The drug resistance of tumor cells to chemotherapy drugs is the main reason for chemotherapy failure. In vitro and in vivo studies have found that the molecular mechanism of tumor drug resistance is very complicated, including target gene mutation, target gene amplification, difference in DNA damage repair ability, and decrease in drug concentration in tumor cells. In this paper, some molecular mechanisms of tumor resistance are reviewed from the aspects of abnormal expression of protooncogene, abnormal expression of DNA damage repair gene and abnormal expression of multidrug resistance-related genes. Abnormal expression of proto-oncogenes 1 Many proto-oncogenes are involved in regulating cell proliferation and apoptosis. The changes of these genes lead to molecular regulation defects, which make cells malignant and reduce their ability to respond to physiological stimuli. Inducing tumor cell apoptosis is an important mechanism of chemotherapy drugs. Therefore, the abnormal expression of proto-oncogenes that inhibit the apoptosis of cancer cells is involved in the drug resistance of tumor cells, mainly including P53, Rb and bcl-2. 1. 1P53 protooncogene wild-type P53 (wtP53) gene is an anticancer gene, and its product is a nuclear transcription factor, which plays a role in gene stability. When cells are damaged, the expression of wtP53 protein increases, which induces the expression of GADD45, a gene related to DNA repair, increases the DNA repair ability of cells, and promotes the death of damaged cells by inducing apoptosis. In recent years, it is believed that P53 protein can also activate the expression of P2 1 waf 1 gene, thus inhibiting the activity of cyclin kinase complexes such as cyclin D/cdk4, cyclin D/cdk6 and cyclin E/cdk2, increasing the dephosphorylation of Rb protein, and thus inhibiting the injured cells from entering S phase from G 1. Increasing the level of activated P53 protein can lower the threshold of apoptosis. Mutation of P53 gene eliminates many P53-dependent reactions, increases chromosome instability, causes tumor cells to enter the cell cycle of DNA damage, and drug-resistant tumor cells are screened out, thus creating favorable conditions for gene amplification, amplifying purine and pyrimidine biosynthesis-specific enzyme genes, and generating drug resistance to metabolic drugs such as methotrexate. On the other hand, tumor cell lines with P53 gene mutation are not sensitive to apoptosis, which leads to the characteristics of tolerance to chemotherapy drugs. It was found that the tumor cells with P53 gene mutation enhanced the cytotoxicity of chemotherapy drug 5-Fu after introducing exogenous wild-type P53 gene. These results indicate that wtP53 mutation is related to the drug resistance of tumor cells to chemotherapeutic drugs [2]. 1.2Rb protooncogene Rb gene product is a nuclear protein, which acts as a trans-acting factor. Rb protein can form a complex with a cell growth regulator E2F, which inhibits the expression of S-phase genes such as DNA polymerase, thymine synthase and dihydrofolate reductase induced by E2F, thus inhibiting cell proliferation. Cyclin D family inhibits the formation of complex with E2F by phosphorylating Rb protein, increases the release of free E2F factor, and participates in the process of Rb protein network controlling the transformation of cells from G 1 phase to S phase. Therefore, when Rb gene mutation or Cyclin D 1 protein expression increases, the activity of E2F factor increases, which leads to the increase of E2F-induced S-phase gene expression, and the sensitivity of tumor cells to chemotherapy drug methotrexate decreases [3]. Bcl2 gene of1.3bl2 proto-oncogene family was found in human follicular lymphoma cells 14 and 18, but Bcl2 protein itself did not promote cell cycle and cause cell division. It is found that Bcl2-2, as an anti-apoptosis gene, can specifically inhibit apoptosis induced by various stimuli, and its mechanism may be related to the inhibition of wild-type P53 protein activity, inhibition of apoptosis induced by C myc, and the formation of heteromer with bax protein to inhibit its activity. Overexpression of bcl-2 protein was found in human prostate cancer, colon cancer and other tumors, and it was found that adenocarcinoma with bcl-2 overexpression was resistant to chemotherapy drug cytarabine [4], and bcl-XL in bcl-2 gene family could also form a complex with Bax protein to inhibit its apoptosis-inducing activity. In highly drug-resistant leukemia strain P388, the level of Bcl XL increased significantly, which was related to the drug resistance of tumor cells [5]. 