逆转晚期原发性肝癌化疗耐药的研究进展

姑息化疗是晚期原发性肝癌的主要治疗手段,但化疗耐药常常是治疗失败的主要因素之一。本文对靶向抑制细胞周期G2检查点、靶向PI3K/Akt/mTOR信号传导通路、抑制肿瘤对乏氧的反应、节拍化疗联合分子靶向药物抗血管生成和热疗化疗联合以及癌细胞微量元素调控等逆转原发性肝癌化疗耐药的研究进展作一综述。     

恩度联合化疗治疗肺癌1例

肿瘤生物学行为的多样性、肿瘤细胞对化疗药物的天然抗药性以及化疗药物的严重细胞毒性等原因使肺癌的治疗陷入“瓶颈期”,而基于“肿瘤生长依赖血管形成”理念产生的抗血管生成治疗已引起肿瘤界浓厚的兴趣。2006年7月全面上市的重组人血管内皮抑制素（endostar,恩度）将可能成为肿瘤靶向治疗的新一轮热点。现将我科一例恩度联合GC方案化疗治疗肺癌的病例报告如下。     

抗血管生成酪氨酸激酶抑制剂在晚期乳腺癌中的应用

晚期乳腺癌不可治愈,而抗血管生成治疗可以抑制肿瘤生长。小分子酪氨酸激酶抑制剂可以在多个靶点抗血管生成,在多种恶性肿瘤中体现出有效的抗肿瘤作用。笔者针对抗血管生成酪氨酸激酶抑制剂在晚期乳腺癌中单药及联合化疗的应用疗效进行概述。     

肿瘤的节拍化疗

节拍化疗指以肿瘤内增殖的血管内皮细胞为靶点,通过持续应用低毒性剂量的药物而抑制肿瘤血管生成的一种化疗模式。节拍化疗在头颈部肿瘤、乳腺癌、消化道肿瘤、卵巢癌和前列腺癌中的成功应用显示了其潜在价值。节拍化疗的作用机制除抗肿瘤血管生成外,还包括刺激免疫和直接抗肿瘤效应,其与其他治疗模式的联合应用尚待深入探索。     

小分子抗血管生成药物在非小细胞肺癌中的研究进展

肺癌是世界上发病率最高的癌症之一,且尚无二线进展后的标准治疗方案,而肿瘤血管生成目前已被确定为恶性肿瘤的重要治疗靶点,小分子多靶点血管激酶抑制剂可通过抑制血管生成相关信号通路,抑制肿瘤血管的生成。目前已开展多项小分子抗血管生成药物治疗非小细胞肺癌的临床试验,且已有部分血管内皮生长因子受体酪氨酸激酶抑制剂(vascular endothelial growth factor receptor-tyrosine kinase inhibitors, VEGFR-TKIs)获批治疗晚期非小细胞肺癌,本文基于国内外多项小分子抗血管生成药物治疗非小细胞肺癌的发展现状,归纳了多个VEGFR-TKIs及成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR)-TKI单药或联合[包括分别与化疗、表皮生长因子受体(epidermal growth factor receptor, EGFR)-TKIs、免疫治疗、放疗等联合)]治疗非小细胞肺癌的疗效与安全性研究,同时探讨了VEGFR-TKIs可能存在的耐药机制及疗效预测指标等,并对未来抗血管治疗非小细胞肺癌的发展趋势以及存在的潜在问题进行展望,同时为肺癌后续的精准治疗及个体化治疗提供新的思路。     

恩度联合化疗治疗肺癌1例

肿瘤生物学行为的多样性、肿瘤细胞对化疗药物的天然抗药性以及化疗药物的严重细胞毒性等原因使肺癌的治疗陷入"瓶颈期",而基于"肿瘤生长依赖血管形成"理念产生的抗血管生成治疗已引起肿瘤界浓厚的兴趣.2006年7月全面上市的重组人血管内皮抑制素(endostar,恩度)将可能成为肿瘤靶向治疗的新一轮热点.现将我科一例恩度联合GC方案化疗治疗肺癌的病例报告如下.     

