Camptothecin powder is a kind of plant anticancer drug with chemical formula of C20H16N2O4 and light yellow needle crystal. Insoluble in water, soluble in chloroform, methanol and ethanol. Its solution shows purple-blue fluorescence under the ultraviolet lamp. It is easy to deteriorate when exposed to light and slightly hygroscopic. It shows yellow-green fluorescence when exposed to concentrated sulfuric acid. It is diluted with distilled water to produce yellow-green fluorescence, which is alkaline. It reacts with potassium bismuth iodide to form orange-red complex salt precipitation. It is extracted from the roots of Camptotheca acuminata or fruit powder with organic solvent. Due to its high toxicity, it should be carefully extracted and has anti-tumor activity. 10-hydroxycamptothecin is less toxic in the treatment of intestinal cancer, rectal cancer, gastric cancer and leukemia.
It is extracted from camptotheca acuminata distributed in south-central and southwest China. In 1976, Chinese chemist Gao Yisheng and others successfully synthesized racemic camptothecin. Camptothecin(CPT) has a good effect on gastrointestinal and head and neck cancer, but it has side effects on a few patients. The anticancer activity of 10-hydroxycamptothecin is higher than that of camptothecin, and it also has obvious curative effect on liver cancer and head and neck cancer with less side effects.
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Chemical Formula |
C20H16N2O4 |
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Exact Mass |
348 |
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Molecular Weight |
348 |
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m/z |
348 (100.0%), 349 (21.6%), 350 (2.2%) |
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Elemental Analysis |
C, 68.96; H, 4.63; N, 8.04; O, 18.37 |
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Camptothecin powder (CPT) is a quinoline alkaloid extracted from the unique Chinese plant Camptotheca acuminata in the Gongtong family. Its molecular formula is C20H16N2O4, and it appears as light yellow needle shaped crystals. Since its first isolation and discovery in 1966, scientists have revealed its multiple biological activities such as anti-tumor, antiviral, and anti-inflammatory through in-depth research on its chemical structure and pharmacological mechanisms.
The core application of this drug is focused on the treatment of malignant tumors. It specifically inhibits DNA topoisomerase I (Topo I), blocks the key link of tumor cell proliferation, and becomes a cell cycle S-phase specific anti-cancer drug.
1. Digestive tract tumors: classic protocols for gastric cancer and colorectal cancer
It has significant therapeutic effect on gastric cancer and can quickly relieve symptoms, but the relief period is relatively short (average 2-3 months). Intravenous injection or arterial infusion are commonly used in clinical practice, for example, in gastric cancer patients, 4-6mg is injected intravenously daily, dissolved in physiological saline, and slowly pushed. For colorectal cancer, intubation through the inferior mesenteric artery and daily arterial injection of 6-8mg of hydroxycamptothecin, combined with 5-fluorouracil (5-FU), can significantly improve local control rate.
Research has shown that the combination of camptothecin, oxaliplatin, and capecitabine can prolong the median survival of patients with advanced gastric cancer to 12.3 months.
2. Head and neck tumors and liver cancer: prominent advantages of local treatment
Patients with head and neck epithelial cancer can be treated with intravenous injection of camptothecin (4-6mg per day) or local arterial infusion (10mg per day). In the treatment of liver cancer, hepatic arterial infusion of camptothecin (4mg/day) combined with high-frequency hyperthermia therapy can increase the tumor shrinkage rate to 45%. 10 hydroxycamptothecin, as a derivative of camptothecin, has an objective remission rate of 32% for liver cancer, and has milder bone marrow suppression side effects.
3. Hematological system tumors: exploration and application of leukemia and lymphoma
It has certain therapeutic effects on acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Adult patients receive intravenous infusion of 6-8mg per day based on their body surface area, with continuous administration for 30 days as one course of treatment. Preclinical studies have shown that camptothecin can induce apoptosis in leukemia cell line K562, and its mechanism is related to the activation of Caspase-3 and upregulation of Bax/Bcl-2 ratio.
4. Other solid tumors: supplementary treatment for bladder cancer and lung cancer
In the treatment of bladder cancer, camptothecin intravesical infusion (30-40mg dissolved in 50ml normal saline) combined with high-frequency diathermy can increase the complete remission rate to 60%. Non small cell lung cancer patients receiving a combination therapy of camptothecin and cisplatin achieved an objective response rate of 41% and a median progression free survival of 5.2 months.
Mechanism of action: Multi target intervention for tumor cell survival
The anti-tumor activity of camptothecin originates from its specific inhibition of DNA topoisomerase I, and its mechanism of action presents a multi-level and multi link characteristic:
1. DNA fragmentation and replication blockade
Camptothecin powder binds to Topo I-DNA cleavable complex, stabilizing the structure of the complex and preventing reconnection after DNA single strand breaks. The continuous accumulation of DNA damage triggers the activation of cell cycle checkpoints, causing S phase cells to be arrested at the G2/M phase junction, ultimately leading to apoptosis.
