The cancer chemotherapy drug etoposide (VP-16) induces proinflammatory cytokine production and sickness behavior-like symptoms in a mouse model of cancer chemotherapy-related symptoms.

Cancer chemotherapy-related symptoms such as fatigue, malaise, loss of interest in social activities, difficulty concentrating, and changes in sleep patterns can lead to treatment delays, dose reductions, or termination and have a profound effect on the physical, psychosocial, and economic aspects of quality of life. Clinicians have long suspected that these symptoms are similar to those associated with "sickness behavior," which is triggered by the production of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6 by macrophages and other cells of the innate immune system in response to immune challenge. The p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the induction of sickness behavior. Several cancer chemotherapy drugs have been shown to activate p38 MAPK, but whether these drugs can also induce the production of inflammatory cytokines to cause sickness behavior is unknown. The aim of this study was to determine whether the cancer chemotherapy drug etoposide (VP-16), which is known to activate p38 MAPK, could induce inflammatory cytokine production by murine macrophages and sickness-like behaviors when injected into mice. VP-16 activated p38 MAPK and induced IL-6 production in murine macrophages in a p38 MAPK- dependent manner. VP-16 administration rapidly increased serum levels of IL-6 in healthy mice and induced sickness-like behaviors as evidenced by a decrease in food intake, body weight, hemoglobin level, and voluntary wheel-running activity. These findings support the idea that the induction of IL-1beta, TNF-alpha, and IL-6 by cancer chemotherapy drugs underlies the fatigue and associated symptoms experienced by people undergoing cancer chemotherapy.

Induction of IL-6 by Cytotoxic Chemotherapy Is Associated With Loss of Lean Body and Fat Mass in Tumor-free Female Mice.

Cancer patients treated with cytotoxic chemotherapy experience fatigue and changes in body composition that can impact physical functioning and quality of life during and after treatment. Interleukin-6 (IL-6) is associated with fatigue in cancer survivors and plays an important role in the regulation of body composition. The purpose of the present study was to determine the specific role of IL-6 in cyclophosphamide-doxorubicin-5-fluorouracil (CAF)-induced changes in fatigue, food intake, and body composition using mice lacking IL-6. Female wild-type (WT) and IL-6 (-/-) mice were injected with four cycles of CAF or normal saline (NS) administered at 21-day intervals. Daily voluntary wheel-running activity (VWRA), used as a proxy for fatigue, and food intake were monitored daily up to 21 days after the fourth dose. Dual-energy X-ray absorptiometry (DEXA) was used to assess treatment-related changes in lean body mass (LBM), fat mass (FM), and bone mineral content (BMC). Patterns of change in fatigue and food intake did not differ between CAF-treated WT and IL-6 (-/-) mice. However, a Genotype × Drug interaction was observed for LBM (p = 0.047) and FM (p = 0.035) but not BMC (p = .569). Whereas WT mice lost LBM and FM during CAF treatment, IL-6-deficient mice did not. Treatment-related decreases in levels of the anabolic hormone insulin-like growth factor-1 (IGF-1) may contribute to LBM and FM loss since CAF decreased IGF-1 levels in an IL-6-dependent manner. These findings implicate IL-6 and possibly IGF-1 in the regulation of body composition in breast cancer patients exposed to cytotoxic chemotherapy.

A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors.

CRKL (CRK-like) is an adapter protein predominantly phosphorylated in cells that express the tyrosine kinase p210(BCR-ABL), the fusion product of a (9;22) chromosomal translocation causative for chronic myeloid leukemia. It has been unclear, however, whether CRKL plays a functional role in p210(BCR-ABL) transformation. Here, we show that CRKL is required for p210(BCR-ABL) to support interleukin-3-independent growth of myeloid progenitor cells and long-term outgrowth of B-lymphoid cells from fetal liver-derived hematopoietic progenitor cells. Furthermore, a synthetic phosphotyrosyl peptide that binds to the CRKL SH2 domain with high affinity blocks association of endogenous CRKL with the p210(BCR-ABL) complex and reduces c-MYC levels in K562 human leukemic cells as well as in mouse hematopoietic cells transformed by p210(BCR-ABL) or the imatinib-resistant mutant T315I. These results indicate that the function of CRKL as an adapter protein is essential for p210(BCR-ABL)-induced transformation.

Inhibition of p38 MAPK suppresses inflammatory cytokine induction by etoposide, 5-fluorouracil, and doxorubicin without affecting tumoricidal activity.

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often experience debilitating fatigue similar to sickness behavior, a normal response to infection or tissue damage caused by the production of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6. The p38 mitogen activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the development of sickness behavior. Targeted inhibitors of p38 MAPK can reduce systemic inflammatory cytokine production and the development of sickness behavior. Several systemic cancer chemotherapy drugs have been shown to stimulate inflammatory cytokine production, yet whether this response is related to a common ability to activate p38 MAPK is not known and is the focus of this study. This understanding may present the possibility of using p38 MAPK inhibitors to reduce chemotherapy-induced inflammatory cytokine production and consequently treatment-related fatigue. One caveat of this approach is a potential reduction in chemotherapeutic efficacy as some believe that p38 MAPK activity is required for chemotherapy-induced cytotoxicity of tumor cells. The purpose of this study was to demonstrate proof of principal that p38 MAPK inhibition can block chemotherapy-induced inflammatory cytokine production without inhibiting drug-induced cytotoxicity using murine peritoneal macrophages and Lewis Lung Carcinoma (LLC1) cells as model cell systems. Using these cells we assessed the requirement of etoposide, doxorubicin, 5-fluorouracil, and docetaxel for p38 MAPK in inflammatory cytokine production and cytotoxicity. Study findings demonstrate that clinically relevant doses of etoposide, doxorubicin, and 5-FU activated p38 MAPK in both macrophages and LLC1 cells. In contrast, docetaxel failed to activate p38 MAPK in either cell type. Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies.

Cancer chemotherapy-related symptoms: evidence to suggest a role for proinflammatory cytokines.

PURPOSE/OBJECTIVES: To provide an overview of the evidence that supports a role for the proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) in the etiology of cancer chemotherapy-related symptoms. DATA SOURCES: Electronic nursing, psychology, and medicine databases; online meeting abstracts; and personal experimental observations. DATA SYNTHESIS: Substantial evidence implicates the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6 in the etiology of chemotherapy-related anorexia, cachexia, anemia, pain, sleep disturbance, fatigue, and depression. CONCLUSIONS: Further investigation into the role of these cytokines in the genesis of chemotherapy-related symptoms is warranted. The development of appropriate animal models likely will be key to understanding the relationship among cancer chemotherapy, proinflammatory cytokines, and symptoms. IMPLICATIONS FOR NURSING: Nurses traditionally have been leaders in symptom management. The symptoms experienced by patients undergoing chemotherapy have a profound negative impact on quality of life and patients' ability to receive prescribed treatments. An understanding of potential mechanisms underlying the physiologic and behavioral consequences of chemotherapy administration will aid nurses in the development of interventions to effectively manage chemotherapy-related symptoms.