节拍疗法治疗晚期原发性肝癌1例

节拍化疗（metronomic chemotherapy）是指采用小剂量化疗药物，即相当于常规剂量的1／10～1／3，较频繁地给药的化学治疗方法，其抗瘤原理是抗肿瘤血管生成。为达到最有效的抑制肿瘤生长目的，节拍化疗还可以与其它方法联合应用，如与分子靶向药物联用，被称为节拍疗法（metronomic therapy）。我们采用节拍疗法治疗1例晚期肝癌患者，现报告如下。     

以抗血管生成为基础的节律化疗研究进展

除增殖的肿瘤细胞和其它多种正常细胞外,传统细胞毒性化疗药物也影响肿瘤血管内皮细胞的生长。当给予节律化疗,即频繁或持续给予低剂量化疗药物且不伴较长间歇期时,化疗的抗血管生成作用最强,尤其是与特异性抗血管生成药物合用时。现就其抗血管生成作用及其机制、联合用药及临床试验现状作一综述。     

以抗血管生成为基础的节律化疗研究进展

除增殖的肿瘤细胞和其它多种正常细胞外,传统细胞毒性化疗药物也影响肿瘤血管内皮细胞的生长。当给予节律化疗,即频繁或持续给予低剂量化疗药物且不伴较长间歇期时,化疗的抗血管生成作用最强,尤其是与特异性抗血管生成药物合用时。现就其抗血管生成作用及其机制、联合用药及临床试验现状作一综述。     

重组人血管内皮抑制素治疗恶性肿瘤的研究进展

重组人血管内皮抑制素(恩度)是一种广谱的抗血管生成分子靶向药物,主要循证证据为联合化疗治疗晚期非小细胞肺癌(NSCLC).近年来,重组人血管内皮抑制素用于治疗多种恶性肿瘤的研究逐渐增多,并取得了较好的疗效.此外,有关重组人血管内皮抑制素联合治疗手段、给药途径、给药方法的研究逐渐开展,有利于其合理应用.     

节拍化疗在乳腺癌治疗中的应用

节拍化疗是近年来兴起的一种全新的化疗模式,是利用低剂量、多次不间断给药的方式,通过持续抑制肿瘤新生血管生成,达到缩小肿瘤体积、控制肿瘤生长、减少相关药物的不良反应、提高相关疗效、减少相关药物耐药性的作用.目前,在转移性乳腺癌患者的临床治疗中已经取得了肯定的治疗效果.随着治疗模式的改变、概念的不断更新以及越来越多的相关治疗机制被发现,目前节拍式治疗已经不仅是节拍化疗,而是贯穿化疗、放疗、内分泌治疗及相关辅助治疗的治疗模式.本文就节拍化疗在乳腺癌治疗中的应用作一综述.     

Metronomic doxifluridine chemotherapy combined with the anti-angiogenic agent TNP-470 inhibits the growth of human uterine carcinosarcoma xenografts

Uterine carcinosarcoma is a highly aggressive gynecological neoplasm that responds poorly to conventional chemotherapy and radiotherapy. Metronomic chemotherapy is accepted as a new approach for cancer treatment, and its underlying mechanism seems to involve the suppression of angiogenesis. However, the efficacy of metronomic and anti-angiogenic therapies against uterine carcinosarcoma is unknown. The anti-angiogenic effect of doxifluridine was assessed in vitro using human umbilical vein endothelial cells (HUVEC) co-cultured with FU-MMT-1 human uterine carcinosarcoma cells. The antitumor and anti-angiogenic effects of metronomic doxifluridine (delivered via oral gavage) in combination with TNP-470 were evaluated in vivo. Tumor vascularity was assessed by contrast-enhanced color Doppler ultrasound, laser Doppler and microvessel density staining. Doxifluridine suppressed tube formation of HUVEC and vascular endothelial growth factor production by FU-MMT-1 cells. Metronomic doxifluridine alone significantly suppressed tumor growth compared with the untreated (control) group, while metronomic doxifluridine in combination with TNP-470 significantly inhibited tumor growth compared with each treatment alone. A significant reduction of intratumoral vascularity was observed in FU-MMT-1 xenografts following treatment with metronomic doxifluridine in combination with TNP-470, as compared with each treatment alone. Intestinal bleeding was only observed when the maximum tolerated dose of doxifluridine was administered in combination with TNP-470. Metronomic doxifluridine chemotherapy in combination with TNP-470 might be effective for uterine carcinosarcoma without marked toxicity, possibly acting via its potent anti-angiogenic effects. Clinical studies are needed to evaluate the safety and efficacy of this treatment in humans.     

