Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment

Targeting glutamine catabolism has been attracting more research attention on the development of successful cancer therapy. Catalytic enzymes such as glutaminase (GLS) in glutaminolysis, a series of biochemical reactions by which glutamine is converted to glutamate and then alpha-ketoglutarate, an intermediate of the tricarboxylic acid (TCA) cycle, can be targeted by small molecule inhibitors, some of which are undergoing early phase clinical trials and exhibiting promising safety profiles. However, resistance to glutaminolysis targeting treatments has been observed, necessitating the development of treatments to combat this resistance. One option is to use synergy drug combinations, which improve tumor chemotherapy’s effectiveness and diminish drug resistance and side effects. This review will focus on studies involving the glutaminolysis pathway and diverse combination therapies with therapeutic implications.     

Clinical applications of dendritic cell vaccination in the treatment of cancer

Dendritic cell (DC) immunotherapy has shown significant promise in animal studies as a potential treatment for cancer. Its application in the clinic depends on the results of human trials. Here, we review the published clinical trials of cancer immunotherapy using exogenously antigen-exposed DCs. We begin with a short review of general properties and considerations in the design of such vaccines. We then review trials by disease type. Despite great efforts on the part of individual investigative groups, most trials to date have not yielded data from which firm conclusions can be drawn. The reasons for this include nonstandard DC preparation and vaccination protocols, use of different antigen preparations, variable means of immune assessment, and nonrigorous criteria for defining clinical response. While extensive animal studies have been conducted using DCs, optimal parameters in humans remain to be established. Unanswered questions include optimal cell dose, use of mature versus immature DCs for vaccination, optimal antigen preparation, optimal route, and optimal means of assessing immune response. It is critical that these questions be answered, as DC therapy is labor- and resource-intensive. Cooperation is needed on the part of the many investigators in the field to address these issues. If such cooperation is not forthcoming, the critical studies that will be required to make DC therapy a clinically and commercially viable enterprise will not take place, and this therapy, so promising in preclinical studies, will not be able to compete with the many other new approaches to cancer therapy presently in development. Trials published in print through June 2003 are included. We exclude single case reports, except where relevant, and trials with so many variables as to prevent interpretation about DC therapy effects.     

贝伐单抗二线治疗转移性结直肠癌的临床观察

目的:观察贝伐单抗二线治疗转移性结直肠癌患者的临床疗效和毒副反应。方法:回顾性分析2008年8月至2011年10月我院经组织病理学证实的转移性结直肠癌患者21例,一线治疗进展后,二线治疗方案中加用贝伐单抗,用法为5mg/kg,每2-3周1次,与化疗方案同步。化疗方案以奥沙利铂及伊立替康为基础,完成2-3周期治疗后评定疗效,观察毒副反应。结果:21例患者中PR1例,SD11例,PD9例,客观缓解率为4.8%,疾病控制率为57.1%,中位TTP为3.7个月。患者出现的不良反应有骨髓抑制、皮疹、恶心呕吐、腹泻、肝功能损害、神经毒性等,贝伐单抗所致高血压的发生率为14.3%(3/21),鼻衄发生率为4%(2/21)。结论:二线治疗中使用贝伐单抗,对一线治疗进展后的转移性结直肠癌疗效有限,毒副反应可耐受。     

联合疗法对慢性乙型肝炎患者红细胞免疫功能的影响

目的观察拉米夫定与氧化苦参碱单用及联合治疗对慢性乙型肝炎(CHB)患者红细胞免疫功能的影响.方法 77例CHB患者随机分成拉米夫定组、氧化苦参碱组和两者联合治疗组,分别对其红细胞膜CD35、CD44s分子定量、红细胞天然免疫粘附功能(CR1分子粘附活性)、红细胞CR1分子密度相关基因型进行测定.结果各组CHB患者红细胞粘附肿瘤细胞能力治疗后较治疗前明显上升(P＜0.05);3组药物对CHB患者红细胞CR1和CD44s分子数量有明显提高作用(P＜0.01),联合组最显著;77例CHB患者治疗前后CR1分子密度相关基因多态性表达型别比率无变化,但CR1分子数量发生明显变化(P＜0.05).结论联合疗法可明显提高CHB患者红细胞免疫功能.     

