Advanced Gastric Cancer
Also known as: Gastric cancer stage IV / Stage IV Gastric Cancer / Metastatic gastric cancer / Gastric cancer stage IV NOS / Malignant neoplasm of stomach stage IV NOS / Gastric malignancy stage IV NOS / Stomach cancer stage IV NOS
| Drug | Drug Name | Drug Description |
|---|---|---|
| DB09257 | Gimeracil | Gimeracil is an adjunct to antineoplastic therapy, used to increase the concentration and effect of the main active componets within chemotherapy regimens. Approved by the European Medicines Agency (EMA) in March 2011, Gimeracil is available in combination with [DB03209] and [DB09256] within the commercially available product "Teysuno". The main active ingredient in Teysuno is [DB09256], a pro-drug of [DB00544] (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called "pyrimidines" that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth. Gimeracil's main role within Teysuno is to prevent the breakdown of [DB00544] (5-FU), which helps to maintin high enough concentrations for sustained effect against cancer cells [L933]. It functions by reversibly and selectively blocking the enzyme dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU [A31408]. This allows higher concentrations of 5-FU to be achieved with a lower dose of tegafur, thereby also reducing toxic side effects. |
| DB00650 | Leucovorin | Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin) is the 5-formyl derivative of tetrahydrofolic acid, a necessary co-factor in the body. Commercially available leucovorin is composed of a 1:1 racemic mixture of the dextrorotary and levorotary isomers, while levoleucovorin contains only the pharmacologically active levo-isomer. In vitro, the levo-isomer has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form is slowly excreted by the kidneys. Despite this difference in activity, the two commercially available forms have been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, 2009). As folate analogs, leucovorin and levoleucovorin are both used to counteract the toxic effects of folic acid antagonists, such as methotrexate, which act by inhibiting the enzyme dihydrofolate reductase (DHFR). They are indicated for use as rescue therapy following use of high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Injectable forms are also indicated for use in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible and for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Folic acid is an essential B vitamin required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. However, in order to function in this role, it must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted when high-dose methotrexate is used for cancer therapy. As methotrexate functions as a DHFR inhibitor to prevent DNA synthesis in rapidly dividing cells, it also prevents the formation of DHF and THF. This results in a deficiency of coenzymes and a resultant buildup of toxic substances that are responsible for numerous adverse side effects associated with methotrexate therapy. As levoleucovorin and leucovorin are analogs of tetrahydrofolate (THF), they are able to bypass DHFR reduction and act as a cellular replacement for the co-factor THF, thereby preventing these toxic side effects. |
| DB03209 | Oteracil | Oteracil is an adjunct to antineoplastic therapy, used to reduce the toxic side effects associated with chemotherapy. Approved by the European Medicines Agency (EMA) in March 2011, Oteracil is available in combination with [DB09257] and [DB09256] within the commercially available product "Teysuno". The main active ingredient in Teysuno is [DB09256], a pro-drug of [DB00544] (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called "pyrimidines" that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth. Oteracil's main role within Teysuno is to reduce the activity of 5-FU within normal gastrointestinal mucosa, and therefore reduce's gastrointestinal toxicity [L933]. It functions by blocking the enzyme orotate phosphoribosyltransferase (OPRT), which is involved in the production of 5-FU. |
| DB05578 | Ramucirumab | Ramucirumab is a human monoclonal antibody (IgG1) against vascular endothelial growth factor receptor 2 (VEGFR2), a type II trans-membrane tyrosine kinase receptor expressed on endothelial cells. By binding to VEGFR2, ramucirumab prevents binding of its ligands (VEGF-A, VEGF-C, and VEGF-D), thereby preventing VEGF-stimulated receptor phosphorylation and downstream ligand-induced proliferation, permeability, and migration of human endothelial cells. VEGFR stimulation also mediates downstream signalling required for angiogenesis and is postulated to be heavily involved in cancer progression, making it a highly likely drug target. In contrast to other agents directed against VEGFR-2, ramucirumab binds a specific epitope on the extracellular domain of VEGFR-2, thereby blocking all VEGF ligands from binding to it. Ramucirumab is indicated for us in advanced gastric or gastro-esophageal junction adenocarcinoma as a single agent or in combination with paclitaxel after prior fluoropyrimidine- or platinum-containing chemotherapy. |
| DB09256 | Tegafur | Tegafur (INN, BAN, USAN) is a prodrug of [DB00544] (5-FU), an antineoplastic agent used as the treatment of various cancers such as advanced gastric and colorectal cancers. It is a pyrimidine analogue used in combination therapies as an active chemotherapeutic agent in conjunction with [DB09257] and [DB03209], or along with [DB00544] as [DB09327]. Tegafur is usually given in combination with other drugs that enhance the bioavailability of the 5-FU by blocking the enzyme responsible for its degradation, or serves to limit the toxicity of 5-FU by ensuring high concentrations of 5-FU at a lower dose of tegafur [L933]. When converted and bioactivated to 5-FU, the drug mediates an anticancer activity by inhibiting thymidylate synthase (TS) during the pyrimidine pathway involved in DNA synthesis. 5-FU is listed on the World Health Organization's List of Essential Medicines. |