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Camptothecin (CPT) is a drug with a five-ring skeleton, consisting of 1 (3,4-β) quinoline group (A and B rings), 1 indene (C and D rings) and 1 An α-hydroxy-δ-lactone ring (E ring), with 1 chiral carbon atom C-20. CPT is an anti-tumor drug that inhibits the maturation of DNA topoisomerase 1 (TOPO1). 20α-hydroxyl group as well as lactone ring (E) and pyridone group (D) are necessary groups to inhibit topoisomerase activity. Most of the analogues appropriately substituted at C-9 and C-10 have the effect of enhancing drug efficacy. Among all CPT analogs, 7-ethyl-10-hydroxycamptothecin (SN38, a metabolite of CPT-11 catalyzed by carboxylesterase in vivo) is the most representative active analog. A semi-synthetic analog of the natural anti-cancer alkaloid camptothecin. The hydroxyl group is at the C-10 position and the ethyl group is at the C-7 position, which is beneficial to improving the stability of SN38 in physiological environments and improving its efficacy compared with other CPT analogs.
The molar mass of SN38 is 392.4g/mol. At 25°C, the ionization constant (pKa) is 2.01 and the partition coefficient (lgP) is 2.65. It is almost insoluble in water (11~38μg/ml) and insoluble in most drugs. Therefore, it be directly prepared into liquid preparations is limited. After a series of dissolution tests, it was found that SN38 can be dissolved in 0.5% (m/m) dimethyl sulfoxide, formic acid and diethylene glycol monoethyl ether; it can also be dissolved in 0.1mol/L sodium hydroxide solution, indicating that the ring-opened form of SN38 is water-soluble. Studies on CPT revealed that the lactone ring of SN38 is reversibly hydrolyzed. The α-hydroxyl group on the C-20 chiral carbon atom promotes the hydrolysis of the lactone ring (E), and the physiological environment pH7.4 is the most favorable condition for opening the lactone; the lactone ring of SN38 is at pH ≤ 4.5 Stable, it will be completely hydrolyzed to form the carboxylate form at pH>9.0. At a pH of 6.7, the two forms are in equilibrium. Since the ring-opened SN38 carboxylate has no therapeutic effect, whether the drug is stable under physiological environment (pH 7.4) is an important factor in determining the therapeutic effect of SN38. SN38 exists in both lactone form and ring-opened carboxylate form in physiological fluid with pH 7.4 and temperature 37°C. The lactone form is mostly bound to plasma proteins (mainly albumin) and is mainly distributed in the liver, kidneys and small intestine. In the liver, SN38 is metabolized by uridine diphosphate glucuronosyltransferase 1A (UGT1A) and converted into the water-soluble inactive metabolite SN38 glucuronide (SN38G). SN38 undergoes enterohepatic circulation and has a rebound peak in the few reports of plasma concentration-time profiles. In the liver, SN38 is taken up by membrane transporters from plasma into hepatocytes. SN38 and SN38G are transported to the biliary tract via an adenosine triphosphate-binding cassette (ABC) and subsequently eliminated into the intestine. In the intestine, SN38G can be regenerated into SN38 by β-glucuronidase secreted by the flora. Excessive SN38 present in the intestine can cause late-stage debilitating diarrhea. A small amount of SN38G can also be eliminated through renal excretion. The elimination half-life of SN38 from the blood is 10 to 209 hours.
CPT has attracted much attention as an effective anti-cancer drug. It regulates the topology of DNA by loosening the double helix structure of supercoiled DNA and promoting DNA replication, thereby inhibiting the synthesis of TOP. It exerts its therapeutic effect by forming a ternary complex with DNA and ToPo1 in the presence of tyrosine, as a result, DNA replication fails, leading to cell death.
CPT-11 has a broad anti-cancer spectrum. It is not only used as a first-line drug in combination with 5-fluorouracil and leucovorin to treat patients with metastatic colon cancer, but can also be used to treat small cell lung cancer, breast cancer, gastric cancer, pancreatic cancer, acute lymphoblastic leukemia, and acute myeloid leukemia and other malignant tumors. As a new specific inhibitor of topoisomerase I, the main anti-tumor mechanism of CPT-11 is the same as that of CPT, and the high expression and activity of ToPoI in tumor tissues help CPT-11 exert anti-tumor activity. In addition, studies have shown that the activity of ToPoI in tumor cells in the S phase will be greatly increased. Therefore, CPT-11 can selectively kill the DNA replication and transcription of tumor cells in the proliferating phase.
Figure 1. Camptothecin, hydroxycamptothecin, SN38 and clinical drugs based on camptothecin. (Dai Y, et al.; 2023)
Unfortunately, CPT-11 has extremely poor anti-tumor activity in vitro, and can only exert anti-tumor effects in vivo after it is converted into its active metabolite SN38 (7-ethyl-10-hydroxycamptothecin, it is approximately hundreds to a thousand times more cytotoxic than CPT-11) through de-esterification by carboxylesterase. Human carboxylesterase (hCE) mainly exists in the liver and includes two isomers, hCE-1 and hCE-2. Among them, hCE-2 has a higher affinity for binding to CPT-11 and its catalytic activity is about 26 times that of hCE-1. However, studies have shown that there are serious species and individual differences in the activity of carboxylesterase. For example, the activity of carboxylesterase in humans is only 65% of the activity of carboxylesterase in rat liver, and genetic factors and external environment factors will also significantly affect the activity of this enzyme. There are reports in the literature that only 2-8% of the injected dose of CPT-11 in the human body can be converted into its anti-cancer active ingredient SN38. Therefore, defects such as low activity of carboxylesterase in the human body and large individual differences significantly interfere with tumor development. Patients' sensitivity to CPT-11 treatment and the predictability of efficacy have thus limited the clinical application of CPT-11.
Reference
| Target | Cat. No. | Product Name | Expression System | Tag/Conjugate | Application | |
| SN 38 | DAG-WZ1009O | SN38 [OVA] | N/A | OVA | ELISA, LF | Inquiry |
| DAG-WZ1009K | SN38 [KLH] | N/A | KLH | ELISA, LF | Inquiry | |
| DAG-WZ1009 | SN38[BSA] | BSA | ELISA, LFIA | Inquiry | ||
| TOP1 | DAGC117 | Native Bovine Scl-70 Protein | Bovien | Unconjugated | SDS-PAGE, ELISA | Inquiry |
| DAG612 | Human Topoisomerase [His] | Insect cells | His | WB, ELISA | Inquiry |
| Target | Cat. No. | Product Name | Size | Species Reactivity | Application | Detection Sample | |
| SN 38 | DEIABL316 | SN38 ADC ELISA Kit | 96T | Human | Quantitative | Serum, plasma | Inquiry |
| TOP1 | DEIA-FN1556 | Human TOP1 (DNA topoisomerase 1) ELISA Kit | 96T | Quantitative | serum, plasma, cell culture supernatants, tissue homogenate | Inquiry | |
| DEIA-FN1557 | Mouse Top1 (DNA topoisomerase 1) ELISA Kit | 96T | Quantitative | serum, plasma, cell culture supernatants, tissue homogenate | Inquiry |
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