卵巢癌干细胞对化疗药物耐药的机制探讨

目的:探讨卵巢癌干细胞(OCSC)对化疗药物的抵抗及其机制。方法:采用有限稀释法、单细胞克隆和无血清培养方法从卵巢癌细胞株OVCAR-3细胞中分离培养OCSC。以卡铂和紫杉醇作用于OCSC和亲代OVCAR-3细胞,采用MTT法检测细胞存活率、Annexin V-FITC/PI双染流式细胞术检测细胞凋亡、JC-1染色流式细胞术检测细胞线粒体膜电位(△ψm),比色测定试剂盒检测caspase-3和caspase-8活性。结果:有限稀释法、单细胞克隆和无血清培养能从OVCAR-3细胞中分离培养OCSC。与亲代OVCAR-3细胞比较,卡铂和紫杉醇作用的OCSC的存活率增加、凋亡率下降、△ψm增加、caspase-3和caspase-8活性下降。结论:OCSC通过抑制化疗药物介导的凋亡内源性和外源性通路对化疗药物产生耐药性。     

On optimal delivery of combination therapy for tumors

A mathematical model for the scheduling of angiogenic inhibitors in combination with a chemotherapeutic agent is formulated. Conditions are given that allow tumor eradication under constant infusion therapies. Then the optimal scheduling of a vessel disruptive agent in combination with a cytotoxic drug is considered as an optimal control problem. Both theoretical and numerical results on the structure of optimal controls are presented.     

吡喃阿霉素联合化疗癌症的有效性与安全性

目的：探讨以吡喃阿霉素（THP）为主的联合化疗方案治疗恶性肿瘤的疗效与安全性。方法：以THP与其他2～3种抗癌药物联合治疗84例各类恶性肿。统计近期疗效,观察THP所致的心脏毒性发生率和其他并发症。结果：完全缓解14例,部分缓解30例、稳定36例,无效5例,总有效率52.38%。67例出现各类不良反应126例次,但程度均较轻。结论：以THP为主的联合化疗方案治疗恶性肿瘤疗效明显,毒性反应程度较轻。     

西妥昔单抗联合FOLFIRI 与单用FOLFIRI 方案治疗转移性结直肠癌近 期疗效的对照研究

目的:比较西妥昔单抗(爱必妥)联合FOLFIRI化疗方案与单用FOLFIRI化疗方案治疗转移性结直肠癌患者的临床疗效和毒副反应。方法:回顾性分析2008年1月至2011年11月解放军总医院经组织病理学证实的46例转移性结直肠癌患者临床资料,其中西妥昔单抗联合FOLFIRI化疗方案组22例,单用FOLFIRI方案组24例,观察比较两组方案的近期疗效和不良反应。结果:两组方案治疗转移性结直肠癌的客观缓解率(CR+PR)分别为41.6%和12.5%,其中联合治疗方案治疗效果明显优于单用FOLFIRI化疗方案,两组比较差异有统计学意义(P<0.05)。患者出现的不良反应有痤疮样皮疹、腹泻、骨髓抑制、恶心呕吐、脱发等。除痤疮样皮疹和腹泻外,两组患者毒副反应无显著性差异。结论:西妥昔单抗联合FOLFIRI化疗方案治疗K-Ras基因野生型转移性结直肠癌近期疗效显著,毒副反应较单用FOLFIRI方案无明显增加,患者可以耐受。     

