Gilbert syndrome ( GS ) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes) may occur.
95-550: Irinotecan , sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer . For colon cancer it is used either alone or with fluorouracil . For small cell lung cancer it is used with cisplatin . It is given intravenously . Common side effects include diarrhea , vomiting , bone marrow suppression , hair loss, shortness of breath, and fever. Other severe side effects include blood clots , colon inflammation , and allergic reactions . Those with two copies of
190-480: A glycopeptide isolated from Streptomyces verticillus , also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion , becomes chemically reduced and reacts with oxygen . Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA. Most chemotherapy is delivered intravenously , although a number of agents can be administered orally (e.g., melphalan , busulfan , capecitabine ). According to
285-456: A meta-analysis of data available up to 2002, and confirmed the incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin. This beneficial effect was attributed to bilirubin IXα which is recognized as a potent antioxidant, rather than confounding factors such as high-density lipoprotein levels. This association
380-459: A nucleobase , a sugar and a phosphate group . The nucleobases are divided into purines ( guanine and adenine ) and pyrimidines ( cytosine , thymine and uracil ). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups . These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting
475-436: 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
570-414: A certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the anti-folates , fluoropyrimidines, deoxynucleoside analogues and thiopurines . The anti-folates include methotrexate and pemetrexed . Methotrexate inhibits dihydrofolate reductase (DHFR), an enzyme that regenerates tetrahydrofolate from dihydrofolate . When
665-444: A high index of suspicion and the use of CT scanning, nonoperative treatment for uncomplicated cases, and sometimes elective right hemicolectomy to prevent recurrence. Nausea , vomiting , anorexia , diarrhea , abdominal cramps, and constipation are common side-effects of chemotherapeutic medications that kill fast-dividing cells. Malnutrition and dehydration can result when the recipient does not eat or drink enough, or when
760-546: A large extent, chemotherapy can be thought of as a way to damage or stress cells, which may then lead to cell death if apoptosis is initiated. Many of the side effects of chemotherapy can be traced to damage to normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the bone marrow , digestive tract and hair follicles . This results in the most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence that also immunosuppression ), mucositis (inflammation of
855-446: A linear pharmacokinetic. Population pharmacokinetic models assumed a three-compartmental model for irinotecan and a two-compartmental model for SN-38. SN-38 has a short distribution half-life (approximately 8 min). It reached its peak plasma concentration within 2 h after infusion. Also SN-38 exhibit a second peak in the plasma concentration because of its enterohepatic re-circulation and its release from erythrocytes. About 2–5% of
950-553: A minor inborn error of metabolism . People with GS predominantly have elevated unconjugated bilirubin , while conjugated bilirubin is usually within the normal range or is less than 20% of the total. Levels of bilirubin in GS patients are reported to be from 20 μM to 90 μM (1.2 to 5.3 mg/dl) compared to the normal amount of < 20 μM. GS patients have a ratio of unconjugated/conjugated (indirect/direct) bilirubin commensurately higher than those without GS. The level of total bilirubin
1045-417: A number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms . All chemotherapy regimens require that the recipient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a person can receive chemotherapy, or whether dose reduction
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#17330853752411140-767: A preventative and treatment effect of diarrhoea related to chemotherapy alone and with radiotherapy. However, a high index of suspicion is appropriate, since diarrhoea and bloating are also symptoms of typhlitis , a very serious and potentially life-threatening medical emergency that requires immediate treatment. Anemia can be a combined outcome caused by myelosuppressive chemotherapy, and possible cancer-related causes such as bleeding , blood cell destruction ( hemolysis ), hereditary disease, kidney dysfunction, nutritional deficiencies or anemia of chronic disease . Treatments to mitigate anemia include hormones to boost blood production ( erythropoietin ), iron supplements , and blood transfusions . Myelosuppressive therapy can cause
