This is the second blog post in a series of posts focused on DPYD and DPYD gene deficiency. This blog post provides an overview of the pharmacogenomics of DPYD gene related drugs. For the first blog post related to the DPYD gene, please check the link below:
What Is DPD in Cancer? What Is DPD in Oncology?
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the pathway of uracil and thymine catabolism. DPD is also the principal enzyme involved in the degradation of 5-fluorouracil (5-FU), which is one of the anticancer chemotherapeutic agents currently used to treat bladder cancer [citation].
European Medicines Agency (EMA) has recommended that patients should be tested for the lack of the DPD enzyme before starting cancer treatment with fluorouracil given by injection or infusion (drip) or with the related medicines, capecitabine and tegafur [citation].
Having a deficiency in the DPD enzyme could make the side effects of certain chemotherapy drugs worse. For some people, these side effects can be life-threatening. This group of drugs is called fluoropyrimidines. Examples include 5-fluorouracil (5FU), capecitabine, and tegafur [citation].
The DPD enzyme helps our body to break down 5FU, capecitabine (also known as Xeloda), and tegafur (also known as tegafur-uracil and UFT) [citation]. 5-FU and capecitabine are two common chemotherapy drugs. Without enough DPD enzyme, these chemotherapy drugs build up in patients’ bodies and cause more severe side effects than usual. In some situations, these side effects can be life-threatening [citation].
What Is Fluoropyrimidine-Based Chemotherapy?
Fluoropyrimidines (FP) 5-fluorouracil (5-FU) and its prodrug capecitabine are the backbone chemotherapy widely used to treat several solid tumors, including head, neck, breast, gastrointestinal, liver [citation], and colorectal cancer (CRC) [citation]. Although often well tolerated, severe toxicity is encountered in ~ 20–30% of the patients. Individualized dosing for these patients can reduce the incidence of severe fluoropyrimidine-related toxicity [citation].
What Is Capecitabine? What Cancer Is Capecitabine Used For?
Capecitabine and 5-fluorouracil (5-FU) are fluoropyrimidines, antimetabolite drugs, and chemotherapy used for cancer treatment, i.e., breast, head, colorectal, and neck cancers [citation]. It works by slowing or stopping the growth of cancer cells [citation].
How Does Capecitabine Work?
Capecitabine is an oral prodrug of 5-FU. Capecitabine converts into 5-FU in tumor cells; three metabolic steps cover this process.
Step 1: Capecitabine passes through the intestinal tract intact, unmetabolized, and it is then transformed into 5′-deoxy-5-fluorocytidine (5′-DFCR) in the hepatic tissue.
Step 2: After that, 5′-DFCR is converted to 5′-deoxyfluorouridine (5′-DFUR) by the action of the enzyme Cytidine deaminase.
Step 3: Afterward, it was converted into 5-FU in the tumor cells [citation].
Capecitabine is widely used in the treatment of several malignancies including colon cancer, metastatic colorectal cancer, and metastatic breast cancer [citation]. The action of Capecitabine weakens the proliferative ability of abnormal cells. In addition, this drug disables the expression of certain genes, so it is used to treat cancer. Capecitabine is usually prescribed with surgery or as monotherapy for colorectal cancer [citation].
How DPYD Gene and Capecitabine Are Related?
The DPYD gene encodes DPD, an enzyme that catalyzes the rate-limiting step in 5-fluorouracil metabolism. DPD inactivates 80–90% of 5-FU into 5,6-dihydro-fluorouracil. Genetic variants in the DPYD gene can lead to different versions of the DPD enzyme where some have reduced or no activity. Individuals who have at least one copy of a nonfunctional DPYD variant will not be able to metabolize fluorouracil at normal rates. Consequently, these individuals are at risk of potentially life-threatening fluorouracil toxicity, such as bone marrow suppression, gastrointestinal toxicity, and, rarely, neurotoxicity [citation].
