Chemotherapy for high-grade gliomas (malignant astrocytomas, glioblastomas) In a 2002 GMT meta-analysis of 12 studies including 3,000 postoperative patients with high-grade gliomas, the 1-year survival rate was 46% in the combination of radiation and chemotherapy group, and 40% in the radiation alone group. Temozolomide (TMZ) belongs to the second generation of alkylating chemotherapeutic agents. It can act directly on the substrate of synthesized DNA and methylate it, thus leading to DNA single-strand and double-strand breaks, inhibiting DNA replication and finally leading to cell death. Because of the small molecule and good lipophilicity, TMZ can better pass the blood-brain barrier, and can reach 40% of the plasma concentration in the central nervous system, which makes it a good application prospect in the treatment of central nervous system tumors.In 1999, the FDA approved TMZ to be used in the chemotherapy of relapsed malignant astrocytoma, and in March 2005, the FDA approved to be used in the treatment of new patients with glioblastoma. tumor patients. In Europe, TMZ is approved for use in recurrent malignant astrocytomas and glioblastomas.In 2005, a recent phase III controlled trial (Stupp R, Mason WP, van den Bent MJ, et al. 2005) of 573 patients with glioblastomas compared (1) simultaneous radiotherapy with TMZ 75 mg?m-2?d-1 with radiotherapy + TMZ 75 mg?m-2?d-1 with radiotherapy + TMZ 75 mg? + radiotherapy followed by TMZ 150-200 mgm-2d-1, d1-5 × 6 cycles. (ii) Radiotherapy alone. the MST was 14.6 and 12.1 months, respectively; the 2-year overall survival rates were 26.5% and 10.4%, respectively. In addition, it has been found that MGMT (a DNA repair enzyme) may help predict the efficacy of TMZ, as MGMT can cause glioma cells to become resistant to alkylating chemotherapeutic agents.Side effects of TMZ include nausea, vomiting, headache, malaise, and anorexia.In addition to general symptomatic management, the FDA recommended in its Talk Paper of March 16, 2005 that the use of cacodylic lung disease should be used in the treatment of TMZ. Pneumocystis cariniipneumonia PCP should be used to alleviate these side effects during treatment (Hegi ME,Diserens AC, Gorlia T,etal.2005). In the final report of NCOG 6G61 in 1990, the results of the phase III controlled trial were reported, in which they showed that BCNU versus PCV regimens of chemotherapy for highly graded gliomas after radiotherapy showed that PCV regimens resulted in higher survival rates in patients with malignant astrocytomas (Levin VA, Silva P, Hannigan J, et al. 1990). Therefore, most people believe that chemotherapy with the PCV regimen should be used after radiotherapy for malignant astrocytomas. However, a 1999 retrospective study of cases enrolled in the RTOG trial showed no significant difference between PCV and BCNU regimens of chemotherapy after radiotherapy (Prados MD, Scott C, Curran WJ Jr, et al. 1999).The results of a 2001 MRC study also showed that PCV regimens of chemotherapy after radiotherapy for malignant astrocytomas did not improve survival (Medical Research Council Brain Tumor Working Party. 2001). There are also some ongoing studies of other chemotherapeutic agents for high-grade gliomas. The current second line of chemotherapy for high-grade gliomas includes CPT-11, cisplatin, and carboplatin. Some studies have shown TMZ and cisplatin to be effective as salvage therapy for recurrent progressive glioblastoma. A new biodegradable polymer-coated BCNU (Gliadel Wafer) can be placed in the operative cavity as a form of localized chemotherapy for the treatment of high-grade gliomas.The BCNU degradable polymer has a duration of action of about 3 months, and can be detected by MRI for up to 1 year.The BCNU degradable polymer is effective in preventing local recurrence of malignant gliomas while at the same time avoiding the need for systemic chemotherapy. It also avoids the side effects of systemic chemotherapy, and it has been shown that BCNU is undetectable in the blood of patients in whom BCNU degradable polymers have been inserted (Brem H, Piantadosi S, Burger PC, etal. 1995). Results of a study showed that in recurrent high-grade gliomas, BCNU-degrading polymers improved patient survival. A