Section 3: Biological treatment of retroperitoneal tumors Luo Chenghua, Center for Retroperitoneal Tumors, Peking University International Hospital Among the biological treatments of retroperitoneal tumors, the treatment of malignant mesenchymal tumors targeting CD117 is currently the most promising and representative biological treatment. The introduction of Gleevec has brought tumor treatment into the era of molecular targeting and established a development model for future drug therapy, which is of epoch-making significance. The application of Gleevec for the treatment of retroperitoneal malignant mesenchymal tumor has become the focus of attention and hot spot of scholars at home and abroad in the past two years. Since the application of this drug, it has produced incredible results. Gleevec is now recognized as an effective drug for the treatment of retroperitoneal malignant mesenchymal tumors. Gleevec (Gleevec or Glivec) is a trade name for Imatinib mesylate, code name STI571, chemically known as 4-[(4-methyl-4-piperazinyl)methyl]-N-[4-methyl-3-{[4-(pyridinyl)-2-pyrimidinyl]amino}phenyl]-anilinomethanesulfonate, which is a derivative of 2-phenylaminopyrimidine. It is a derivative with the molecular formula C29H31N70CH4SO3 and a molecular weight of 589.7. Gleevec was originally designed to target the molecular cause of chronic granulocytic leukemia (CML) and was the first cell signaling inhibitor used in the clinical treatment of malignancies. The use of Gleevec for the treatment of malignant mesenchymal tumors was first reported in 2001 by Joensu et al. In fact, the synthesis of tyrosine kinase inhibitors was initiated as early as 1988, when it was noted that the sustained activation of BCR-ABL protein kinase played an important role in the pathogenesis of CML. At Druker’s suggestion, a research group at the Swiss pharmaceutical company Sparkle-Gage began a search for small molecule compounds of BCR-ABL protein kinase. Through screening, 2-phenylaminopyrimidine was identified as the lead compound, and through conformational analysis, CGP5714B, or STI571, was designed and synthesized based on the ATP site of tyrosine kinase, and was first shown to be an inhibitor of PDGFR tyrosine kinase, and was later shown to specifically inhibit BCR-ABL tyrosine protein kinase activity. It was found that Gleevec competitively binds to the nucleotide-binding site of the tyrosine kinase catalytic site with ATP, making the kinase unable to exert catalytic activity and the tyrosine residues of the substrate unable to be phosphorylated so that they cannot do further work with the downstream effector molecules, leading to inhibition of cell proliferation and induction of apoptosis. 1992 Gleevec was synthesized in the laboratory of Steamboat-Gage Pharmaceuticals, September 1994 In July 1998, December 1999 and June 2000, phase I, II and III clinical trials of Gleevec for the treatment of CML were conducted. 10 May 2001 was approved by the US FDA for the treatment of CML, and on 1 February 2002 was approved by the FDA to add gastrointestinal and retroperitoneal malignant mesenchymal tumors Indications. The oral bioavailability of Gleevec is 98%, 95% is bound to plasma proteins, and the metabolite is an N-desmethylpiperazine derivative. The clearance half-life of the drug is 18h and the active product half-life is 40h. 81% of the drug can be excreted within 1 week, of which 68% is excreted in the stool and 13% in the urine, about 25% is excreted as the original drug and the rest as metabolites. Common side effects include mild digestive reactions, myalgia, muscle cramps, periorbital and lower limb swelling, water retention and bone marrow suppression, all of which are tolerated by patients. At doses >600 mg/d, side effects increase. Patients who are effectively treated with Gleevec may undergo surgery again and should continue to take the drug if they are stable after dosing. If resistance to Gleevec occurs, other conventional treatment options such as tumor reduction surgery, radiotherapy, arterial embolization chemotherapy, and intraperitoneal chemotherapy are available. For recurrent retroperitoneal malignant mesenchymal tumors Gleevec may be used in combination with conventional therapies. It is an undisputed fact that Gleevec can only control but not completely cure retroperitoneal malignant mesenchymal tumor. Therefore, it has been suggested that after treatment with the maximum dose of Gleevec, if there are still imaging-detectable lesions, resection or tumor reduction should be used. The increasing problem of drug resistance found in Gleevec therapy is generally considered to be due to two main factors: (1) the host has chemically modified the drug through hepatic P450 enzymes to make it ineffective or reduce its effectiveness. Alternatively, acidic glycoproteins of acute response proteins have been produced in plasma that bind to Gleevec and inhibit Gleevec binding to the tyrosine ATP site. (ii) Mutation of the tyrosine ATP site that prevents it from binding to Gleevec. Or tyrosine gene amplification, resulting in an increase in the tyrosine kinase product, when increased dosage of Gleevec is required. Increased intracellular expression of multidrug-resistant P-glycoprotein, with the result that drug pumping is increased, decreasing the intracellular concentration of gleevec do. In CML, the use of 600 mg/d or even up to 800 mg/d in some patients does increase the efficacy or make it effective again in some patients who are ineffective (drug resistant), but such an attempt has not been made in patients with retroperitoneal malignant mesenchymal tumors. Excerpted from the book “Retroperitoneal Tumors”, edited by Chenghua Luo, Director, Department of General Surgery, Peking University International Hospital This article is published with permission from Dr. Chenghua Luo.