The role of the mitochondria in mediating cytotoxicity of anti-cancer therapies

Optimal cytotoxic anticancer therapy, at the cellular level, requires effective and selective induction of cell death to achieve a net reduction of biomass of malignant tissues. Standard cytotoxic chemotherapeutics have been developed based on the observations that mitotically active cancer cells are more susceptible than quiescent normal cells to chromosomal, microtubular or metabolic poisons. More recent development of molecularly targeted drugs for cancer focuses on exploiting biological differentials between normal and transformed cells for selective eradication of cancers. The common thread of “standard” and “novel” cytotoxic drugs is their ability to activate the apoptosis-inducing machinery mediated by mitochondria, also known as the intrinsic death signaling cascade. The aim of this article is to provide an overview of the role of the mitochondria, an energy-generating organelle essential for life, in mediating death when properly activated by cytotoxic stresses.     

Fungal infections following treatment with monoclonal antibodies and other immunomodulatory therapies

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in a wide range of important physiologic processes and has a pathologic role in some diseases. TNF antagonists (infliximab, adalimumab, etanercept) are effective in treating inflammatory conditions. Antilymphocyte biological agents (rituximab, alemtuzumab), integrin antagonists (natalizumab, etrolizumab and vedolizumab), interleukin (IL)-17A blockers (secukinumab, ixekizumab) and IL-2 antagonists (daclizumab, basiliximab) are widely used after transplantation and for gastroenterological, rheumatological, dermatological, neurological and hematological disorders. Given the putative role of these host defense elements against bacterial, viral and fungal agents, the risk of infection during a treatment with these antagonists is a concern. Fungal infections, both opportunistic and endemic, have been associated with these biological therapies, but the causative relationship is unclear, especially among patients with poor control of their underlying disease or who are undergoing steroid therapy. Potential recipients of these drugs should be screened for latent endemic fungal infections. Cotrimoxazole prophylaxis could be useful for preventing Pneumocystis jirovecii infection in patients over 65 years of age who are taking TNF antagonists, antilymphocyte biological agents or who have lymphopenia and are undergoing concomitant steroid therapy. As with other immunosuppressant drugs, TNF antagonists and antilymphocyte antibodies should be discontinued for patients with active infectious disease.     

Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer

Successful treatment of cancer patients with a combination of monoclonal antibodies (mAb) and chemotherapeutic drugs has spawned various other forms of additional combination therapies, including vaccines or adoptive lymphocyte transfer combined with chemotherapeutics. These therapies were effective against established tumors in animal models and showed promising results in initial clinical trials in cancer patients, awaiting testing in larger randomized controlled studies. Although combination between immunotherapy and chemotherapy has long been viewed as incompatible as chemotherapy, especially in high doses meant to increase anti-tumor efficacy, has induced immunosuppression, various mechanisms may explain the reported synergistic effects of the two types of therapies. Thus direct effects of chemotherapy on tumor or host environment, such as induction of tumor cell death, elimination of regulatory T cells, and/or enhancement of tumor cell sensitivity to lysis by CTL may account for enhancement of immunotherapy by chemotherapy. Furthermore, induction of lymphopenia by chemotherapy has increased the efficacy of adoptive lymphocyte transfer in cancer patients. On the other hand, immunotherapy may directly modulate the tumor’s sensitivity to chemotherapy. Thus, anti-tumor mAb can increase the sensitivity of tumor cells to chemotherapeutic drugs and patients treated first with immunotherapy followed by chemotherapy showed higher clinical response rates than patients that had received chemotherapy alone. In conclusion, combination of active specific immunotherapy or adoptive mAb or lymphocyte immunotherapy with chemotherapy has great potential for the treatment of cancer patients which needs to be confirmed in larger controlled and randomized Phase III trials.     