1235-601: A recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans. There are many intravenous methods of drug delivery, known as vascular access devices. These include the winged infusion device , peripheral venous catheter , midline catheter, peripherally inserted central catheter (PICC), central venous catheter and implantable port . The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent. Depending on
1330-401: A state of assembly and disassembly. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite: Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce mitotic catastrophe in
1425-571: 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. Click on genes, proteins and metabolites below to link to respective articles. Irinotecan can be administered by 30- or 90-minute intravenous infusions of either 125 mg/m weekly for four of every six weeks or 350 mg/m every three weeks. Irinotecan
1520-514: A tendency to bleed easily, leading to anemia. Medications that kill rapidly dividing cells or blood cells can reduce the number of platelets in the blood, which can result in bruises and bleeding . Extremely low platelet counts may be temporarily boosted through platelet transfusions and new drugs to increase platelet counts during chemotherapy are being developed. Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover. Gilbert%27s syndrome Gilbert syndrome
1615-484: Is systemic therapy for cancer: they are introduced into the blood stream (the system) and therefore can treat cancer anywhere in the body. Systemic therapy is often used with other, local therapy (treatments that work only where they are applied), such as radiation , surgery , and hyperthermia . Traditional chemotherapeutic agents are cytotoxic by means of interfering with cell division (mitosis) but cancer cells vary widely in their susceptibility to these agents. To
1710-479: Is a "life-threatening gastrointestinal complication of chemotherapy." Typhlitis is an intestinal infection which may manifest itself through symptoms including nausea , vomiting , diarrhea , a distended abdomen , fever , chills , or abdominal pain and tenderness. Typhlitis is a medical emergency . It has a very poor prognosis and is often fatal unless promptly recognized and aggressively treated. Successful treatment hinges on early diagnosis provided by
1805-509: Is a hydrophilic compound with a large volume of distribution (400 L/m). At physiological pH, irinotecan and its active metabolite ethyl-10-hydroxy-camptothecin (SN-38) are present in two pH-dependent equilibrium isoforms; the anti tumor active lactone ring which hydrolyzed to the carboxylate isoform. In plasma, the majority of irinotecan and SN-38 are bound to albumin, which stabilizes their lactone forms. In blood, irinotecan and SN-38 are bound to platelets and red blood cells. Irinotecan has
1900-1054: Is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death. Capecitabine is a prodrug of 5-fluorouracil that is broken down in cells to produce the active drug. The deoxynucleoside analogues include cytarabine , gemcitabine , decitabine , azacitidine , fludarabine , nelarabine , cladribine , clofarabine , and pentostatin . The thiopurines include thioguanine and mercaptopurine . Anti-microtubule agents are plant -derived chemicals that block cell division by preventing microtubule function. Microtubules are an important cellular structure composed of two proteins, α-tubulin and β-tubulin . They are hollow, rod-shaped structures that are required for cell division, among other cellular functions. Microtubules are dynamic structures, which means that they are permanently in
1995-467: Is a yellowish pigment made when your body breaks down old red blood cells, and then being converted to conjugated bilirubin during the reaction. Conjugated bilirubin passes from the liver into the intestines with bile. It's then excreted in stool. People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function, which contributes to a lower rate of glucuronidation of unconjugated bilirubin. This substance then accumulates in
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#17330853752412090-399: Is adversely impacted by irinotecan. This is reflected in lowered white blood cell counts in the blood, in particular the neutrophils . 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
2185-563: Is an important factor in achieving better treatment outcomes. Similar results were found in a study involving people with colorectal cancer who have been treated with the popular FOLFOX regimen. The incidence of serious diarrhea was reduced from 12% in the BSA-dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe mucositis was reduced from 15% to 0.8%. The FOLFOX study also demonstrated an improvement in treatment outcomes. Positive response increased from 46% in
2280-495: Is an independent prognostic predictor of survival in various cancer types. Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War I , there are now many types of alkylating agents in use. They are so named because of their ability to alkylate many molecules, including proteins , RNA and DNA . This ability to bind covalently to DNA via their alkyl group
