Estrogen Receptors as Molecular Targets of Endocrine Therapy for Glioblastoma

Hormonal factors may participate in the development and progression of glioblastoma, the most aggressive primary tumor of the central nervous system. Many studies have been conducted on the possible involvement of estrogen receptors (ERs) in gliomas. Since there is a tendency for a reduced expression of ERs as the degree of malignancy of such tumors increases, it is important to understand the role of these receptors in the progression and treatment of this disease. ERs belong to the family of nuclear receptors, although they can also be in the plasmatic membrane, cytoplasm and mitochondria. They are classified as estrogen receptors alpha and beta (ER⍺ and ERβ), each with different isoforms that have a distinct function in the organism. ERs regulate multiple physiological and pathological processes through the activation of genomic and nongenomic pathways in the cell. Nevertheless, the role of each isoform in the development and progression of glioblastoma is not completely clear. Diverse in vitro and in vivo studies have shown encouraging results for endocrine therapy as a treatment for gliomas. At the same time, many questions have arisen concerning the nature of ERs as well as the mechanism of action of the proposed drugs. Hence, the aim of the current review is to describe the drugs that could possibly be utilized in endocrine therapy for the treatment of high-grade gliomas, analyze their interaction with ERs, and explore the involvement of these drugs and receptors in resistance to standard chemotherapy.     

Emerging Glycation-Based Therapeutics—Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.     

Tumor-Activated Prodrug with Synergistic Anti-Stemness Chemical and Photodynamic Therapies

Photodynamic therapy (PDT) has received extensive attention as a promising cancer treatment approach. Still, challenges to in vivo photodynamic therapy have existed for decades. First, the “always on” nature of conventional photosensitizers will cause damage to normal tissues thereby limiting the treatment efficiency of PDT. Second, the hypoxic TME protects cancer stem cells (CSCs) deeply harbored in the center of tumors from PDT administration, thus contributing to the recrudescence and metastasis of tumors. Herein, a ROS-triggered self-immolative therapeutic prodrug ( Mu-PS ) is reported, comprising of an activatable photosensitizer, an indomethacin (IMC) part, and a ROS-responsive trigger, for the anti-stemness chemical and photodynamic therapy of tumors. Intriguingly, Mu-PS can target the tumor and selectively release the photosensitizer and IMC upon the activation of TME-related ROS, generating massive phototoxic ¹O₂ to kill most non-CSCs tumor cells under the action of PDT and block the growth of CSCs by IMC, hence, it multiplies the therapeutic index. Noteworthy, the anti-stemness mechanism of IMC in tumors is confirmed and elucidated for the first time. Overall, this study introduces a self-immolatative prodrug for combined CSCs-involved chemical therapy and activatable PDT for tumors and provides a design paradigm of prodrug for the precise prognosis and treatment of tumors.     

Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis,Diagnosis and Therapy

Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented.     

国产重组人粒细胞集落刺激因子在妇科恶性肿瘤化疗中的应用

目的: 探讨不同剂量国产重组人粒细胞集落刺激因子（rhG-CSF)在妇科恶性肿瘤化疗中的疗效,并与进口 rhG-CSF比较。方法: 98例卵巢癌、宫体癌和宫颈癌患者随机分成3组,分别按75 μg·d^-1和150 μg·d^-1剂量皮下注射国产rhG-CSF和进口75 μg·d^-1 rhG-CSF,直到白细胞或中性粒细胞绝对数升至正常水平以上。结果: 不同剂量国产或进口rhG-CSF均能使3组患者血WBC和ANC水平在用药d4后升至正常水平以上;在初次化疗时,用不同剂量（75 μg 和 150 μg）国产和进口（75 μg) rhG-CSF升WBC至正常水平的天数无显著差异（P>0.05),但重复化疗期间150μg国产rhG-CSF升白细胞的疗效显著优于75μg国产或进口 rhG-CSF;同等剂量国产AG-CSF与进口 rhG-CSF升WBC效果一致。结论: 75μg小剂量国产rhG-CSF在妇科恶性肿瘤初期化疗中升WBC的疗效肯定,重复化疗时较大剂量(150μg）rhG-CSF升WBC的效果优于小剂量rhG-CSF。同等剂量国产rhG-CSF与进口 rhG-CSF的疗效无明显差异。     

5-氟尿嘧啶、表阿霉素、丝裂霉素单用及合用时对胰腺癌细胞Aspc-1 和Bxpc-3 的抑制作用

目的 观察5-氟尿嘧啶(5-FU)、表阿霉素(EADM)和丝裂霉素(MMC) 体外对胰腺癌细胞(Aspc-1及Bxpc-3) 的作用和药物联合应用时的相互作用。 方法 采用MTT 测定法观察5-FU、E-ADM 和MMC 单用及合用时对细胞的抑制作用, 并应用中效原理判定药物合用的效果。 结果 单用或者合用时随着药物浓度的增加其对细胞的抑制作用也增加, 5-FU 和MMC 合用于Aspc-1 细胞株, 当效应为0.84 时CI 为1, 大剂量时(效应大于0.84) 是协同作用(CI <1), 小剂量时(效应小于0.84) 是拮抗作用(CI >1)。MMC和E-ADM 合用时表现为轻度的拮抗作用。5-FU 和MMC、MMC 和E-ADM 合用于Bxpc-3, 当效应分别为0.49、0.62 时CI 为1, 大于此效应表现为轻度拮抗(C >1), 小于此效应则相反。5-FU 和E-ADM 合用对两株细胞量效曲线图的形态相似表现为轻度的拮抗作用, 随着效应的增加拮抗作用略有下降。 结论 药物的相互作用与药物浓度有关, 药物及细胞株的不同其量效曲线存在较大差异。通过动脉灌注或保留导管持续灌注以提高化疗药物局部浓度能够改善胰腺癌的化疗效果。     