Trade-off between BCG vaccination and the ability to detect and treat latent tuberculosis

Policies regarding the use of the Bacille Calmette-Guérin (BCG) vaccine for tuberculosis vary greatly throughout the international community. In several countries, consideration of discontinuing universal vaccination programs is currently under way. The arguments against mass vaccination are that the effectiveness of BCG in preventing tuberculosis is uncertain and that BCG vaccination can interfere with the detection and treatment of latent tuberculosis.In this work, we pose a dynamical systems model for the population-level dynamics of tuberculosis in order to study the trade-off which occurs between vaccination and detection/treatment of latent tuberculosis. We assume that latent infection in vaccinated individuals is completely undetectable. For the case of a country with very low levels of tuberculosis, we establish analytic thresholds, via stability analysis and the basic reproductive number, which determine the optimal vaccination policy, given the effectiveness of the vaccine and the detection/treatment rate of latent tuberculosis.The results of this work suggest that it is unlikely that a country detects and treats latent tuberculosis at a high enough rate to justify the discontinuation of mass vaccination from this perspective.     

Intratumoral delivery of vector mediated IL-2 in combination with vaccine results in enhanced T cell avidity and anti-tumor activity

Systemic IL-2 is currently employed in the therapy of several tumor types, but at the price of often severe toxicities. Local vector mediated delivery of IL-2 at the tumor site may enhance local effector cell activity while reducing toxicity. To examine this, a model using CEA-transgenic mice bearing established CEA expressing tumors was employed. The vaccine regimen was a s.c. prime vaccination with recombinant vaccinia (rV) expressing transgenes for CEA and a triad of costimulatory molecules (TRICOM) followed by i.t. boosting with rF-CEA/TRICOM. The addition of intratumoral (i.t.) delivery of IL-2 via a recombinant fowlpox (rF) IL-2 vector greatly enhanced anti-tumor activity of a recombinant vaccine, resulting in complete tumor regression in 70–80% of mice. The anti-tumor activity was shown to be dependent on CD8⁺ cells and NK1.1⁺. Cellular immune assays revealed that the addition of rF-IL-2 to the vaccination therapy enhanced CEA-specific tetramer⁺ cell numbers, cytokine release and CTL lysis of CEA⁺ targets. Moreover, tumor-bearing mice vaccinated with the CEA/TRICOM displayed an antigen cascade, i.e., CD8⁺ T cell responses to two other antigens expressed on the tumor and not the vaccine: wild-type p53 and endogenous retroviral antigen gp70. Mice receiving rF-IL-2 during vaccination demonstrated higher avidity CEA-specific, as well as higher avidity gp70-specific, CD8⁺ T cells when compared with mice vaccinated without rF-IL-2. These studies demonstrate for the first time that the level and avidity of antigen specific CTL, as well as the therapeutic outcome can be improved with the use of i.t. rF-IL-2 with vaccine regimens.     

TP方案化疗对恶性肿瘤患者血糖代谢的影响

目的探讨紫杉醇（Taxol）联合顺铂（Cisplatin）组成的TP方案化疗对恶性肿瘤患者血糖代谢的影响。方法取TP方案化疗的恶性肿瘤患者76例,回顾性分析其化疗前后的血糖变化情况及相关临床资料。结果76例患者中,化疗后空腹血糖升高者占18．4％（14／76）,其中糖耐量减低4例,占5．3％（4／76）;诊断为糖尿病者4例,占5．3％（4／76）;一过性血糖增高6例,占7．9％（6／76）。各患者化疗前后血糖值的差异有显著性（P〈0．05）。化疗诱发的血糖异常多发生在化疗的第2、3个周期。不同肿瘤患者化疗后血糖异常升高发生率差异无显著性（P〉0．05）。结论恶性肿瘤患者接受TP方案化疗后可引起血糖增高,甚至发生糖耐量减低或2型糖尿病,化疗期间应密切监测血糖变化。     

Effects of education, vaccination and treatment on HIV transmission in homosexuals with genetic heterogeneity