2. Anti angiogenic effect
It can downregulate the expression of vascular endothelial growth factor (VEGF) and inhibit the luminal formation of human umbilical vein endothelial cells (HUVEC). Animal experiments have shown that camptothecin treatment can reduce tumor tissue microvascular density by 55% and decrease tumor nutrient supply.
3. Immune regulatory effect
By upregulating the expression of co stimulatory molecules (CD80/CD86) on the surface of dendritic cells, their antigen presentation ability is enhanced. Preclinical studies have confirmed that the combination of camptothecin and PD-1 inhibitors can significantly increase the proportion of tumor infiltrating lymphocytes (TIL) in mouse models.
Clinical application: innovative dosage forms and breakthroughs in combination therapy
In response to the problem of poor water solubility and strong toxicity of camptothecin, scientists have developed a series of derivatives through structural modification and explored various administration methods:
1. Clinical translation of water-soluble derivatives
Irinotecan: By introducing cyclohexylpiperidine groups, its active metabolite SN-38 has anti-cancer activity 1000 times higher than camptothecin. The FDA has approved it as a first-line treatment for metastatic colorectal cancer, and the combination of 5-FU/calcium folinate can prolong the median survival of patients to 20.5 months.
Topotecan: Introducing hydroxyl groups into the E ring of camptothecin increases its water solubility by 100 times. Approved for second-line treatment of ovarian cancer and small cell lung cancer, with objective response rates of 17% and 22%, respectively.
2. Precise treatment with local administration
Bladder perfusion: Camptothecin intravesical perfusion combined with electrochemical therapy can improve the 2-year recurrence free survival rate of superficial bladder cancer to 78%.
Ointment preparation: 0.05% camptothecin ointment is used for the treatment of psoriasis vulgaris. After 8 weeks of treatment, the Skin Surface Area Index (PASI) decreases by 65%, and its mechanism is related to the inhibition of keratinocyte proliferation and induction of differentiation.
3. Synergistic effect of combination therapy
Combined use with anti angiogenic drugs: Camptothecin combined with bevacizumab in the treatment of metastatic colorectal cancer can extend progression free survival from 5.8 months to 9.2 months.
Combined use with immune checkpoint inhibitors: Irinotecan combined with nivolumab for the treatment of microsatellite stable (MSS) colorectal cancer achieved an objective response rate of 34%, significantly higher than the monotherapy group.
Potential Expansion: From Antitumor to Multi Field Application Exploration
In addition to the anti-tumor field, the biological activity of camptothecin has shown potential applications in antiviral, anti-inflammatory, neuroprotective and other aspects:
1. Antiviral therapy: inhibits HIV and HPV replication
By interfering with the activity of HIV integrase, it blocks the integration of viral DNA into the host genome. Preclinical studies have shown that it can inhibit HIV-1 replication, with a half maximal inhibitory concentration (IC ₅₀) of 0.1 μ M. For HPV infection, camptothecin can downregulate E6/E7 oncogene expression and induce senescence in cervical cancer cell line SiHa.
2. Anti inflammatory and immune regulation: psoriasis and rheumatoid arthritis
Camptothecin inhibits the activation of the NF - κ B pathway and reduces the release of pro-inflammatory factors such as TNF - α and IL-6. In psoriasis models, local application of camptothecin can reduce IL-17A expression in skin lesions by 70%. Rheumatoid arthritis patients receiving treatment with camptothecin derivatives showed a 45% decrease in joint swelling index.
3. Neuroprotection: Alzheimer's disease and Parkinson's disease
It can penetrate the blood-brain barrier, activate the Nrf2/ARE pathway, upregulate glutathione (GSH) levels, and reduce A β - ₁₋₄₂ - induced neuronal apoptosis. In Parkinson's disease models, pre-treatment with camptothecin can increase the survival rate of dopaminergic neurons in the substantia nigra by 40%.
Camptothecin powder, a cytotoxic quinoline alkaloid, can inhibit DNA topoisomerase (TOPO I). Anti-cancer drugs discovered by M.E. Wall and M.C. Wani in 1966 through systematic screening of natural substances.
Camptothecin was isolated from the bark and branches of camptotheca acuminata (Camptotheca acuminata, happiness tree) produced in China, and was used as a traditional Chinese medicine treatment for cancer in the early stage. Camptothecin has significant anticancer properties, low solubility and high adverse drug reaction characteristics in preliminary clinical trials. Pharmaceutical chemists then developed a variety of synthetic camptothecin and various derivatives based on these characteristics to increase good effects. Currently, two analogues of camptothecin have been approved and chemotherapy for cancer, such as topotecan and irinotecan.
Camptothecin synthesis: It is an alkaloid extracted from the root, skin and fruit of Camptotheca acuminata, a plant of the genus Eclipta in the Davidia family. It can also be synthesized. The crude powder of Camptotheca acuminata was soaked in 10 times of 80% ethanol for 24 hours, the percolate was collected, and the ethanol was concentrated under reduced pressure. The concentrated solution is still to take the clear solution, which is extracted with chloroform. The extracted solution is distilled to recover chloroform to dry, and then methanol solution is added. After cooling and filtering, the filter cake is crude camptothecin. The crude product is recrystallized with methanol-chloroform mixed solvent to obtain camptothecin. For the crude drug Camptotheca acuminata juice, the total yield is 0.03-0.04%.