2 Abnormal repair ability of DNA damage Many chemotherapeutic drugs, such as nitrogen mustard and cisplatin, kill tumors by damaging DNA, such as cross-linking between DNA strands. When the ability of tumor cells to repair DNA damage is enhanced, tumors will become resistant to chemotherapy drugs. Recently, it was found that another kind of chemotherapy drugs can selectively inhibit topoisomerase from breaking DNA chain. Different inhibitors can be stabilized with topoisomerase in different sites of DNA in the form of * * * valence complexes, usually in the attachment region of DNA matrix and the activated transcription region of c myc gene, resulting in DNA chain breakage and cell death. When the topoisomerase of tumor cells changes, such as the decrease of the transcription level and activity of topoisomerase II or the mutation of topoisomerase I, tumor cells become resistant to topoisomerase inhibitors of chemotherapy drugs [6]. On the other hand, it was found that O- methylguanine DNA methyltransferase MGMT can scavenge O-6 ethylguanine and react with N 65438+O-6 ethanol guanine to form an irreversible complex, thus inhibiting the formation of N 3C N 1G interchain conjugate. Tumor cell lines lacking MGMT are highly sensitive to the chemotherapeutic agent benzyl chloronitrosourea CENUs, but after transfection of human MGMT into cell lines lacking this enzyme, it is found that the formation of interchain cross-linking is reduced and resistance to CENUs is produced. In brain tumors, the low level of MGMT expression is related to the improvement of the basic therapeutic effect of carbazolone [7, 8]. In vitro, it was found that the repair of DNA mismatch was related to protein hMSH2 (human Muts homologue 2) and GTBP(G T binding protein dimer) which recognized the mismatch site and hMLH 1 protein (human Mutl homologue) which bound the heterodimer. The deletion of hMSH2 or hMLH 1 leads to tumor occurrence and low tolerance to cisplatin [9]. In addition, the damage recognition protein DPR s is related to platinum resistance. DPRs is a kind of protein containing migration gene HMG, which selectively binds to the interchain dimer of cisplatin GG and AG, losing the normal function of its transcription factor, thus affecting the transcription of specific genes and making tumor cells platinum-resistant. The activity of IXR 1 gene encoding HMG protein in yeast is lost, which can produce double resistance to cisplatin [10]. Ultraviolet damage recognition protein UVDRP is highly specifically bound to 6,4 photosynthetic products induced by ultraviolet rays, and its expression activity in cisplatin-resistant tumor cell lines is enhanced [1 1]. In recent years, it has been reported that the expression of DNA polymerase α and β in phenylalanine, nitrogen mustard and platinum-resistant cell lines has greatly increased. After in vivo treatment with cisplatin, the activities of DNA polymerase α, β and DNA ligase in tumor cells were greatly improved [12], which enabled tumor cells to replicate under the condition of DNA strand damage, and eliminated the interchain cross-linking and interchain dimer in G2 phase of cells, and inhibited P53-induced apoptosis, thus resulting in platinum tolerance. In the tumor tissues of patients with malignant ovarian cancer who did not respond to platinum chemotherapy, it was found that the expression of excision and repair genes P33 and P3 1 related to nucleic acid was much higher than that of patients with effective platinum chemotherapy. In the study of leukemia patients, it was found that the overexpression of P33 was related to its resistance to nitrogen mustard [13]. Therefore, the increase of enzyme activity related to DNA repair is an important reason for tumor resistance to chemotherapy drugs, and screening selective inhibitors related to DNA repair can increase the chemotherapy effect. Due to the cross-resistance of tumor cells to various chemotherapeutic drugs, the abnormal expression of multidrug resistance-related genes is an important reason for the failure of tumor chemotherapy. It is found that the multidrug resistance mechanism of human tumors and cultured tumor