Pathways

Capecitabine is a nucleoside metabolic inhibitor, orally-administered chemotherapeutic agent indicated to treat colon, colorectal and breast cancer. Capecitabine is a prodrug, that is enzymatically converted to fluorouracil (antimetabolite) in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. Capecitabine is used for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. May also be used in combination with docetaxel for the treatment of metastatic breast cancer in patients who have failed to respond to, or recurred or relasped during or following anthracycline-containing chemotherapy. Capecitabine is used alone as an adjuvant therapy following the complete resection of primary tumor in patients with stage III colon cancer when monotherapy with fluroprymidine is preferred. Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase, an enzyme found in higher concentrations in many tumors compared to normal tissues or plasma. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, therefore a deficiency of this compound can inhibit cell division. Secondly, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis through the production of fraudulent RNA.

Capecitabine is a fluoropyrimidine anticancer drug. After absorption, it is metabolized in the liver to the intermediate 5’-deoxy-5-fluorouridine, which is subsequently converted into 5-fluorouracil (5-FU) by intracellular thymidine phosphorylase. 5-FU exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase. Since thymidine phosphorylase is present at 3-10 fold higher concentration in cancer cells compared normal cells, capecitabine’s cytotoxic effect is selective for cancer cells.

Cantharidin is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Cantharidin passes through the liver and is then excreted from the body mainly through the kidney.

Endogenous cannbinoids the most common being 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide, AEA), that acts upon the cannabinoid receptors (CB1), these receptors can also be activated by exogenous cannabinoids such as tetrahydrocannabinol (THC). 2-AG and AEA binds to cannabinoid receptors 1 that goes on to activate g coupled protein Gi and Go, these go on to inhibit adenylate cyclase and calcium voltage gated channels and activates MAP kinases and inward retictifying potassium channels overall eliciting diverse effects. The inhibition of adenylate cyclase leads to reduced ATP production and inhibition of calcium voltage gated channels halts vesicle fusion and release of glutamate and GABA from excitatory and inhibitory pre synaptic terminals respectively. This leads to depolarization induced supression of excitation and inhibition that can cause long term synaptic change that being long term depression (LTD). If endogenous cannabinoids are continously activated and released this leads to continous inactivation causing LTD, with the post synaptic neuron only acting to synthesize and release endogenous cannabinoids to act retrogradely onto the pre synaptic terminals and later taken up again to be degraded. AEA is taken up by the post synaptic neuron to be degraded by fatty acid amino hydrolase (FAAH) and 2-AG is broken down by hydrolytic enzymes and can be converted into prostaglandins which is an inflammatory mediator. Some exogenous cannabinoids such as tetrahydrocannabinol (THC) acts as an agonist to act on the CB1 receptors much like the endogenous cannabinoids to elicit similar effects and cannabidiol (CBD) acts as an antagonist to attenuate the effects of THC.

Hexanoate is first catalyzed to make hexanoyl-CoA with the enzyme hexanoyl CoA synthase in the cytosol and within the membrane of the cell. Hexanoyl-CoA branches paths to olivetol biosynthesis which creates the byproducts of this pathway. The other pathway is catalyzed by olivetol synthase to make 3,5-dioxodecanoyl-CoA which is catalyzed to make 3,5,7-trioxododecanoyl-CoA. This is similar to the olivetol biosynthesis pathway, however here 3,5,7-trioxododecanoyl-CoA is catalyzed by olivetolic acid cyclase to make olivetolate. This takes place in the cytoplasm. Olivetolate along with geranyl diphosphate is catalyzed by olivetolate geranyltransferase to make cannabigerolate or cannabigerolic acid. This compound branches into three separate pathways each catalyzed by a different enzymes. One pathway is catalyzed by Δ9-tetrahydrocannabinolate synthase along with oxygen to make Δ9-tetrahydrocannabinolate. This compound spontaneously reacts with hydrogen to synthesize the drug Δ9-tetrahydrocannabinol (THC). The second pathway is catalyzed by cannabidiolate synthase and oxygen to make cannabidiolate or cannabidiolic acid. Cannabidiolate spontaneously reacts with hydrogen to synthesize the drug cannabidiol (CBD). The final pathway is catalyzed by cannabichromenate synthase along with an unknown oxidized electron carrier to make cannabichromenate or cannabichromenic acid. This, like the others, spontaneously reacts with hydrogen to synthesize the drug cannabichromene (CBC).