雾化吸入疗法治疗呼吸道肿瘤

雾化吸入化疗、免疫治疗是近几年开展的呼吸道肿瘤治疗新技术。具有操作简便、局部治疗有效率高、副作用小等特点, 采用的药物有氟尿嘧啶、顺铂、紫杉醇、喜树碱、白细胞介素Ⅱ及粒细胞巨噬细胞集落刺激因子等, 对原发性肺癌和其它肿瘤肺及纵隔转移均有较好疗效。     

An evolutionary approach to cancer chemotherapy scheduling

In this paper, we investigate the employment of evolutionary algorithms as a search mechanism in a decision support system for designing chemotherapy schedules. Chemotherapy involves using powerful anti-cancer drugs to help eliminate cancerous cells and cure the condition. It is given in cycles of treatment alternating with rest periods to allow the body to recover from toxic side-effects. The number and duration of these cycles would depend on many factors, and the oncologist would schedule a treatment for each patient’s condition. The design of a chemotherapy schedule can be formulated as an optimal control problem; using an underlying mathematical model of tumour growth (that considers interactions with the immune system and multiple applications of a cycle-phase-specific drug), the objective is to find effective drug schedules that help eradicate the tumour while maintaining the patient health’s above an acceptable level. A detailed study on the effects of different objective functions, in the quality and diversity of the solutions, was performed. A term that keeps at a minimum the tumour levels throughout the course of treatment was found to produce more regular treatments, at the expense of imposing a higher strain on the patient’s health, and reducing the diversity of the solutions. Moreover, when the number of cycles was incorporated in the problem encoding, and a parsimony pressure added to the objective function, shorter treatments were obtained than those initially found by trial and error.

A reconstituted thermosensitive hydrogel system based on paclitaxel-loaded amphiphilic copolymer nanoparticles and antitumor efficacy

Combination delivery systems composed of injectable hydrogels and drug-incorporated nanoparticles are urgently in regional cancer chemotherapy to facilitate efficient delivery of chemotherapeutic agents, enhance antitumor efficiency, and decrease side effects. Here, we developed a novel thermosensitive amphiphilic triblock copolymer consisting of methoxy poly(ethylene glycol), poly(octadecanedioic anhydride), and d,l-lactic acid oligomer (PEOALA), built a combination system of thermosensitive injectable hydrogel PTX/PEOALA^Gel based on paclitaxel (PTX)-loaded PEOALA nanoparticles (NPs). PTX/PEOALA^Gel could be stored as freeze-dried powders of paclitaxel-loaded PEOALA NPs, which could be easily redispersed into the water at ambient temperature, and form a hydrogel at the injected site in vivo. The in vitro cytotoxicity of PTX/PEOALA^Gel showed no obvious cytotoxicity in comparison with Taxol® against MCF-7 and HeLa cells. However, the in vivo antitumor activity showed that a single intratumoral injection of the PTX/PEOALA^Gel formulation was more effective than four intravenous (i.v.) injections of Taxol^® at a total dosage of 20?mg/kg in inhibiting the growth of MCF-7 tumor-bearing Balb/c mice, and the inhibition could be sustained for more than 17 d. The pharmacokinetic study demonstrated that the intratumoral injection of PTX/PEOALA^Gel could greatly decrease the systemic exposure of PTX, as confirmed by the rather low plasma concentration, and prolonged circulation time and enhanced tumor PTX accumulation, implying fewer off-target side effects. In summary, the PTX/PEOALA^Gel combination local delivery system could enhance tumor inhibition effect and tumor accumulation of PTX, and lower the systemic exposure. So, the reconstituted PTX/PEOALA^Gel system could potentially be a useful vehicle for regional cancer chemotherapy.     

Near‐Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH‐/H2O2‐Responsive O2‐Evolving Synergetic Cancer Therapy

Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen‐dependent photodynamic therapy (PDT), but also antitumor drug‐based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen‐dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)‐mediated cytotoxicity of the drug toward normal tissues. Herein, a synergetic one‐for‐all mesoporous cerium oxide upconversion biophotocatalyst is developed to achieve intratumorally endogenous H₂O₂‐responsive self‐sufficiency of O₂ and near‐infrared light controlled PDT simultaneously for overcoming hypoxia cancer. Furthermore, the sufficient O₂ plays an important role in overcoming the chemotherapeutic drug‐resistant cancer caused by hypoxia, therefore inducing tumor cell apoptosis significantly.