2375-499: Is another risk factor for increased toxicity The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38. Irinotecan is metabolized by intrahepatic cytochrome P450 enzymes, CYP3A4 and CYP3A5 into inactive metabolites APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin). NPC can be further converted by CES1 and CES2 in
2470-407: Is based on higher levels of unconjugated bilirubin in the blood without either signs of other liver problems or red blood cell breakdown . Typically no treatment is needed. Gilbert syndrome is associated with decreased cardiovascular health risks. If jaundice is significant phenobarbital may be used, which aids in the conjugation of bilirubin. Gilbert syndrome affects about 5% of people in
2565-496: Is characterized by a 70–80% reduction in the glucuronidation activity of the enzyme (UGT1A1). The UGT1A1 gene is located on human chromosome 2 . More than 100 polymorphisms of the UGT1A1 gene are known, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region . UGT1A1 is associated with a TATA box promoter region; this region most commonly contains
2660-636: Is closely related to the reduction in the prevalence of chronic diseases, especially cardiovascular disease and type 2 diabetes, related risk factors, and all-cause mortality. Observational studies emphasize that the antioxidant effects of unconjugated bilirubin may bring survival benefits to patients. Several analyses have found a significantly decreased risk of coronary artery disease (CAD) in individuals with GS. Specifically, people with mildly elevated levels of bilirubin (1.1 mg/dl to 2.7 mg/dl) were at lower risk for CAD and at lower risk for future heart disease. These researchers went on to perform
2755-526: Is considered harmless, it is clinically important because it may give rise to a concern about a blood or liver condition, which could be more dangerous. However, these conditions have additional indicators: Typically no treatment is needed. If jaundice is significant phenobarbital may be used. Studies conducted so far suggest that subjects with GS may have lower levels of vitamin D and folic acid than control subjects, having these levels inversely correlated with bilirubin levels. It may be that GS may impair
2850-465: Is due to a genetic variant in the UGT1A1 gene which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme. It is typically inherited in an autosomal recessive pattern and occasionally in an autosomal dominant pattern depending on the type of variant. Episodes of jaundice may be triggered by stress such as exercise, menstruation , or not eating. Diagnosis
2945-486: Is high (30%) interindividual variability in irinotecan pharmacokinetic parameters which can be altered by several factors including age, sex, dose, administration timing, hepatic function, enzyme activity or hematocrit levels. Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation. People with variants of the UGT1A1 called TA 7 , also known as
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3040-421: Is more often a consequence of heterozygote missense mutations (such as Gly71Arg also known as UGT1A1*6 , Tyr486Asp also known as UGT1A1*7 , Pro364Leu also known as UGT1A1*73 ) in the actual gene coding region, which may be associated with significantly higher bilirubin levels. Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as
3135-531: Is obtained from the Chinese ornamental tree Camptotheca acuminata . Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death ( apoptosis ). These agents include etoposide , doxorubicin , mitoxantrone and teniposide . The second group, catalytic inhibitors, are drugs that block
3230-425: Is often further increased if the blood sample is taken after fasting for two days, and a fast can, therefore, be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose of phenobarbital : the bilirubin will decrease substantially. Tests can also detect DNA variants of UGT1A1 by polymerase chain reaction or DNA fragment sequencing. While Gilbert syndrome
3325-615: Is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype. In February 2024, the FDA approved irinotecan liposome, in combination with oxaliplatin , fluorouracil, and leucovorin, for the first-line treatment of metastatic pancreatic adenocarcinoma. Efficacy was evaluated in NAPOLI 3 (NCT04083235), a randomized, multicenter, open-label, active-controlled trial in 770 participants with metastatic pancreatic adenocarcinoma who had not previously received chemotherapy in
3420-901: Is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer , which is called medical oncology . The term chemotherapy now means the non-specific use of intracellular poisons to inhibit mitosis (cell division) or to induce DNA damage (so that DNA repair can augment chemotherapy). This meaning excludes the more-selective agents that block extracellular signals ( signal transduction ). Therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones (primarily estrogens for breast cancer and androgens for prostate cancer), are now called hormonal therapies . Other inhibitions of growth-signals, such as those associated with receptor tyrosine kinases , are targeted therapy . The use of drugs (whether chemotherapy, hormonal therapy, or targeted therapy)
