Anticancer Function of Topotecan Hydrochloride



Topotecan (TPT) is a water-soluble, semi-synthetic camptothecin derivative developed by Smithkline Beecham, USA. Its chemical name is 9-dimethylamino 10-hydroxyhydrocamptothecin, which is superior to CPT and 10-hydroxy CPT. Compared with other hydroxycamptothecin compounds, it has stronger anti-tumor effect and less adverse reactions, but its structure contains a lactone ring. It is pH-dependent and readily converts into a non-physiologically active form of carboxylate, which is unstable under physiological conditions.

Pharmacologic action

Mammalian Topq is the target of TPT. Topq enzyme is widely distributed in prokaryotic cells and eukaryotic cells, mainly causing two-dimensional and three-dimensional structural changes of DNA, which are closely related to DNA replication and repair, cell proliferation and gene expression. Topq first binds to DNA to unwind the double strand and form a single-strand gap, causing the undamaged single strand to gyrate from the gap, allowing the DNA to relax, and then joining the gaps to form a negative supercoiled DNA.


TPT is mostly used for chemotherapy of neuroblastoma, breast cancer, colon cancer, small cell lung cancer and ovarian cancer, and is effective as a radiosensitizer in the treatment of head and neck cancer, ovarian cancer and the like. Zhang Xiaozhi et al demonstrated that the radiosensitization effect of TPT on esophageal cancer cell line Eca-109 was related to G2/M phase arrest by colony formation experiments. Clinical trials have shown that TPT combined with cisplatin (DDP) and carboplatin (CBP) is effective in the treatment of head and neck squamous cell carcinoma and small cell lung cancer, respectively. In the second phase of clinical application, high dose of TPT can effectively reduce the volume of pancreatic cancer and colorectal cancer, but it is necessary to use granulocyte colony-stimulating factor to reduce the toxicity of the drug.

Pharmacokinetics and metabolism

The tumor-bearing (S180) mice were used as test subjects, and the drug distribution in mouse plasma and various tissues or organs at different time points was measured by tail vein injection to evaluate the in vivo behavior of TPT liposomes. The results showed that the distribution of TPT in the body after liposome encapsulation changed, and the stability in vivo was improved. Compared to free drugs, liposome encapsulation reduces the rate of drug clearance in the blood, increases the concentration of the drug in plasma, and increases the proportion of lactone-type drugs. Liposomal membrane fluidity has a great influence on the in vivo distribution behavior of TPT liposomes. Compared with SPC liposomes, the distribution of HSPC liposomes in plasma and tissues is significantly increased, and tumor targeting is improved. The tumor relative uptake rate (compared to free drug) in the H-Lip group was 2.7 times that of the S-Lip group.

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