randomized study of 32 primary cases of high-grade gliomas showed that BCNU-degradable polymers in combination with radiotherapy significantly prolonged survival compared with radiotherapy alone (Valtonen S, Timonen U, Toivanen P, et al. 1997). Another phase III controlled study (Westphal M, Hilt DC, Bortey E, etal. 2003) comparing BCNU degradable polymers with placebo in 240 patients with first-treatment malignant gliomas found that the patients’ MST was extended from 11.6 months (placebo) to 13.9 months (BCNU degradable polymers). As a result, in February 2003, the FDA expanded the use of BCNU degradable polymers from recurrent malignant gliomas to cases of recurrent or primary high-grade gliomas. The same expansion of indications was made in Europe in 2004. Attention must also be paid to the effect of certain antiepileptic drugs on chemotherapeutic agents. Antiepileptic drugs such as phenytoin sodium and carbamazepine induce the activity of the hepatic cytochrome P450 isoenzyme system, which increases the hepatic metabolic clearance of the drug. This class of drugs is known as hepatic enzyme-inducing antiepileptic drugs (HEIAs), and they will significantly reduce the effects of chemotherapeutic drugs such as CPT-11 and Tessoday. Therefore, in chemotherapy for patients taking HEIAs, the dose of the drug should be increased or the patient should be advised to use non-HEIAs drugs, such as gabapentin, lamotrigine, or levetiracetam. In conclusion, the role of chemotherapy in the treatment of high-grade gliomas includes: ① BCNU and PCV regimens can be used as adjuvant radiotherapy for malignant astrocytomas; ② TMZ adjuvant radiotherapy is used for malignant astrocytoma or glioblastoma; ③ BCNU degradation polymer can be used for postoperative placement of malignant gliomas in primary or recurrent cases; ④ A treatment regimen of TMZ 75 mgm-2d-1 simultaneous radiotherapy + TMZ 150-200 mgm-2d-1, d1-5×6 cycles after radiotherapy can be used in patients with primary postoperative treatment of glioblastoma. Chemotherapy for low-grade gliomas Because the occurrence of hematologic toxicity caused by chemotherapy is more common, and even after regular surgery + radiotherapy treatment, most cases can obtain a longer-term survival rate. Therefore, currently, chemotherapy is only used for salvage treatment after recurrence of low-grade gliomas. Among the low-grade gliomas, oligodendrogliomas and oligodendrogliomas-astrocytomas are the most sensitive to chemotherapy. In particular, patients with chromosome 1p or 1p19q deletions are more sensitive to alkylating chemotherapeutic agents. PCV regimens are effective in 33% to 65% of recurrent lesions and in 20% to 33% of primary cases. The only prospective study evaluating the value of adjuvant chemotherapy for low-grade astrocytomas, SWOG, reported 54 cases with subtotal tumor resection randomized to radiotherapy alone and radiotherapy + oral CCNU (100 mg/6 weeks) for 2 years and showed no statistically significant difference in median survival or survival rate (Eyre HJ, Crowley JJ, Townsend JJ, etal. 1993).TMZ for low-grade gliomas with failed PCV chemotherapy remains highly effective, with the literature reporting an effectiveness rate of approximately 40% (Chinot OL, Honore S, Dufour H, et al. 2001). The main problematic issues facing glioma chemotherapy today are how to penetrate the blood-brain barrier and how to address multidrug resistance. Blood-brain barrier (BBB) and chemotherapy Hypertonic BBB opening: arterial injection with 20% mannitol 150-250 mL at a rate of 5-10 mL/s can rapidly change BBB permeability. Animal experiments showed that after perfusion of hypertonic solution via carotid artery, the vascular endothelial cells of BBB contracted, the cell gap widened, and the water content of brain tissue increased by 1.0% to 1.5%, and the effect returned to normal in 4 h. This method has been used in the clinic since the 1980s, but its action has not been confirmed in phase III studies so far. Recent studies have shown that opening the BBB with mannitol, whose destruction of endothelial cells in normal brain tissue lasts longer than that of tumor endothelial cells, is non-selective in opening the BBB and increases the exposure of normal