Diarrhea
Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or atropine with the first loose bowel movement. Immunosuppression
The immune system is adversely impacted by irinotecan. This is reflected in – sometimes dramatically – lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience neutropenia (a clinically significant decrease of neutrophils in the blood). Mechanism of action
Camptothecin, one of the four major structural classifications of plant-derived anti-cancerous compounds, is a cytotoxic alkaloid which consists of a pentacyclic ring structure containing a pyrrole (3, 4 β) quinoline moiety, an S-configured lactone form, and a carboxylate form. Camptothecin is an inhibitor of topoisomerase I. Its analogue, irinotecan, is activated by hydrolysis to SN-38, and is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.The molecular action of irinotecan occurs by trapping a subset of topoisomerase-1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence. One irinotecan molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the topoisomerase 1 enzyme. Interactive pathway
Click on genes, proteins and metabolites below to link to respective articles. Pharmacokinetics
Administration
Irinotecan can be administrated by 30- or 90-minute intravenous infusions of either 125 mg/m2 weekly for four of every six weeks or 350 mg/m2 every three weeks.
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL gene markers. In PMF, the healthy marrow is replaced by scar tissue (fibrosis), resulting in a lack of production of normal blood cells. Symptoms include anemia, increased infection and an enlarged spleen (splenomegaly). In 2016, prefibrotic primary myelofibrosis was formally classified as a distinct condition that progresses to overt PMF in many patients, the primary diagnostic difference being the grade of fibrosis. Signs and symptoms
The primary feature of primary myelofibrosis is bone marrow fibrosis, but it is often accompanied by:

Abdominal fullness related to an enlarged spleen (splenomegaly). Bone pain
Bruising and easy bleeding due to inadequate numbers of platelets
Cachexia (loss of appetite, weight loss, and fatigue)
Enlargement of both the liver and spleen
Fatigue
Gout and high uric acid levels
Increased susceptibility to infection, such as pneumonia
Pallor and shortness of breath due to anemia
In rarer cases, a raised red blood cell volume
Cutaneous myelofibrosis is a rare skin condition characterized by dermal and subcutaneous nodules. : 746

Causes
The underlying cause of PMF is unknown (idiopathic disease). There is an association between mutations to the JAK2, CALR, or MPL gene and myelofibrosis. Approximately 90% of those with myelofibrosis have one of these mutations and 10% carry none of these mutations.