X scale "interaction" within the Internalization factor. Those learning-disabled children who also experienced "internal" difficulties tended to score high on the Somatic Concern Scale, while behavior-disordered children typically scored high on the other Internalization scales (i.e., Anxiety, Withdrawal, etc.). A total of seven of the PIC clinical and validity scales were selected in the discriminant function that separated the two groups.