cell lines is related to multidrug resistance genes, glutathione transferase, protein kinase C and other factors. Multidrug resistance gene MDR is located on chromosome 7. The protein coding region of this gene consists of 27 exons, and its encoded p glycoprotein 170KD belongs to the ATP binding protein superfamily. Overexpression of P- glycoprotein on drug-resistant cell membrane can pump chemotherapy drugs out of the cell, and intracellular chemotherapy drugs can not reach the effective killing dose, resulting in drug resistance. Non-classical multidrug-resistant cell lines, such as adriamycin-resistant human HL60, express the protein 1 10KD on the endoplasmic reticulum. Because the protein gene was isolated from lung cancer cells, it was named LRP 56. The homology analysis of cDNA sequence shows that the protein belongs to cytoplasmic vault protein and is an organelle related to nuclear cytoplasmic transport. Therefore, the action pathway of LRP 56 may be: on the one hand, reducing the effective concentration of drugs by reducing the nuclear-cytoplasmic distribution ratio, on the other hand, expelling drugs from cytoplasm through vesicle transport and exocytosis mechanism, and reducing the absolute concentration of drugs. LRP 56 protein is expressed in many human tumor cell lines and solid tumors, and highly expressed in human colorectal cancer [14]. The expression level of LRP 56 in hematological tumors and solid tumors is also related to chemotherapy sensitivity. In addition, multidrug resistance-related protein MRP was found in tumor cell lines with negative expression of P glycoprotein. MRP encodes 7.8 ~ 8.2 kb mRNA, which is located on chromosome 16 p 13. 1, MRP+0, and the MRP product is 190KD membrane-bound glycoprotein. Cloning and transformation experiments show that MRP gene can make tumor cells resistant to many drugs [65438]. In vitro and in vivo experiments prove that glutathione transferase GST can catalyze the detoxification of glutathione and drugs to form a complex, and the GST activity of tumor cells increases, resulting in drug resistance. It was found that the expression level of GST π in human tumor tissues such as gastric cancer, colon cancer and lung cancer increased, and the drug resistance of several tumor cell lines to phenylalanine nitrogen mustard and cyclophosphamide and the expression level of GST π increased. Using antisense technology to block the expression of GST π in tumor cells can obviously enhance their sensitivity to various chemotherapeutic drugs [16]. Another drug metabolism mechanism is related to the binding of nucleophiles such as nitrogen and sulfur with glucuronic acid, which is catalyzed by the UDPGTS family of glucuronosyltransferase. In mouse leukemia cell line P338, it was found that the level of UDPGTS increased, which inactivated the metabolically toxic daunorubicin and produced drug resistance [17]. Protein kinase C is a Ca2+/ phospholipid-dependent isoenzyme, which consists of a single polypeptide chain, including two different calcium-dependent sulfhydryl protease decomposition sites and hydrophilic catalytic sites/active centers containing ATP and substrate protein binding regions. Compared with the corresponding sensitive strains, the drug-resistant cell lines established in vitro have significantly higher protein kinase C activity. Studies have shown that protein kinase Cα plays an important role in the formation of multidrug resistance in tumors, but protein kinase C is heterogeneous in various tumor tissues. Protein kinase C may regulate its transport function by phosphorylating membrane proteins encoded by drug-resistant genes, or participate in the formation of multidrug resistance through nuclear gene transcription. Therefore, it is necessary to further study the role of protein kinase C in the occurrence and development of multidrug resistance [18]. To sum up, the mechanism of tumor cell resistance to chemotherapeutic drugs is complex. In view of the abnormal expression of proto-oncogene in tumor cells, people use gene therapy to introduce normal genes into cells to increase their sensitivity to chemotherapy, and many compounds such as calcium channel blockers can reverse the multidrug resistance of tumor cells. Therefore, clinical chemotherapy should combine drugs with different mechanisms and different treatment methods to achieve good clinical efficacy.