3515-668: Is required. Because only a fraction of the cells in a tumor die with each treatment ( fractional kill ), repeated doses must be administered to continue to reduce the size of the tumor. Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity. The effectiveness of chemotherapy depends on the type of cancer and the stage. The overall effectiveness ranges from being curative for some cancers, such as some leukemias , to being ineffective, such as in some brain tumors , to being needless in others, like most non-melanoma skin cancers . Dosage of chemotherapy can be difficult: If
3610-596: Is seen less often, around 3% of alleles, in Southeast and East Asian people and Pacific Islanders. In most populations, Gilbert syndrome is most commonly associated with homozygous A(TA) 7 TAA alleles. In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected. However, Gilbert syndrome can arise without TATA box promoter polymorphic variants; in some populations, particularly healthy Southeast and East Asians, Gilbert's syndrome
3705-444: Is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action: etoposide and teniposide . Topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase I and topoisomerase II . When the DNA double-strand helix is unwound, during DNA replication or transcription , for example,
3800-426: Is that they interrupt cell division . The most important subgroup is the anthracyclines and the bleomycins ; other prominent examples include mitomycin C and actinomycin . Among the anthracyclines, doxorubicin and daunorubicin were the first, and were obtained from the bacterium Streptomyces peucetius . Derivatives of these compounds include epirubicin and idarubicin . Other clinically used drugs in
3895-455: Is the primary cause for their anti-cancer effects. DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during cell division , or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis . Alkylating agents will work at any point in
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3990-828: The PICC line . These have a lower infection risk, are much less prone to phlebitis or extravasation , and eliminate the need for repeated insertion of peripheral cannulae. Isolated limb perfusion (often used in melanoma ), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases . Topical chemotherapies, such as 5-fluorouracil , are used to treat some cases of non-melanoma skin cancer . If
4085-427: The UGT1A1 gene lead to Gilbert Syndrome. The gene provides instructions for making the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme, which can be found in the liver cells and is responsible for preparing bilirubin for removal from the body. The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation . Glucuronic acid is transferred to unconjugated bilirubin, which
4180-623: The UGT1A1*28 gene variant are at higher risk for side effects. Use during pregnancy can result in harm to the baby. Irinotecan is a topoisomerase inhibitor —it blocks the topoisomerase I enzyme, resulting in DNA damage and cell death . Irinotecan was approved for medical use in the United States in 1996. It is on the World Health Organization's List of Essential Medicines . It is made from
4275-399: The amino , carboxyl , sulfhydryl , and phosphate groups in biologically important molecules. Non-classical alkylating agents include procarbazine and hexamethylmelamine. Anti-metabolites are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are nucleotides ; a molecule comprising
4370-521: The immune system , often by paralysing the bone marrow and leading to a decrease of white blood cells , red blood cells , and platelets . Anemia and thrombocytopenia may require blood transfusion . Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 10 / litre ) can be improved with synthetic G-CSF ( granulocyte -colony-stimulating factor, e.g., filgrastim , lenograstim , efbemalenograstim alfa ). In very severe myelosuppression , which occurs in some regimens, almost all
4465-520: The liver 's ability to detoxify certain drugs. For example, Gilbert syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan , which is metabolized by UGT1A1. While paracetamol (acetaminophen) is not metabolized by UGT1A1, it is metabolized by one of the other enzymes also deficient in some people with GS. A subset of people with GS may have an increased risk of paracetamol toxicity. The mild increase in unconjugated bilirubin due to Gilbert syndrome
4560-407: The "*28 variant", express fewer UGT1A1 enzymes in their liver and often have Gilbert's syndrome . During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea. In 2004, a clinical study was performed that both validated prospectively