Genetic studies report the existence of a mutant allele Delta32 of CCR5 chemokine receptor gene at high allele frequencies (approximately 10%) in Caucasian populations. The presence of this allele is believed to provide partial or full resistance to HIV. In this study, we look at the impact of education, temporarily effective vaccines and therapies on the dynamics of HIV in homosexually active populations. In our model, it is assumed that some individuals possess one or two mutant alleles (like Delta32 of CCR5) that prevent the successful invasion or replication of HIV. Our model therefore differentiates by genetic and epidemiological status and naturally ignores the reproduction process. Furthermore, HIV infected individuals are classified as rapid, normal or slow progressors. In this complex setting, the basic reproductive number R0 is derived in various situations. The separate or combined effects of therapies, education, vaccines, and genetic resistance are analyzed. Our results support the conclusions of Hsu Schmitz that some integrated intervention strategies are far superior to those based on a single approach. However, treatment programs may have effects which counteract each other, as may genetic resistance.     

心理治疗对支气管肺癌患者化疗依从性的影响

目的:探讨心理治疗对支气管肺癌患者化疗依从性的影响。方法:本院收治的支气管肺癌患者80例,随机分为对照组和观察组。对照组进行化疗的支气管肺癌患者采用常规专业护理措施。观察组:在对照组常规专业护理措施的同时,患者行心理治疗措施。结果:观察组满意度高于对照组;观察组的依从性优于对照组。结论:心理治疗不但可以提高支气管肺癌患者在化疗期间的满意度;而且可以提高支气管肺癌患者对化疗的依从性。     

微生态制剂治疗肝源性肠道菌群失调与保肝作用

目的:观察采用常规保肝治疗及或加服乐托尔或加服培菲康来治疗慢性肝病疗效.方法:慢迁肝41例及慢活肝37例,各随机分成三组:A组:常规治疗 乐托尔胶囊,2粒/次,2次/d;B组:常规治疗 培菲康胶囊,3粒/次,3次/d;C组:常规治疗:益肝灵 Vit.C Vit.B Co,各2片/次,3次/d,三组疗程均为2个月.结果:75例完成治疗及复查,失访3例.腹胀、腹泻、肝区不适消失率及ALT、内毒素试验复常率二项三组相比有显著意义(P<0.01).乏力、SB复常率在慢活肝中三组相比有显著意义(P<0.01).总有效率:慢迁肝三组分别为83.3%、69.2%、35.7%;慢活肝三组分别为:63.7%、61.5%、33.3%,三组相比有显著意义(P<0.01).结论:常规保肝治疗加服微生态制剂,不论是死菌及其代谢产物或活菌制剂均有肯定的价值,但死菌制剂具有活菌制剂不具备的优点.     

Chemical conjugation of muramyl dipeptide and paclitaxel to explore the combination of immunotherapy and chemotherapy for cancer

Paclitaxel (Taxol) conjugated to muramyl dipeptide (MDP) is described. Biological testing showed that the conjugation of MDP at 2'-O-paclitaxel (2'- O -MTC-01) not only has antitumor activity, but also have immunoenhancement capacity. Compared with paclitaxel or MDP alone or with a mixture of paclitaxel + MDP, 2'- O -MTC-01 significantly increases the production and expression of TNF-alpha and IL-12 from mouse peritoneal macrophages, which demonstrates a synergism of MDP and paclitaxel in one conjugated molecule.     

Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, are a group of incurable neurological disorders, characterized by the chronic progressive loss of different neuronal subtypes. However, despite its increasing prevalence among the ever-increasing aging population, little progress has been made in the coincident immense efforts towards development of therapeutic agents. Research interest has recently turned towards stem cells including stem cells-derived exosomes, neurotrophic factors, and their combination as potential therapeutic agents in neurodegenerative diseases. In this review, we summarize the progress in therapeutic strategies based on stem cells combined with neurotrophic factors and mesenchymal stem cells-derived exosomes for neurodegenerative diseases, with an emphasis on the combination therapy.