Molecularly targeted drugs mainly target the key targets of the pathophysiological occurrence and development of malignant tumors for therapeutic intervention, and some molecularly targeted drugs have shown better efficacy in the corresponding tumor treatment. Although molecularly targeted drugs have outstanding curative effect on the tumors they target, with good tolerance and mild toxicity, it is generally believed that they cannot completely replace traditional cytotoxic anti-tumor drugs in a long period of time. A more common case is a combination of the two. The expression and mutation status of drug target molecules carried by tumor cells before and after treatment often determine the efficacy and disease prognosis of molecularly targeted drugs, which puts forward higher requirements for individualized treatment of such drugs.
Single target inhibitor
There is currently no unified classification method for molecularly targeted drugs. At therapeutic doses, drugs that only act on a single target are called single-target inhibitors.
BCr-Abl inhibitors
1. Imatinib
Imatinib, a 2-phenylaminopyrimidine compound, is a highly specific tyrosine kinase inhibitor. It was artificially synthesized in 1992 and approved by the FDA in 2001, creating a signal transduction pathway that inhibits tumor cell proliferation. Conduction pathway to achieve a new way of anti-tumor.
【Pharmacokinetics】 Oral absorption is rapid, and the bioavailability of commonly used capsules can reach 98%. The mean area under the curve (AUC) was proportional to dose over the 25-1000 mg dose range. A high-fat diet may slightly reduce the absorption of this drug. The plasma protein binding rate is about 95%, most of which are bound to albumin, a small part is bound to α-acid glycoprotein, and only a very small part is bound to lipoprotein. The overall concentration of distribution in vivo is high, the volume of distribution is 4.9L/kg, but the distribution ratio in red blood cells is low. The elimination half-life is 18 hours, the half-life of its active metabolite is 40 hours, and the drug excretion is 81% within 7 days.
【Pharmacological action】Imatinib acts on Bcr-Abl tyrosine kinase, which can selectively inhibit the proliferation of Bcr-Abl positive cells, Ph chromosome-positive chronic myeloid leukemia and fresh cells from patients with acute lymphoblastic leukemia and induce their apoptosis. In addition, it can inhibit the tyrosine kinase of platelet-derived growth factor (PDGF) receptor, stem cell factor (SCF) c-Kit receptor, thereby inhibiting cell behavior mediated by PDGF and stem cell factor.
[Clinical application] It is mainly used for chronic myeloid leukemia (CML) in blast phase, accelerated phase or chronic phase of interferon alpha resistance, and patients with malignant gastrointestinal stromal tumor that cannot be resected or metastasized.
[Adverse reactions] The adverse reactions are mild to moderate, mainly nausea, vomiting, diarrhea, muscle cramps, edema, headache, dizziness, etc.
Epidermal Growth Factor (EGFR) Inhibitors
1. Gefitinib
Gefitinib, an aniline quinazoline derivative, is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.
【Pharmacokinetics】The peak plasma concentration can be reached 3-7 hours after oral administration. The protein binding rate is about 90%, and the volume of distribution at steady state is 1400L. It is mainly metabolized in the liver and is related to the activity of CYP3A4. There are 5 kinds of metabolites, and only the oxygen-desmethyl gefitinib compound has pharmacological activity. 10 days after a single oral administration, 90% is mainly excreted with feces, less than 4% is excreted with urine, and the elimination half-life is 6-49 hours.
【Pharmacological action】Selective tyrosine kinase inhibitor, competitively binds to EGFR, blocks the binding of epidermal growth factor (EGF) and EGFR, blocks the downstream signal transduction pathway mediated by EGFR, thereby inhibiting tumor cell proliferation , induce differentiation, promote cell apoptosis, inhibit tumor angiogenesis, and enhance the efficacy of radiotherapy and chemotherapy.
[Clinical application] It is suitable for locally advanced or metastatic non-small cell lung cancer who have received chemotherapy or are not suitable for chemotherapy. Combined use of other games does not improve the efficacy.
[Adverse reactions] The most common adverse drug reactions are gastrointestinal and skin reactions, such as diarrhea, vomiting, rash and itching, and rare allergic reactions such as urticaria, which are usually seen within the first month after taking the drug and are usually reversible. Interstitial pneumonia, corneal erosion, etc. occurred in less than 1% of patients.
2. Icotinib
Icotinib is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which only has obvious inhibitory effect on EGFR wild type and its mutant type, and has no inhibitory effect on other kinases. It is rapidly absorbed orally, with a peak time of 0.5-4 hours, and is mainly metabolized by CYP2C19 and CYP3A4 of the liver cytochrome P450 enzyme system. It is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after at least one chemotherapy regimen has failed in the past. Previous chemotherapy mainly refers to platinum-based combination chemotherapy. Common adverse reactions were rash (39.5%), diarrhea (18.5%) and increased aminotransferase (8.0%).