4655-468: The 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA. In the same study, investigators compared the incidence of common 5-FU-associated grade 3/4 toxicities between the dose-adjusted people and people dosed per BSA. The incidence of debilitating grades of diarrhea
4750-597: The BSA-dosed group to 70% in the dose-adjusted group. Median progression free survival (PFS) and overall survival (OS) both improved by six months in the dose adjusted group. One approach that can help clinicians individualize chemotherapy dosing is to measure the drug levels in blood plasma over time and adjust dose according to a formula or algorithm to achieve optimal exposure. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm
4845-562: The US Food and Drug Administration (FDA) approved irinotecan liposome, in combination with oxaliplatin , fluorouracil, and leucovorin, for the first-line treatment of metastatic pancreatic adenocarcinoma. The most significant adverse effects of irinotecan include diarrhea, nausea and vomiting, neutropenia and fever, infections of blood or lungs (sepsis, pneumonia), shock, dehydration, kidney failure and thrombocytopenia (low levels of blood platelets). Early diarrhea occurs during or shortly after
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#17330853752414940-487: The United States. Males are more often diagnosed than females. It is often not noticed until late childhood to early adulthood. The condition was first described in 1901 by Augustin Nicolas Gilbert . Gilbert syndrome produces an elevated level of unconjugated bilirubin in the bloodstream , but normally has no consequences. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but
5035-410: The activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin , merbarone, and aclarubicin , which also have other significant mechanisms of action. The cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. The common theme that they share in their chemotherapy indication
5130-560: The adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double-strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes. Two topoisomerase I inhibitors, irinotecan and topotecan , are semi-synthetically derived from camptothecin , which
5225-405: The anthracycline group are pirarubicin , aclarubicin , and mitoxantrone . The mechanisms of anthracyclines include DNA intercalation (molecules insert between the two strands of DNA), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition. Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis . Bleomycin,
5320-519: The antioxidant and anti-inflammatory properties of bilirubin. Hyperbilirubinaemia in GS may protect against oxidative stress and inflammation-related diseases, such as cardiovascular diseases, cancers, diabetes, and neurodegenerative disorders. However, the mechanisms and pathways of bilirubin protection are not fully elucidated, and the optimal level and range of bilirubin are unknown. The genetic and environmental factors that influence UGT1A1 expression and activity are also poorly characterized and may affect
5415-633: The assembly of tubulin into microtubules. The original vinca alkaloids are natural products that include vincristine and vinblastine . Following the success of these drugs, semi-synthetic vinca alkaloids were produced: vinorelbine (used in the treatment of non-small-cell lung cancer ), vindesine , and vinflunine . These drugs are cell cycle -specific. They bind to the tubulin molecules in S-phase and prevent proper microtubule formation required for M-phase . Taxanes are natural and semi-synthetic drugs. The first drug of their class, paclitaxel ,
5510-462: The association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration. In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses. Irinotecan
5605-400: The body, causing mild hyperbilirubinemia. Gilbert syndrome is a phenotypic effect, mostly associated with increased blood bilirubin levels, but also sometimes characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form. Gilbert's syndrome
5700-645: The bone marrow stem cells (cells that produce white and red blood cells ) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the person before the treatment, multiplied and then re-injected afterward; in allogenic BMTs, the source is a donor.) However, some people still develop diseases because of this interference with bone marrow. Although people receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in
5795-469: The cancer cells. Following this, cell cycle arrest occurs, which induces programmed cell death ( apoptosis ). These drugs can also affect blood vessel growth , an essential process that tumours utilise in order to grow and metastasise. Vinca alkaloids are derived from the Madagascar periwinkle , Catharanthus roseus , formerly known as Vinca rosea . They bind to specific sites on tubulin, inhibiting