Camptothecin is an alkaloid extracted from the seeds or root bark of Camptotheca acuminata, a deciduous plant of Davidia involucrata family. It can directly destroy the DNA structure and DNA binding, and make DNA vulnerable to the attack of endonuclease, while inhibiting DNA polymerase and affecting DNA replication. It is mainly sensitive to proliferating cells. It is a cell cycle-specific drug, which acts on the S phase, and has a slight killing effect on G1, G2 and M phase cells. It has an inhibitory effect on a variety of animal tumors, and has no cross-resistance with common anti-tumor drugs. When combined with monoamine glycyrrhizinate, it can reduce toxicity without reducing efficacy. The mechanism of external treatment of psoriasis is to inhibit the mitosis of rapidly dividing keratinocytes, make the hyperplastic spinous cell layer thinner, the incomplete keratinization disappear, and the granular layer resume to form.
After intravenous injection, most of the drugs are combined with plasma protein, and the half-life in plasma, kidney and liver is 30 minutes. The content of gastrointestinal, bone marrow and kidney is the highest. This product is excreted slowly, mainly by urine in its original form, and can be excreted by 17% in 48 hours. It is mainly used for gastric cancer, colon cancer, rectal cancer, head and neck cancer and bladder cancer, etc.
Camptothecin (CPT) is a pyrrolic quinoline cytotoxic alkaloid and one of the most studied natural anti-tumor drugs besides paclitaxel. It mainly exists in the fruit or root bark of the unique Chinese plant Camptothecin in the family of Gongtong.
Camptotheca acuminata, also known as drought lotus, water chestnut, thousand zhang tree, etc., is a tall deciduous tree that often grows at forest or stream edges below an altitude of 1000 meters. Due to the increasing scarcity of wild resources, Camptotheca acuminata was listed as one of the first batch of nationally protected wild plants in China in 1999. According to the "Commonly Used Herbs in Zhejiang Folk Medicine", the root bark of Camptotheca acuminata has the effects of clearing heat and detoxifying, dispersing and reducing swelling, and the fruit has the effect of promoting blood circulation and removing blood stasis. It is commonly used for decoction and oral administration or grinding powder and swallowing to treat symptoms such as psoriasis and sores.
In 1966, Wall et al. from the National Cancer Institute in the United States first isolated a pentacyclic monoterpene alkaloid from the bark and trunk of introduced camptothecin in China, which was the earliest study of camptothecin. From 1967 to 1970, researchers discovered that the alkaloid exhibited strong anti-tumor activity in vitro against Hela cells (a cell line of cervical cancer cells), L1210 cells (mouse lymphocytic leukemia cells), and rodents, which sparked a research boom in the scientific community on plant camptothecin and camptothecin derivatives. Pharmacological experiments have shown that camptothecin has certain therapeutic effects on various malignant tumors such as gastric cancer, rectal cancer, and leukemia. However, due to the side effects such as nausea, vomiting, diarrhea, and hair loss caused by the alkaloid, as well as its poor water solubility and reduced anti-tumor activity when made into water-soluble sodium salts, clinical research on camptothecin almost stagnated in the mid to late 1970s.
Until 1985, when Hsiang et al. discovered that camptothecin powder and its derivatives exert anticancer effects by inhibiting DNA synthesis through topoisomerase I (Topo I) as a target, it once again attracted widespread attention, and many derivatives emerged, becoming a new hotspot in the field of anti-cancer research.
FAQ
1. Why does the powder change color and separate after being left to stand?
The psoralen powder is prone to photochemical degradation and slow oxidation under light or humid conditions, forming colored impurities such as quinone structures, which causes the color to turn yellow or even brown. The stratification may be due to local moisture absorption and agglomeration, suggesting that the active components have become unstable.
2. Why is "anti-static" emphasized during laboratory weighing?
The powder of camptothecin is extremely light and dry, and it is prone to generating static electricity, which can cause floating, adhere to weighing instruments, and lead to loss and cross-contamination. A more concealed risk is that the static electricity may trigger local high temperatures, accelerating the degradation of this thermally sensitive compound.
3. Can the stock solution be directly prepared using DMSO and stored for a long time?
It is not feasible. Although dimethyl sulfoxide (DMSO), as a strong solvent, can dissolve camptothecin, it will accelerate the conversion of its open-ring form (active form) to the ineffective closed-carboxylic acid form, especially during storage. It is recommended to use a specific buffer system (such as an alcohol solution containing a small amount of dilute base) for immediate preparation and use.
4. Is the toxicity towards aquatic organisms often overlooked?
Camptothecin is a potent topoisomerase I inhibitor. Even a very small amount may interfere with the DNA replication of aquatic organisms. If the experimental waste is directly washed, it may cause long-term and concealed genetic toxicity effects on the local aquatic ecosystem, and it needs to be treated as a high-risk medical waste.
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