Additional Supportive Care Models

Biomodels offers animal models in several other areas related to cancer supportive care: Esophagitis, Fibrosis, Gastro-Intestinal Mucositis, Cachexia and Myelosuppression.

Esophagitis Esophagitis is a condition in which the esophagus becomes inflamed (swollen, irritated and red).Esophagitis is usually caused by Gastro-esophageal Reflux Disease (GERD), infectious etiologies, or adverse effects of medications or focal radiation therapy to the thorax. Infective esophagitis is most commonly observed in immunosuppressed hosts, and therefore may occur in patients undergoing therapy with cytotoxic agents or a bone marrow transplant ablative regimen. A wide range of abnormalities in host defense may predispose an individual to opportunistic infections, such as neutropenia, impaired chemotaxis and phagocytosis, alteration in humoral immunity, and impaired T-cell lymphocyte function. Steroids, cytotoxic agents, radiation, and immune modulators can also contribute to impaired host immune function. Disruption of mucosal protective barriers and antibiotics that suppress the normal bacterial flora may contribute to the invasive ability of commensal organisms. Patients with esophagitis may experience dysphagia, pain, odynophagia, and malnutrition in severe esophagitis. Rarely, life-threatening bleeding occurs and may lead to death. Outcomes and survival in these patients are related to the severity of their underlying systemic illness. Treatment for esophagitis depends on the cause of the condition. In the case of GERD,eating habits may need to be changed (e.g., avoiding alcohol, caffeine, carbonated beverages, chocolate, fatty foods or overly large meals), drugs may be necessary to reduce stomach acid and the patient may need to sleep with the head raised. Infections are treated with drugs to specifically target the cause of the infection. In the case of patients whose esophagitis is due to radiation and/or chemotherapy, treatment with drugs to reduce infection and changes in eating habits with or without the use of antacids may help minimize the symptoms and adventitious infections, but they will not prevent the occurrence of the esophagitis, particularly in the case of radiation induced esophagitis. Animal Model for Radiation Induced Esophagitis Esophagitis 1s induced in mice using a standardized radiation protocol in which mice received a single dose of radiation to anesthetized mice. Lead shielding is used to protect the head and abdominal areas from radiation. The extent of radiation-induced esophagitis is evaluated histologically at time points from 10-20 days post radiation. Fibrosis In the Cancer Supportive Care setting, fibrosis is generally a long-term consequence of radiation therapy.  Radiation can cause pulmonary fibrosis in patients undergoing radiation to the chest for disease such as lung cancer.  In addition, patients with cancer of the head and neck can suffer from a variety of radiation related problems including soft tissue fibrosis, temporomandibular tightness and trimus associated with muscle damage.  Radiation therapy can also lead to restrictions in joint motility in other forms of cancer as fibrosis impacts the tissues surrounding any joint in the vicinity of the radiation treatment. Animal Models for Fibrosis Radiation Induced Fibrosis of the Hamster Cheek Pouch Fibrosis of the hamster cheek pouch is a long-term consequence of the radiation used to induce mucositis, and can be evaluated histologically 4-8 weeks post radiation.  Hamsters are anesthetized and the cheek pouch exposed and exposed to radiation.  Four  to  eight weeks later the extent of fibrosis is evaluated using standard histological stains (Sirius red, Trichrome) or immunohistochemistry. UUO Model Experimental Unilateral Ureter Obstruction (UUO) represents a model for obstructive nephropathy but also allows insight into the process of interstitial fibrosis that is a common characteristic of many chronic nephropathies. Markers of renal fibrosis, such as interstitial fibroblasts, interstitial volume, mRNA and protein expression for collagen I, are all increased in UUO animals, making the UUO model a good experimental system for studying fibrosis.  In this model of fibrosis, animals are subject to UUO on Day 0 and the kidneys are removed (for histological assessment of fibrosis) and blood is collected on day 14. Bleomycin Induced Pulmonary Fibrosis. Mice are anesthetized by inhalation of 2% isoflurane, and the trachea was exposed by a cervical incision. Bleomycin in PBS is then instilled intratracheally. At time points from 48 hours to 28 days post instillation, animals are sacrificed and lungs evaluated for evidence of fibrosis. Lungs are inflation-fixed with 10% neutral-buffered formalin, and the trachea is ligated. Heart and lungs are removed and fixed, en bloc, in paraffin. Slides are stained with hematoxylin and eosin or Gomori’s trichrome to detect collagen. GI Mucositis Mucositis of the gastro-intestinal tract, particularly the small intestine are a common side effect of syto-toxic cancer chemotherapy and may also be induced by radiation therapy that targets the abdominal area.  The symptoms of GI mucositis are varied and may include diarrhea, constipation, gas, cramping, bloating and blood in the stool.  In severe cases, perforation or obstruction may be life threatening if not treated quickly.  The course of GI mucositis is variable and includes progressively chronic and persistent forms, to others that are characterized by periods of remission and relapse.   Pharmaceutical treatments of GI mucositis  include the use of anti-inflammatories (including steroids), immunosuppressives, and antibiotics to control bacterial overgrowth.  Generally treatment is focused on symptom management. Animal Models for GI Mucositis In mice mucositis of the small intestine can be induced with either cyto-toxic chemotherapies such as 5-FU or radiation, and the disease is evaluated over 1-7 days using histological endpoints.   In the colon and rectum, evaluation may also be conducted with a rodent endoscope. Cachexia Cachexia is the loss of weight often seen in cancer patients.  The formal definition of cachexia is the loss of body mass that cannot be reversed nutritionally.  Cachexia increases the probability of death and infection as well as weakening the patient and reducing quality of life.  As with many of the other side effects associated with cancer and cancer therapy, cachexia is thought to be driven by the cytokines of the inflammatory cascade, tumor necrosis factor-alpha (TNF-a) – Interferon gamma (IFN?), and Interleukin 6 (IL-6), in addition to tumor derived factors such as proteolysis inducing factor (PIF). Animal Models for Cachexia Animal models of cancer are models where cachexia is a direct consequence of the tumor.  In rats, the Walker 256 carcinosarcoma causes cachexia that can be evaluated through weight loss in adult animals. In mice the 4T1 breast carcinoma and colon 26 colorectal carcinoma cell lines also induce cachexia and can be used to evaluate treatments for cachexia. Myelosuppression Cytotoxic chemotherapy drugs can produce the side effect of lowering the level of cells in the bone marrow, resulting in abnormally low number of cells in the blood, the condition is called myelosuppression.  The effects of myelosuppression are anemia (low red blood cell counts)  neutropenia (low neutrophils counts) and thrombocytopenia (low platelet counts). Cancer patients may experience one or more of the following types of symptoms of the myelosuppressive side effects during the treatment:  Fatigue due to anemia, infections due to neutropenia and bruising and bleeding due to thrombocytopenia. These symptoms generally resolve after the completion of chemotherapy, however, for some patients, they are severe enough to cause a reduction in dose or a break in treatment.  When reductions and breaks in therapy occur, the chances of an increase in cancer recurrence increase, consequently, agents that reduce myelosuppression in patients undergoing cancer chemotherapy decrease the probably of a reduction or break in therapy and therefore reduce the chances of the cancer recurring. Animal Models for Myelosuppression The impact of cytotoxic anti-cancer drugs can be evaluated in both rat and mouse models by evaluating the impact of drugs on blood counts (CBCs) and on bone marrow histology.