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#17330853752415890-602: The cancer has central nervous system involvement, or with meningeal disease, intrathecal chemotherapy may be administered. Chemotherapeutic techniques have a range of side effects that depend on the type of medications used. The most common medications affect mainly the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Chemotherapy-related iatrogenic toxicities can occur acutely after administration, within hours or days, or chronically, from weeks to years. Virtually all chemotherapeutic regimens can cause depression of
5985-933: The cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug. The subtypes of alkylating agents are the nitrogen mustards , nitrosoureas , tetrazines , aziridines , cisplatins and derivatives, and non-classical alkylating agents. Nitrogen mustards include mechlorethamine , cyclophosphamide , melphalan , chlorambucil , ifosfamide and busulfan . Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin . Tetrazines include dacarbazine , mitozolomide and temozolomide . Aziridines include thiotepa , mytomycin and diaziquone (AZQ). Cisplatin and derivatives include cisplatin , carboplatin and oxaliplatin . They impair cell function by forming covalent bonds with
6080-436: The condition is otherwise usually asymptomatic. Severe cases are seen by yellowing of the skin tone and yellowing of the conjunctiva in the eye. Gilbert syndrome has been reported to contribute to an accelerated onset of neonatal jaundice . The syndrome cannot cause severe indirect hyperbilirubinemia in neonates by itself, but it may have a summative effect on rising bilirubin when combined with other factors, for example in
6175-452: The dose is too low, it will be ineffective against the tumor, whereas, at excessive doses, the toxicity ( side-effects ) will be intolerable to the person receiving it. The standard method of determining chemotherapy dosage is based on calculated body surface area (BSA). The BSA is usually calculated with a mathematical formula or a nomogram , using the recipient's weight and height, rather than by direct measurement of body area. This formula
6270-402: The elevated levels of unconjugated bilirubin in adults. However, other substances glucuronidized by the affected enzymes in those with Gilbert's syndrome could theoretically, at their toxic levels, cause these symptoms. Consequently, debate exists about whether GS should be classified as a disease. However, Gilbert syndrome has been linked to an increased risk of gallstones . Mutations in
6365-622: The enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for thymidylate and purine production, which are both essential for DNA synthesis and cell division. Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme thymidylate synthase , but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase . The fluoropyrimidines include fluorouracil and capecitabine . Fluorouracil
6460-443: The enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, DNA damage can occur and programmed cell death ( apoptosis ) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case S-phase (the DNA synthesis phase). For this reason, at
6555-582: The formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, sex, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which have major impacts on the actual concentration of the drug in the person's bloodstream. As a result, there is high variability in the systemic chemotherapy drug concentration in people dosed by BSA, and this variability has been demonstrated to be more than ten-fold for many drugs. In other words, if two people receive
6650-461: The genetic sequence A(TA) 6 TAA; this variant accounts for about 50% of alleles in many populations. However, several allelic polymorphic variants of this region occur, the most common of which results from adding another dinucleotide repeat TA to the promoter region, resulting in A(TA) 7 TAA, which is called UGT1A1*28 ; this common variant accounts for about 40% of alleles in some populations, but
6745-536: The immune system is suppressed to a critically low level. In Japan , the government has approved the use of some medicinal mushrooms like Trametes versicolor , to counteract depression of the immune system in people undergoing chemotherapy. Trilaciclib is an inhibitor of cyclin-dependent kinase 4/6 approved for the prevention of myelosuppression caused by chemotherapy. The drug is given before chemotherapy to protect bone marrow function. Due to immune system suppression, neutropenic enterocolitis (typhlitis)
6840-443: The infusion of Irinotecan, and is usually transient and infrequently severe. Late diarrhea occurs more than 24 hours after administration of Irinotecan and can be life threatening, 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. The immune system