Metronomic therapy for breast cancer

Conventional cytotoxic chemotherapeutic drugs treat cancer either by direct killing or by inhibition of growth of cycling tumor cells. In addition, evidence suggests that cytotoxic agents may inhibit tumor growth through an antiangiogenic mechanism. "Metronomic" or frequent continuous administration of the same chemotherapeutic agents at lower doses may optimize their antiangiogenic properties. The effectiveness of metronomic chemotherapy regimens can be improved significantly by concurrent administration of antiangiogenic, endothelial-specific drugs. Preclinical studies have shown that integrating chemotherapy with antiangiogenic drugs can improve efficacy and circumvent the toxicity and drug resistance associated with standard or high-dose chemotherapy. Preliminary clinical studies have shown similar results. Further confirmation of this concept is required with randomized, controlled clinical trials.     

Metronomic therapy for breast cancer

Conventional cytotoxic chemotherapeutic drugs treat cancer either by direct killing or by inhibition of growth of cycling tumor cells. In addition, evidence suggests that cytotoxic agents may inhibit tumor growth through an antiangiogenic mechanism. "Metronomic" or frequent continuous administration of the same chemotherapeutic agents at lower doses may optimize their antiangiogenic properties. The effectiveness of metronomic chemotherapy regimens can be improved significantly by concurrent administration of antiangiogenic, endothelial-specific drugs. Preclinical studies have shown that integrating chemotherapy with antiangiogenic drugs can improve efficacy and circumvent the toxicity and drug resistance associated with standard or high-dose chemotherapy. Preliminary clinical studies have shown similar results. Further confirmation of this concept is required with randomized, controlled clinical trials.     

Breast cancer: Muscarinic receptors as new targets for tumor therapy

The development of breast cancer is a complex process that involves the participation of different factors. Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors (mAChRs) in different tumor tissues and their role in the modulation of tumor biology, positioning them as therapeutic targets in cancer. The conventional treatment for breast cancer involves surgery, radiotherapy, and/or chemotherapy. The latter presents disadvantages such as limited specificity, the appearance of resistance to treatment and other side effects. To prevent these side effects, several schedules of drug administration, like metronomic therapy, have been developed. Metronomic therapy is a type of chemotherapy in which one or more drugs are administered at low concentrations repetitively. Recently, two chemotherapeutic agents usually used to treat breast cancer have been considered able to activate mAChRs. The combination of low concentrations of these chemotherapeutic agents with muscarinic agonists could be a useful option to be applied in breast cancer treatment, since this combination not only reduces tumor cell survival without affecting normal cells, but also decreases pathological neo-angiogenesis, the expression of drug extrusion proteins and the cancer stem cell fraction. In this review, we focus on the previous evidences that have positioned mAChRs as relevant therapeutic targets in breast cancer and analyze the effects of administering muscarinic agonists in combination with conventional chemotherapeutic agents in a metronomic schedule.     

Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer

Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic taxanes alone and in combination with AEE788-a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor-in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested in vivo using both chemotherapy-sensitive (HeyA8 and SKOV3ip1) and chemotherapy-resistant (HeyA8-MDR) models. Treated tumors were stained for microvessel density (CD31), proliferation index (proliferating cell nuclear antigen), and apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling). The cytotoxic effects of MTD and metronomic dosing were tested with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of metronomic regimens on circulating endothelial precursors (CEP) and tumor-specific cell-free DNA levels were assessed. In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials.     

Metronomic chemotherapy for patients with metastatic breast cancer: Review of effectiveness and potential use during pandemics

Metronomic chemotherapy (M-CT) is defined as dose dense administration of chemotherapy at lower doses than maximum tolerated dose but at shorter free intervals, to obtain a near continuous exposure of cancer cells to those potentially effective drugs. M-CT is a useful strategy to obtain response, overcome resistance and reduce side effects, with low costs. This review will focus on the use of M-CT in advanced breast cancer (ABC). Cytostatic and cytotoxic effect on cancer cells, the anti-angiogenic and the immunomodulatory effects are its main mechanisms of actions. Many clinical trials proved the efficacy and tolerability of different monotherapies and combinations of chemotherapeutic agents administered in metronomic doses and frequencies in ABC. M-CT is a reasonable option for second and later lines of chemotherapy in metastatic breast cancer including those with prior anthracycline or taxane exposure, older patients and patients with comorbidities, and even as first-line in certain groups of patients. The acceptable efficacy and low toxicity of oral metronomic chemotherapy makes it a reasonable option during COVID-19 pandemic as well as in the post-COVID era which is projected to last for some time.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.