3. Nimosphere
Nimotuzumab is the first epidermal growth factor receptor (EGFR) monoclonal antibody that can specifically compete with EGFR. It is mainly used in combination with radiotherapy for the treatment of epidermal growth factor receptor (EGFR) positive stage III/IV nasopharyngeal patients. cancer. Adverse reactions include fever, dizziness, headache, nausea, rash, nausea, vomiting, dysphagia, dry mouth, flushing, precordial pain, drowsiness, myalgia, hematuria, elevated aminotransferase, etc.
4. Cetuximab
It is also an antibody drug that can specifically bind to EGFR (with an affinity 5-10 times higher than that of endogenous ligands) and inhibit the function of the receptor, thereby inhibiting tumor growth and metastasis. After intravenous administration, it generally takes effect within 6 weeks, and is metabolized by binding to EGFR or endocytosis in hepatocytes and skin, with an elimination half-life of 3-7 days. Suitable for EGFR-expressing colorectal cancer, EGFR-expressing advanced non-small cell lung tumor, and metastatic or recurrent head and neck squamous cell carcinoma. The main adverse reactions were headache, conjunctivitis, respiratory system reactions, gastrointestinal reactions, skin reactions, infusion reactions and allergic reactions.
Epidermal growth factor receptor 2 (HER-2) inhibitors
1. Trastuzumab
Trastuzumab is a DNA recombinant humanized monoclonal antibody, which was approved by the US FDA for clinical use in 1998 and launched in my country in 2002.
【Pharmacokinetics】Studies on metastatic breast cancer showed that the pharmacokinetics of trastuzumab 10 mg, 50 mg, 100 mg, 250 mg and 500 mg once a week by intravenous infusion were dose-dependent. The mean half-life increased and the clearance decreased with increasing dose level. In clinical trials using a 4 mg/kg initial loading dose of trastuzumab and a weekly maintenance dose of 2 mg/kg, a mean half-life of 5.8 days (1-32 days) was observed between 16-32 weeks , the plasma concentration of trastuzumab reached a steady state, with a mean trough concentration of approximately 75 µg/ml.
[Pharmacological action] Trastuzumab mainly binds to the HER-2 receptor and interferes with its autophosphorylation, thereby antagonizing the transmission of growth signals, downregulating the expression of the HER-2 gene, and accelerating the internalization of the HER-2 protein receptor and degradation, down-regulates the activity of vascular endothelial growth factor and other angiogenic growth factors, restores E-cadherin expression levels, suppresses tumor metastasis, while enhancing immune cell attack and killing tumor target cells through antibody-dependent cell-mediated cytotoxicity Ability.
[Clinical application] It is mainly used for the treatment of metastatic breast cancer with over-expression of HER-2 and metastatic breast cancer that has received one or more chemotherapy regimens. It is used in combination with taxanes for the treatment of chemotherapy-naïve breast cancer. of metastatic breast cancer.
[Adverse reactions] Adverse reactions mainly include chest pain, diarrhea, muscle pain, edema, dyspnea, weakened myocardial contractility, etc. Myelosuppression and liver damage occur less frequently.
Vascular endothelial growth factor (VEGF0 inhibitor
1. Bevacizumab
Bevacizumab, a recombinant humanized monoclonal antibody, is the first drug approved in the United States to inhibit tumor angiogenesis.
【Pharmacokinetics】In the dose range of 1-10 mg/kg, the pharmacokinetics of bevacizumab is linear. Bevacizumab is primarily catabolized by proteolysis in the body and is not eliminated by the kidneys and liver. Because the binding of IgG to FcRn protects it from being metabolized, its terminal half-life is long, with elimination half-lives of 20 days and 18 days in male and female patients, respectively.
【Pharmacological action】Selectively bind to human vascular endothelial growth factor (VEGF), inhibit the binding of VEGF to its receptors on endothelial cells-Flt-1 and KDR, reduce tumor angiogenesis, inhibit tumor growth and metastasis. Bevacizumab produces broad antitumor activity against a variety of human tumors, including colon, breast, pancreatic, and prostate cancer, and the combination of bevacizumab and sunitinib malate increases microvascular Risk of hemolytic anemia.
[Clinical application] It is mainly used in combination with fluorouracil-containing regimen for the treatment of metastatic colorectal cancer, in combination with carboplatin and paclitaxel in the treatment of metastatic non-squamous non-small cell lung cancer, in combination with interferon alpha for the treatment of metastatic renal cancer, Advanced malignant glioma.