6935-417: The lining of the digestive tract), and alopecia (hair loss). Because of the effect on immune cells (especially lymphocytes), chemotherapy drugs often find use in a host of diseases that result from harmful overactivity of the immune system against self (so-called autoimmunity ). These include rheumatoid arthritis , systemic lupus erythematosus , multiple sclerosis , vasculitis and many others. There are
7030-609: The liver to SN-38. Induction or inhibition of CYP3A enzymes by smoking, some herbs and medications may result in interactions with irinotecan. Irinotecan is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2. Irinotecan clearance is mainly biliary (66%) and estimated 12–21 L/h/m. All metabolites, except SN-38G, are mainly excreted in feces. Irinotecan elimination half-lives were reported between 5 and 18 h. SN-38 half-lives were reported between 6 and 32 h. There
7125-564: The metabolism or absorption of these vitamins, or that these vitamins may affect the expression or activity of the UGT1A1 enzyme that is responsible for bilirubin conjugation. However, these studies had limitations, such as the small sample size, the lack of a standardized definition of GS, the possible confounding factors of diet, lifestyle, and medication use, and the cross-sectional and observational design that does not allow for causal inference. Ongoing studies suggest that mild hyperbilirubinaemia in GS may have beneficial effects, probably due to
7220-698: The metastatic setting. Randomization was stratified by region, liver metastases, and ECOG performance status. Participants were randomized (1:1) to receive one of the following treatments: NALIRIFOX: irinotecan liposome 50 mg/m2 as an intravenous infusion over 90 minutes, followed by oxaliplatin 60 mg/m2 as an intravenous infusion over 120 minutes, followed by leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400 mg/m2 intravenously over 46 hours, every 2 weeks; Gem+NabP: Nab-paclitaxel 125 mg/m2 as an intravenous infusion over 35 minutes, followed by gemcitabine 1000 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 of each 28-day cycle. The application
7315-533: The natural compound camptothecin which is found in the Chinese ornamental tree Camptotheca acuminata . Its main use is in colon cancer , in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI , which consists of infusional 5-fluorouracil , leucovorin , and irinotecan. The regimen XELIRI consists of capecitabine and irinotecan. It may also be used together with fluorouracil and folinic acid for pancreatic cancer following failure of initial treatment. In February 2024,
7410-514: The organic anion transporting polypeptide (OATP) 1B1 transporter. SN-38 is inactivated by glucuronidation to SN-38G (β-glucuronide conjugate) by several uridine diphosphate glucuronosyltransferase enzymes (UGTs) in the liver (UGT1A1, UGT1A9) and extra-hepatic (UGT1A1, UGT1A7, UGT1A10) and excreted into the bile. Several UGT polymorphisms affects irinotecan pharmacokinetics, for example, the decreased UGT1 activity, may lead to severe toxicity. Also, UGT1A1 conjugates bilirubin and bilirubin glucuronidation
7505-412: The person vomits frequently, because of gastrointestinal damage. This can result in rapid weight loss, or occasionally in weight gain, if the person eats too much in an effort to allay nausea or heartburn. Weight gain can also be caused by some steroid medications. These side-effects can frequently be reduced or eliminated with antiemetic drugs. Low-certainty evidence also suggests that probiotics may have
7600-818: The person's own gastrointestinal tract (including oral cavity ) and skin. This may manifest as systemic infections, such as sepsis , or as localized outbreaks, such as Herpes simplex , shingles , or other members of the Herpesviridea . The risk of illness and death can be reduced by taking common antibiotics such as quinolones or trimethoprim/sulfamethoxazole before any fever or sign of infection appears. Quinolones show effective prophylaxis mainly with hematological cancer. However, in general, for every five people who are immunosuppressed following chemotherapy who take an antibiotic, one fever can be prevented; for every 34 who take an antibiotic, one death can be prevented. Sometimes, chemotherapy treatments are postponed because
7695-511: The person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the Hickman line , the Port-a-Cath , and
7790-416: The presence of increased red blood cell destruction due to diseases such as G6PD deficiency . This situation can be especially dangerous if not quickly treated, as the high serum bilirubin can cause irreversible neurological disability in the form of kernicterus . The enzymes that are defective in GS – UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) – are also responsible for some of
7885-400: The pro-drug irinotecan is hydrolyzed into its active metabolite SN-38 in the liver by two carboxylesterase converting enzymes (CES1 and CES2) and in plasma by butyrylcholinesterase (hBChE). CES2 has a 12.5-fold higher affinity for irinotecan than CES1. While, butyrylcholinesterase has a 6-fold higher activity for irinotecan than CES. After conversion, SN-38 is actively transported to the liver by