Capecitabine is a prodrug that is enzymatically converted to its active form, fluorouracil (also called 5-fluorouracil; 5-FU), which acts as an anti-metabolite to slow tumor growth [citation].
How Do DPYD Mutations/ DPD Deficiency Affect the Capecitabine Drug?
As we already partially mentioned in the previous paragraphs, mutations that cause DPD deficiency lead to the cytotoxicity of this drug, which requires additional pharmacological and medical intervention. Usually, such cases are reported after administration and the first cycle of taking the drug. Stomatitis, nausea, mucositis, diarrhea, and vomiting are some symptoms of increased cytotoxicity [citation].
To reduce the chance of these side effects, the dose of the drugs will be adjusted to a level that the body should be able to process. This should not reduce the cancer treatment effect but aims to reduce the drug building up in the system and should reduce unwanted side effects. Even though the treatment will be adjusted, side effects may be developed because not all side effects are caused by DPD deficiency [citation].
Can Capecitabine Affect Your Eyes?
It may contribute to the development of watery eyes [citation].
Can I Drink Alcohol While Taking Capecitabine?
The drinking of alcohol (in small amounts) does not appear to affect the safety or usefulness of capecitabine [citation].
Can You Drive While Taking Capecitabine?
Capecitabine may make one feel dizzy, sick, or tired. This could affect the ability to drive or operate machinery safely, so it is better to avoid driving or using machinery if one has any symptoms that may affect their ability [citation].
Does Capecitabine Affect the Immune System?
Yes, it does in a variety of ways. Capecitabine is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that Capecitabine may have immunosuppressive effects, but a lack of clear experimental verification exists. Capecitabine was found not to cause myelosuppression in bone marrow tissue; Capecitabine selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of Capecitabine in vivo, and the study confirmed that T-cells express TP. Still, the bone marrow tissue lacks TP expression, which explains the selectivity in the pharmacodynamic effects of Capecitabine. In addition, it was confirmed that Capecitabine can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that Capecitabine-induced T-cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Differential expression of TP in cells and tissues explains why Capecitabineavoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, Capecitabine may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies [citation].
What Are the Side Effects of Capecitabine?
Capecitabine and 5-FU cause cardiac toxicity associated with myocardial ischemia, ventricular arrhythmias, left ventricular dysfunction, and sudden death. Such conditions can go unnoticed, that is, asymptomatic, therefore, special attention and monitoring are required, primarily with the use of the ECG method [citation].
Nausea, vomiting, loss of appetite, constipation, tiredness, weakness, headache, diarrhea, dizziness, trouble sleeping or changes in taste may occur [citation].
Does Capecitabine Cause Neuropathy?
5-Fluorouracil (5-FU)-associated peripheral neuropathy is an uncommon event. Capecitabine is a pro-drug of 5-FU, and peripheral neuropathy associated with Capecitabine has not been reported. As Capecitabine is rapidly metabolized to 5-FU in patients with normal liver function, 5-FU or its active metabolites (fluoro-β-alanine) are likely contributing factors to neurotoxicity. Knowledge regarding the potential adverse effects of Capecitabine is paramount, and dose modification is indicated with the development of neurotoxicity. [citation].
Does Capecitabine Cause Weight Gain?
No, one of its side effects includes the loss of appetite [citation].
Does Capecitabine Make You Tired?
Yes, it is also one of the side effects [citation].
Does Capecitabine Cross the Blood-Brain Barrier?
Capecitabine may cross the blood-brain barrier (BBB) and has demonstrated activity in breast cancer brain metastasis (BCBM) [citation].
How Can I Reduce the Side Effects of Capecitabine?
Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects [citation].
How Do You Take Oral Capecitabine?
It is a tablet taken twice daily, morning and evening [citation]. XELODA (capecitabine) is supplied as biconvex, oblong film-coated tablets for oral administration. Each tablet contains 150mg or 500mg of Capecitabine [citation].
Is Xeloda a Fluoropyrimidine?
Capecitabine (brand name Xeloda) is a chemotherapy agent that belongs to the drug class of fluoropyrimidines [citation].