brain tissue to chemotherapeutic agents (Zunkeler B, Carson RE, Olson J, et al. 1996). Selective opening of the blood-tumor barrier (BTB): Several drugs have been found to have selective BTB-opening effects: arachidonic acid, leukotrienes, bradykinin, NO donors, and RMP-7, with RMP-7 receiving the most attention (Weyebrock A, Walbridge S, Pluta RM, et al. 2003). RMP-7 is a derivative of bradykinin, and animal experiments have shown that RMP-7 does not significantly alter the capillary permeability of normal rat brain tissue, but increases the permeability of intracranial tumor capillaries.The mechanism of action of RMP-7 is to open the tight junctions of capillaries via bradykinin receptors, which are significantly more abundant in brain tumor blood vessels than in normal brain capillaries.The RMP-7 receptor is a key component in the opening of the BBB, which is generally smaller than that in normal brain capillaries. RMP-7 opens the BBB for less than 20 min, after which the BBB closes automatically. RMP-7 is superior to bradykinin because it has a reduced peptide bond and is less susceptible to degradation by angiotensin-converting enzyme (Prados MD, ScholdSC JR, Fine HA, etal. 2003). BBB avoidance: interstitial chemotherapy can avoid the BBB, increase the local drug concentration in the tumor, and reduce the toxic side effects of systemic drugs, which can be divided into 2 types: intraoperative and postoperative interstitial chemotherapy. Chemotherapeutic resistance and countermeasures Multidrug resistance (MDR) and reversal: one of the main reasons for chemotherapy failure in malignant glioma is the development of MDR in tumor cells in response to chemotherapeutic drugs. typical MDR is caused by overexpression of membrane glycoprotein-P-glycoprotein (P-gp) encoded by a multidrug resistance gene. ), protein kinase C (PKC), tumor necrosis factor (TNF-a), glutathione and its related enzymes. Drug reversal is the main approach against MDR, and in vitro experiments have shown that drugs that can reverse MDR include calcium antagonists (isobarbital), calcineurin inhibitors (phenothiazine), immunosuppressants (cyclosporine A), quinidine analogs, synthetic isoprenoid-like drugs such as N-(P-phenyl)bisbentylamine, triparanol and its analogs (triamcinolone acetonide), depigmenting agents ( Cremophor FL), elemene analogs, PKC inhibitors (Calphosinc). Among them, calcium antagonists are the most used, and their mechanism of action is to cause inhibition of P-gp expression as well as increase apoptosis in MDR cells. In addition, chemotherapeutic drugs (e.g., adriamycin) wrapped in polyethylene acrylic acid microspheres can effectively reduce P-gp-mediated MDR in C6 glial cells, which is caused by the cleavage of the microspheres inside the cells and the cytotoxicity of the microspheres; at present, this method and the gene therapy of MDR are still in the stage of in vitro experiments. Combination chemotherapy: improve the sensitivity of chemotherapy, Brandes et al. found that the combination of VM-26 and BCNU can significantly improve the sensitivity of glioma to chemotherapy, and the mechanism may be to inhibit the overexpression of MDR-1 or P-gp (Brandes AA, Vastola F, Basso U, et al. 2003).Brandes et al. also found that the combination of PCV regimen with chemotherapy can improve the sensitivity of glioma to chemotherapy. found that the PCV regimen combined with chemotherapy significantly enhanced the sensitivity of glioblastoma multiforme to BCNU analogs, possibly because pre-exposure of tumor cells to alkylating agents inhibited AGT (06-alkylguanine-DNA alkylating convertase) activity in tumor cells, which is a major target for enhancing the sensitivity of tumor cells to BCNU analogs, and thus enhanced the sensitivity to BCNU analogs. action of BCNU analogs (Brandes AA, Turazzi S, Basso U, et al. 2002). MOLECULAR THERAPY The malignant phenotype of tumors involves amplification and overexpression of oncogenes, deletion of oncogenes and aberrations in several important signaling pathways. These molecular alterations affect a series of biological behaviors such as proliferation, apoptosis, angiogenesis, invasion and metastasis of tumor cells. Targeted moleculartherapy, which aims at