7980-500: The right dose to achieve optimal treatment effectiveness with minimized toxic side effects. Some people are overdosed while others are underdosed. For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard—68% were underdosed and 17% were overdosed. There has been controversy over
8075-429: The same dose of a given drug based on BSA, the concentration of that drug in the bloodstream of one person may be 10 times higher or lower compared to that of the other person. This variability is typical with many chemotherapy drugs dosed by BSA, and, as shown below, was demonstrated in a study of 14 common chemotherapy drugs. The result of this pharmacokinetic variability among people is that many people do not receive
8170-468: The slowing down of the atherosclerotic process. Symptoms, whether connected or not to GS, have been reported in a subset of those affected: fatigue (feeling tired all the time), difficulty maintaining concentration, unusual patterns of anxiety , loss of appetite , nausea , abdominal pain, loss of weight, itching (with no rash), and others, such as humor change or depression . But scientific studies found no clear pattern of adverse symptoms related to
8265-473: The use of BSA to calculate chemotherapy doses for people who are obese . Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of overdosing . In many cases, this can result in sub-optimal treatment. Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced. In
8360-492: The variability and penetrance of GS. Despite the fact that hyperbilirubinemia in GS is associated with reduced incidence of cardiovascular diseases, diabetes, and metabolic syndrome, the clinical significance and implications of these GS research findings are unclear, and can not yet be translated into preventive or therapeutic strategies. Gilbert syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901. In German literature, it
8455-704: Was also seen in long-term data from the Framingham Heart Study . Moderately elevated levels of bilirubin in people with GS and the (TA) 7 /(TA) 7 genotype were associated with one-third the risk for both coronary heart disease and cardiovascular disease as compared to those with the (TA) 6 /(TA) 6 genotype (i.e. a normal, nonmutated gene locus). Platelet counts and MPV (mean platelet volume) are decreased in patients with Gilbert's syndrome. The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on
8550-534: Was granted orphan drug designation. Irinotecan received accelerated approval from the US Food and Drug Administration (FDA) in 1996, and full approval in 1998. A liposome encapsulated version of irinotecan sold under the brand name Onivyde, was approved by the FDA in October 2015, to treat metastatic pancreatic cancer . It was approved for medical use in the European Union in October 2016. During development, it
8645-481: Was known as CPT-11. Anti-cancer medication Chemotherapy (often abbreviated chemo , sometimes CTX and CTx ) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents ) in a standard regimen . Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim only to prolong life or to reduce symptoms ( palliative chemotherapy). Chemotherapy
8740-438: Was originally derived in a 1916 study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans. The study only included nine human subjects. When chemotherapy was introduced in the 1950s, the BSA formula was adopted as the official standard for chemotherapy dosing for lack of a better option. The validity of this method in calculating uniform doses has been questioned because
8835-560: Was originally extracted from Taxus brevifolia , the Pacific yew. Now this drug and another in this class, docetaxel , are produced semi-synthetically from a chemical found in the bark of another yew tree, Taxus baccata . Podophyllotoxin is an antineoplastic lignan obtained primarily from the American mayapple ( Podophyllum peltatum ) and Himalayan mayapple ( Sinopodophyllum hexandrum ). It has anti-microtubule activity, and its mechanism
8930-412: Was reduced from 18% in the BSA-dosed group to 4% in the dose-adjusted group and serious hematologic side effects were eliminated. Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time. BSA-dosed people were treated for a total of 680 months while people in the dose-adjusted group were treated for a total of 791 months. Completing the course of treatment
9025-508: Was used in the clinical trials cited above and resulted in significantly improved treatment outcomes. Oncologists are already individualizing dosing of some cancer drugs based on exposure. Carboplatin and busulfan dosing rely upon results from blood tests to calculate the optimal dose for each person. Simple blood tests are also available for dose optimization of methotrexate , 5-FU, paclitaxel , and docetaxel . The serum albumin level immediately prior to chemotherapy administration
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