How Effective Is Capecitabine?
Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumor site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials [citation].
How Long Does Capecitabine Stay in Your System? What Is the Half-Life of Capecitabine?
It generally takes about 48 to 72 hours for your body to break down and/or get rid of most chemo drugs [citation]. Enhanced cell killing was maximized if cells were continuously exposed to 5-FU for 48 hours following radiation [citation].
The pharmacokinetics of Capecitabine varies among patients due to differences in metabolism and other factors. The time for Capecitabine plasma concentration to peak is approximately 1-2 hours [citation].
It has a relatively short elimination half-life (t(1/2)) [0.55 to 0.89 h; citation].
How Many Cycles of Capecitabine Can You Take?
One might have capecitabine as a course of several cycles of treatment. Each cycle is often over 3 weeks, but this depends on the type of cancer you have. It is arranged in accordance with a doctor [citation].
For clinical practice, FDA recommended a dose of 2,500 mg/m2 given in two divided daily doses for 14 days followed by 7 days of rest [citation].
Is There an Alternative to Capecitabine?
Most chemotherapy regimens in colorectal cancer treatment are 5-fluorouracil (5-FU)/leucovorin or capecitabine-based. Cardiotoxicity is a less common but potentially lethal complication of 5-FU or capecitabine treatment, and some physicians might be unfamiliar with treatment alternatives. Rechallenging should be avoided because it carries a high risk of recurrence of cardiac symptoms, and prophylactic treatment is not always protective. Possible alternative treatment options to be considered are to replace the oral capecitabine or intravenous 5-FU with a 5-FU bolus regimen, by uracil-tegafur or tegafur/gimeracil/oteracil, both oral fluoropyrimidines combining a 5-FU prodrug with a dihydropyrimidine dehydrogenase (DPD) inhibitor, or by raltitrexed, a thymidilate synthase inhibitor whose metabolism is independent of DPD. Patients with advanced colorectal cancer and fluoropyrimidine-induced cardiotoxicity can be treated with other non-fluoropyrimidine related chemotherapy, either as a single agent, combined, or in combination with biological agents [citation].
What Is Fluorouracil Chemotherapy?
Fluorouracil has been proven to increase the success of cancer therapy and treatment, and many cases of patient survival have been documented thanks to this drug [citation].
Fluorouracil is part of a group of chemotherapy drugs known as anti-metabolites. Anti-metabolites are similar to normal body molecules but have slightly different structures. These differences mean anti-metabolites stop cancer cells from proliferating and their regular function and DNA repair [citation].
Does Fluorouracil Affect the Immune System?
The anticancer activity of 5-fluorouracil (5FU) relies on the restoration of T-cell immunity following the elimination of myeloid-derived suppressor cells (MDSCs). [citation].
5FU-mediated depletion of MDSCs increased interferon γ (IFNγ) production by tumor-specific CD8+ T cells [citation].
5FU, while eliminating immunosuppressive MDSCs, also induces the activation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome in dying MDSCs, leading to the secretion of interleukin (IL)-1β, elicitation of TH17 cells, IL-17 production and tumor growth following increased angiogenesis [citation].
Does Fluorouracil Make Your Hair Fall Out?
Yes, side effects include temporary hair loss [citation].
Is 5-Fluorouracil an Antineoplastic Drug?
Yes, it has antineoplastic activity [citation].
Is 5-FU Toxic?
The clinical presentation of 5-fluorouracil toxicity may include fever, mucositis, stomatitis, nausea, vomiting, and diarrhea. Neurologic abnormalities such as cerebellar ataxia and changes in cognitive function can also be seen but only less than one percent of the population [citation].
Why Is 5-FU Given Over 46 Hours?
5-FU dosing has been typically determined using body surface area (BSA). However, it is now well-established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variations of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goal of increasing antitumor efficacy while reducing drug-associated toxicity. Dose adjustment of 5-FU is feasible, and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy [citation].