Effect of Atorvastatin on 5-Fluorouracil Induced Mucositis

5-Fuorouracil (5-Fu) remains one of the most effective and most commonly used drugs to treat colorectal cancer. Mucositis is a major complication that occurs in approximately 80% of patients receiving 5-FU and results in abdominal bloating as well as vomiting and diarrhea. oral mucositis (OM) are often very painful and compromise nutrition and oral hygiene as well as increase risk for local and systemic infection.

OM is characterized by an intense inflammatory reaction on the mucosa lamina propria cells, which results in activation of the transcription factor NF-kB. The activation of NF-kB leads to transcription of genes involved in the synthesis of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Agents known to attenuate the expression of cytokines have demonstrated efficacy in the prevention of experimental mucositis.

The use of atorvastatin were associated with reduced production of TNF-α and IL-1β and decreased neutrophil infiltration evidenced by histopathological analysis and Myeloperoxidase (MPO) activity. In addition, atorvastatin also reduced oxidative stress and induced an increase in non-protein sulfhydryl groups showing anti-inflammatory and immunomodulatory action.

Chemotherapy has life-threatening or distressing side effects such febrile neutropenia, infections, mucositis, nausea, vomiting, fatigue. Mucositis is deﬁned as inﬂammatory and/or ulcerative lesions of the oral and/or gastrointestinal tract that can be caused by high dose chemotherapy, Infectious disease, immune deﬁciency and medications..

Lesions of oral mucositis (OM) are often very painful and compromise nutrition and oral hygiene as well as increase risk for local and systemic infection. Mucositis can also involve other areas of the alimentary tract; for example, gastrointestinal (GI) mucositis can manifest as diarrhea. Thus, mucositis is a highly significant and sometimes dose-limiting complication of cancer therapy.

OM leads to an increased risk of microbial infections and often entails parenteral nutrition, long-lasting intake of analgesics and extended hospitalization periods. This causes substantial costs to the health system and, also has a considerable impact on the patient's quality of life. Furthermore, dose reduction might become necessary, which limits the efficacy of the antitumor therapy.

OM is characterized by an intense inflammatory reaction on the mucosa lamina propria cells, which results in activation of the transcription factor NF-kB. The activation of NF-kB leads to transcription of genes involved in the synthesis of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, and agents known to attenuate the expression of cytokines have demonstrated efficacy in the prevention of experimental mucositis.

Conventional chemotherapeutic drugs most frequently associated with mucositis include antimetabolites, such as 5-fluorouracil (5-FU), methotrexate, and purine antagonists. Anthracycline antitumor antibiotics (eg, doxorubicin) and taxanes (eg, paclitaxel and docetaxel) are other chemotherapeutic drugs that commonly cause mucositis.

Over the last five decades, 5-fluorouracil (5-Fu) remains one of the most effective and most commonly used drugs to treat colorectal cancer. The commonly side effects of 5-FU include myelosuppression, dermatitis, cardiac toxicity, diarrhea, and mucositis. Among these adverse effects, gastrointestinal mucositis is a major complication that occurs in approximately 80% of patients receiving 5-FU and results in abdominal bloating as well as vomiting and diarrhea. 5-FU induces inflammation in the small intestine, characterized by the increased intestinal wall thickness and crypt length, the decreased villus height, and the increased myeloperoxidase (MPO) activity in tissues and pro-inflammatory cytokine production in sera..

Statins are potent inhibitors of cholesterol biosynthesis and have been shown to decrease mortality from cardiovascular disease. In addition to their lipid lowering properties by inhibiting 3-hydroxy-3-methylgluteryl coenzyme A (HMG CoA) reductase. Statins possess various pleiotropic effects that include improvement in endothelial dysfunction, increased expression of endothelial nitric oxide synthase (eNOS), enhanced bioavailability of nitric oxide (NO), potent antioxidant potential and anti-inflammatory properties.

It has been reported that simvastatin had significant preventive effects on esophageal, gastric and intestinal damage in a rat model using 10 mg / Kg of simvastatin microemulsion by gavage, beginning one week prior to treatment with MTX, and during treatment with this drug. Animals received i.p. injection of atorvastatin (ATV; 1 or 5 mg/kg), saline or saline/ethanol 30 min before 5-FU and daily for 5 days (5 days) or 10 days (10 days). in hamsters showing significant reduction the macroscopic and micro-scopic lesions induced by 5-FU in the OM of hamsters.

The macroscopic protective effects of atorvastatin were associated with reduced production of TNF-α and IL-1β and decreased neutrophil infiltration evidenced by histopathological analysis and Myeloperoxidase (MPO) activity. In addition, atorvastatin also reduced oxidative stress and induced an increase in non-protein sulfhydryl groups showing anti-inflammatory and immunomodulatory action.

Eligibility Criteria:
Inclusion Criteria:

1. Adult patients (\>18 years old).
2. Colon cancer patients ???? who will receive adjuvant FOLFOX 6\& FOLFIRI 6 for 6 cycles.
3. ECOG performance status 0-2
4. Adequate bone marrow function (white blood count ≥4,000/mm3, platelet count ≥100,000/mm3), liver function (serum total bilirubin \<1.5 mg/dl), renal function (creatinine \<1.5 mg/dl).

Exclusion Criteria:

1. Patients who have Clinical GIT mucositis or Periodontal disease.
2. Patients with other primary malignancy.
3. Patients receiving mTOR inhibitors (eg, rapamycin, everolimus, and temsirolimus), EGFR inhibitors (eg, bevacizumab and erlotinib) and tyrosine-kinase inhibitors (eg, sorafenib and sunitinib).
4. Hypersensitivity to Atorvastatin.

6-Pregnant and lactating women. 7- Patients treated with ATV for any other indication. 8- Patient who already have a mucositis