[Adverse reactions] Common adverse reactions include hypertension, fatigue or fatigue, diarrhea and abdominal pain, and serious adverse drug reactions include gastrointestinal perforation, bleeding, and arterial thromboembolism.
mTOR inhibitors
1. Everolimus
【Pharmacokinetics】In patients with advanced solid tumors, the plasma drug concentration reaches a peak after 1-2 hours of oral administration, and reaches a steady state concentration after 2 weeks. Fatty foods can reduce its absorption, and high-fat foods can reduce AUC by 16%. The plasma protein binding rate is about 74%, and the average elimination half-life is about 30 hours.
【Pharmacological action】The small molecule inhibitor of mammalian target of rapamycin (mToR) has dual effects of anti-tumor and inhibition of blood vessels, and can effectively inhibit tumor cell proliferation, metabolism and angiogenesis.
【Clinical application】Clinically used for the treatment of advanced pancreatic neuroendocrine tumors; renal angiomyolipoma with tuberous sclerosis; subependymal giant cell astrocytoma with tuberous sclerosis; advanced hormone receptor-positive HER -2-negative breast cancer and advanced renal cell carcinoma that failed sunitinib or sorafenib.
[Adverse reactions] Common adverse reactions include stomatitis, pneumonia and dyspnea, and serious adverse reactions include acute respiratory failure, infection, and acute renal failure.
【Drug Interactions】Everolimus is a substrate and inhibitor of CYP3A4 and PgP. Erythromycin and verapamil, grapefruit, grapefruit juice can significantly increase the exposure dose in vivo, should avoid concomitant use with strong CYP3A4 inhibitors. Caution should be exercised when this product is used in combination with moderate CYP3A4 and/or Pgp inhibitors, and the dose of this product must be reduced when combined. After combined use with strong CYP3A4 inducers (such as rifampicin), the AUC and Cmax of this product were reduced by 63% and 58%, respectively, and the dose of this product should be increased when combined. The effect of St. John’s wort on the internal process of this product is still unpredictable, and it should be avoided as much as possible.
Multi-target inhibitor
Compared with single-target inhibitors, drugs that act on multiple targets at the same time at therapeutic doses are called multi-target inhibitors.
Example: sunitinib
【Pharmacokinetics】Cmax is reached 6-12 hours after oral administration, the plasma protein binding rates of sunitinib and its main active metabolite are 95% and 90%, respectively, and the elimination half-lives are 40-60 hours and 80-hours, respectively. 110 hours. Mainly excreted through feces (61%) and kidneys (16%) with a total clearance of 34-62 L/h. After repeated daily dosing, sunitinib accumulated 3-4-fold, while its major metabolite accumulated 7-10-fold, reaching steady-state concentrations (62.9-101 ng/ml) within 10-14 days.
[Pharmacological action] Sunitinib and its metabolites in vivo are small molecule multi-target tyrosine kinase (RTK) inhibitors, which are multi-target inhibitors, which can inhibit platelet-derived growth factor receptor-α/β (PDGFR) -α/β, Vascular endothelial growth factor receptor-1/2/3 (VEGFR-1/2/3), stem cell factor receptor (KIT), FmS-like tyrosine kinase-3 (FLT-3), 1 Colony-stimulating factor receptor (CSF-1R) and glial cell-derived neurotrophic factor receptor (RET). By inhibiting PDGFR, RET or KIT and other targets mediated tumor cell growth as well as PDGFR-β and VEGFR-2 Dependent tumor angiogenesis produces antitumor effects.
[Clinical application] It is clinically suitable for gastrointestinal stromal tumor (GIST), inoperable advanced renal cell carcinoma (RCC), metastatic renal cell carcinoma (MRCC) and Advanced pancreatic neuroendocrine tumor (PNET).
[Adverse reactions] Serious adverse reactions include hepatotoxicity, left ventricular dysfunction, Q-T interval prolongation, bleeding, hypertension, thyroid dysfunction, adrenal dysfunction, and venous thrombosis. Common adverse reactions include fatigue, diarrhea, nausea, vomiting, constipation, rash, headache, pain in joints and extremities, and cough.
[Drug Interactions] Strong inhibitors of CYP3A4 can increase the plasma concentration of sunitinib; CYP3A4 inducers, such as rifampicin, can decrease the plasma concentration of sunitinib.
Prospects
Tumor is a complex disease caused by the interaction of many different factors such as environment, nutrition and diet, genetics, etc. A large number of tumor biological studies have also shown that signal transduction related to tumor cell growth, proliferation, differentiation and metastasis is an extremely important factor. The complex, multi-factor, and multi-pathway protein network system, therefore, targeting a single target is often not enough to curb the progression of tumors. It is necessary to combine drugs with different pathways and mechanisms to block signal transduction and inhibit tumors. grow. However, the optimal application mode of drug combination and its efficacy on other tumors still require a large number of clinical trials to further study, and strive to implement individualized treatment for specific and suitable tumor patients, so as to obtain the best therapeutic effect with the smallest economic cost or cost. The research of molecularly targeted drugs will certainly promote its further development.