molecules specific (or relatively specific) to tumor tissues or cells in the above pathways, has made some progress in recent years (Kondo Y, Hollingsworth EF, Kondo S. 2004). A number of molecularly targeted drugs have entered clinical applications or trials. Monoclonal antibodies, soluble receptors, antisense molecules and small molecule inhibitors against PDGFR are being developed.SU101 is the first small molecule PDGFR signaling inhibitor applied to brain tumors.Imatinib (Gleevec) is another promising small-molecule tyrosine kinase inhibitor that inhibits PDGFR, and preclinical and clinical studies have shown that Gleevec has some anti-glioma effects. The tyrosine kinase inhibitors Gefitinib (Iressa) and erlotinib (Tarceva) act by competitively inhibiting the ATP-binding site in the intracellular region of the EGFR tyrosine kinase, and the NABTC has conducted a clinical phase I/II study of Iressa in the treatment of recurrent malignant gliomas, with promising results. The trial demonstrated the anti-glioma activity of tipifarnib (R115777, Zarnestra) and SCH66336, two farnesyltransferase inhibitors (FT inhibitors, FTIs). Marimastat (BB-251) is a low molecular weight matrix metallopro- teinases inhibitors (MMPIs). AG3340 is a potent MMP-2 inhibitor that also inhibits MMP-3, -9, and -13. Metastat (CMT-3, COL-3) is a chemical inhibitor that inhibits MMP-3, -9, and -13. Metastat (CMT-3, COL-3) is a chemically modified tetracycline analog that inhibits the activity of MMP-2 and MMP-9 (Zhongping Chen, Junping Zhang. 2005). Whether they are clinically effective in glioma patients is still being explored. Tumor growth is dependent on the supply of nutrients from tumor blood vessels, and blocking angiogenesis is an effective strategy to curb tumor growth. With the understanding of the mechanism of tumor blood vessel formation, anti-angiogenesis treatment strategies designed for the formation of molecular mechanisms have become a hot research area in tumor therapy, and many angiogenesis inhibitors have entered clinical trials.PTK787/ ZK222584 (PTK/ZK) is an orally administered VEGFR (vascular endothelial growth factor receptor, VEGFR) agent. PTK787/ ZK222584 (PTK/ZK) are orally administered VEGFR (vascular endothelial growth factor receptor) tyrosine kinase inhibitors, which also weakly block PDGFR, interfering with VEGFR and PDGFR-mediated angiogenesis, and have antitumor activity. Integrins are involved in mediating cell adhesion to the extracellular matrix, cell migration, invasion and neovascularization. Blocking integrins reduces angiogenesis and initiates endothelial cell apoptosis. Recently, it has been found that invasive melanoma cells can form lumens bounded by extracellular matrix without vascular endothelial cell coatings, which is different from Angiogenesis, and, therefore, it is termed vasculogenic mimicry (VM). This phenomenon has been successively found in a variety of tumors (breast, ovarian, lung, prostate, synovial sarcoma, rhabdomyosarcoma, pheochromocytoma, astrocytoma, etc.). We have also found the presence of VM in human brain astrocytomas, which may be a tumor microcirculation pattern, so naturally, tumor therapeutic measures targeting VM have become an area of great interest. It has been found that the VM regulatory pathway and the angiogenesis regulatory pathway share common molecules, such as Flt-1, Tie-2, Tie-1, VEGF, Ang-1, Ang-2, and VEGF, and in-depth study of the role of these molecules will provide clues for the development of more effective tumor therapeutic tools (Maniotis AJ, Folberg R, Hess A, et al. 1999). Recently, a new drug, Lapatinib, was used in the molecular treatment of brain metastases from breast cancer. It is an oral, small-molecule epidermal growth factor tyrosine kinase inhibitor that acts on both EGFR and HER2. In a phase II trial of lapatinib for the treatment of HER2-positive breast cancer with brain metastases, 39 patients who had been previously treated with trastuzumab, 38 of whom had progressed to tumor progression after whole-brain radiotherapy, were treated with daily oral lapatinib 750 mg bid. 2 patients achieved partial remission, 5 patients were stable, and the other 20 patients achieved at least one site remission in 30%.