Retroviral association with ovarian adenocarcinoma in laying hens.

The laying hen has been used as a model for ovarian adenocarcinoma (OAC) in women. Previous work has shown an association between expression of endogenous retroviral proteins and elevated envelope mRNA and occurrence of OAC in humans, but causality has not been demonstrated. The objective of this study was to determine whether there is a similar association between retrovirus presence and OAC in a commercial laying hen flock at the University of Illinois Poultry Research facility with a history of a high OAC prevalence in older hens. Laying hens of three age strata were randomly selected for a cross-sectional study. Blood samples were collected, and serum was tested for antigens of endogenous or exogenous avian leukosis virus (ALV) by ELISA. Birds were humanely euthanized, and spleens, ovaries, and any tissues with gross lesions were sampled. Ovaries and gross lesions were examined histologically and spleens were used for RT-PCR to detect endogenous ALV via ALV-E env mRNA expression. Overall, hens with OAC were 5.2 times more likely to be ALV positive than hens without OAC (95% C.I. 2.06-13.14). Controlled for age, OAC positive hens were 3.6 times more likely to be positive for ALV via antigen-capture ELISA (95% C.I. 1.08-11.96). Endogenous ALV-E in hens may be analogous to human endogenous retroviruses, which have also been associated with OAC in women. Further studies to establish causation are warranted to better understand the potential for laying hens to serve as a laboratory model for viral-induced ovarian tumours in humans. RESEARCH HIGHLIGHTSOAC in hens was associated with age, seropositivity for ALV, and endogenous ALV mRNA expression.Older hens with OAC were more likely to be ALV seropositive by ELISA and ALV-E mRNA-positive.Associations between OAC, age, and endogenous retrovirus expression have been reported in humans.These findings support the use of hens as models for OAC in humans.

Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma.

PURPOSE: The purpose was to determine the safety and antitumor activity of a folate-tubulysin conjugate (EC0531) in a relevant preclinical animal model, dogs with naturally-occurring invasive urothelial carcinoma (iUC). Canine iUC is an aggressive cancer with high folate receptor (FR) expression similar to that in certain forms of human cancer. EXPERIMENTAL DESIGN: A 3+3 dose escalation study of EC0531 (starting dose 0.2 mg/kg given intravenously at two-week intervals) was performed in dogs with iUC expressing high levels of FRs (>50% positive tumor cells). Pharmacokinetic (PK) analysis was performed, and the maximum tolerated dose (MTD) was determined. The dose cohort at the MTD was expanded to determine antitumor activity. RESULTS: The MTD of EC0531 was 0.26 mg/kg every two weeks, with grade 3-4 neutropenia and gastrointestinal toxicity observed at higher doses. Treatment at the MTD was well tolerated. Clinical benefit was found in 20 of 28 dogs (71%), including three dogs with partial remission and 17 dogs with stable disease. Plasma EC0531 concentrations in the dogs far exceeded those required to inhibit proliferation of FR-expressing cell in vitro. Unlike human neutrophils, canine neutrophils were found to express FRs, which contributes to the neutropenia at higher doses of EC0531 in dogs. CONCLUSION: EC0531 was well tolerated and had good antitumor activity in dogs with iUC. It is likely that humans will tolerate higher, potentially more effective doses of folate-tubulysin without myelotoxicity because of the absence of FRs on human neutrophils. The results clearly justify the evaluation of folate-tubulysin in human clinical trials.