Effects of Analgesics on Tumor Growth in Mouse Models of Prostate Cancer Bone Metastasis.

Murine models of tumor development often require invasive procedures for tumor implantation, potentially causing pain or distress. However, analgesics are often withheld during implantation because of concerns that they may adversely affect tumor development. Previous studies examining the effects of analgesics on the development and metastasis of various tumor lines show that the effect of analgesics depends on the tumor line and analgesic used. A blanket statement that analgesics affect the general growth of tumors is not adequate scientific justification for withholding pain relief, and pilot studies or references are recommended for each specific tumor cell line and treatment combination. In this study, we evaluated the effects of 2 commonly used analgesics on tumor growth in 2 models of prostate cancer (PCa) bone metastasis. We hypothesized that a one-time injection of analgesics at the time of intratibial injection of tumor cells would not significantly impact tumor growth. Either C57BL/6 or SCID mice were injected subcutaneously with an analgesic (carprofen [5 mg/kg], or buprenorphine [0.1 mg/kg]) or vehicle (0.1 mL of saline) at the time of intratibial injection with a PCa cell line (RM1 or PC3, n = 10 to 11 per group). Tumor growth (measured by determination of tumor burden and the extent of bone involvement) and welfare (measured by nociception, locomotion, and weight) were monitored for 2 to 4 wk. Neither carprofen or buprenorphine administration consistently affected tumor growth or indices of animal welfare as compared with the saline control for either cell line. This study adds to the growing body of literature demonstrating that analgesia can be compatible with scientific objectives, and that a decision to withhold analgesics must be scientifically justified and evaluated on a model-specific basis.

Heat stress-induced heat shock protein 70 expression is dependent on ERK activation in zebrafish (Danio rerio) cells.

Heat shock response is a common event that occurs in many species. Despite its evolutionary conservation, comparative studies of heat shock response have been largely unexplored. In mammals, heat shock response decreases with age through unclear mechanisms. Understanding how the age-related decline in heat shock response occurs may provide information to understanding the biology of aging. We have previously shown that heat shock response similarly declines with age in zebrafish. However, signaling pathways that regulate the heat shock response in zebrafish are unknown. In mammals there is evidence that mitogen-activated protein kinases (MAPKs) of the ERK family alter Hsp70 transcription, serving as a potential regulator of the heat shock response. We explored if heat stress-induced Hsp70 expression is altered by activation of ERK in the zebrafish Pac2 fibroblast cell line as occurs in mammalian cells. Heat stress induced both Hsp70 mRNA expression and phosphorylation of both ERK1 and ERK2 (ERK1/2) in Pac2 cells. ERK inhibitors PD98059 and U0126 blocked both heat stress-induced and plated-derived growth factor (PDGF)-induced ERK1/2 phosphorylation, and also diminished heat-induced Hsp70 expression. Pac2 cell viability was not affected by either the ERK inhibitors or heat stress. These results demonstrate that induction of Hsp70 in response to heat stress is dependent on ERK activation in Pac2 cells. This suggests that the heat shock response in zebrafish utilizes a similar signaling pathway to that of mammals and that zebrafish are a good model for comparative studies of heat shock response.

A safety-modified SV40 Tag developed for human cancer immunotherapy.

Simian virus 40 (SV40)-like DNA sequences have been found in a variety of human tumors, raising the possibility that strategies targeting SV40 may provide a potential avenue for immunotherapy directed against SV40 large T Antigen (Tag)-expressing tumors. We generated a recombinant vaccinia (vac-mTag) expressing mTag and herein assessed the ability of mTag to transform cells and to interact with anti-oncoproteins, as well as screened for the presence of potential HLA-A2.1-restricted epitopes within mTag. We found that transfection of cells with mTag did not lead to their transformation. Also, we demonstrated that mTag protein is degraded rapidly in cells. In addition, our work revealed that mTag did not physically interact with certain anti-oncoproteins. Finally, two potential HLA-A2.1-restricted functional epitopes within mTag sequence were identified. Our results show that mTag lacks the oncogenicity of full-length Tag and harbors potential HLA-A2.1-restricted immunogenic epitopes, hence suggesting the safety of vac-mTag for use in cancer immunotherapy.