Irinotecan is a topoisomerase inhibitor. In 1980s, people found that irinotecan can play role in of Topo I and have a very important intervention function in the DNA space configuration, replication, recombination, transcription, and mitosis process. It makes the DNA single-strand and double strand breaks and induce cancer cells wither die. Therefore, it becomes an anticancer drug widely used in clinical. In recent years, it was discovered that many anti-cancer drugs interfere DNA replication through the topo enzymes. They also though the recombination and gene expression to play the efficacy. The various inhibitors using enzyme DNATopo for target molecules design have become a new hot spot for cancer chemotherapy research. In the late 1990s, with oxaliplatin, irinotecan and other new drugs come out, the treatment of metastatic colorectal cancer has achieved important progress. The efficiency and lifetimes are significant improved.
Irinotecan is one of the new camptothecin drugs. Camptothecin department of an alkaloid extracted from Camptotheca acuminata fruit of Dravidian involucrata plant or root, the main clinical for digestive malignancies, but due to its water solubility is poor and difficult to predict severe toxicity limits its further application. Irinotecan for the semi-synthetic camptothecin derivative anti-tumor activity, in the form of hydrochloride, water-soluble and better.
Irinotecan plasma concentrations of irinotecan and sport were eliminating often index. The mean elimination half-life of 6 to 12 hours, the active metabolite SN-3 8 elimination half-life of 10 to 20 hours. Lactone and hydroxy acid is a chemical equilibrium, so the active lactone and SN-38 half-life similar to the complete half-life of irinotecan Kang and SN-38. The area under the curve of the intensity of the main side effects with the parent drug and its metabolite SN -38 of. In monotherapy, hematological toxicity or diarrhea, the degree of irinotecan and its metabolite SN-38 under the curve area was significantly related.
Pharmaceutical raw materials irinotecans effect in the field of clinical colorectal cancer are significant. But the unpredictable toxicity inconvenience to patients and clinicians. Irinotecan healthy dose limiting toxicity of diarrhea and neutrophils to reduce. Its toxic side effects of high fat rate is a thorny issue, because the toxic effects can cause patients with dehydration, infection, discomfort, add other drug treatment (such as antidiarrheal economic, parenteral rehydration and colony-stimulating factor use) as needed, hospitalization, death and so on. Early studies have shown that SN-38 conversion to reduce the serious side effects caused by irinotecan is closely related to the activity of the SN-38G.
Irinotecan is a semi-synthetic derivative of camptothecin. It can specific inhibit DNA topoisomerase I. In most organizations, it is metabolized by carboxylesterase and becomes SN-38. The activity of the latter is greater than irinotecan on topology. And cytotoxicity of several mouse and human tumor cell lines are also stronger than Irinotecan. SN-38 or irinotecan can induce single-stranded DNA damage, thereby blocking the DNA replication fork and resulting in cytotoxicity. This cytotoxicity is time dependent and has specific role in S phase. In vitro experiments, researchers did not find that irinotecan and SN-38 can be effectively identified by P-glycoprotein MDR. It shows that it still has toxic effect on the cytotoxicity of doxorubicin and vinca alkali resistant cell lines.Source:http://www.cospcn.com