Clinical trials of antioxidants as cancer prevention agents: past, present, and future

The purpose of this review is to summarize the most important human clinical trials of antioxidants as cancer prevention agents conducted to date, provide an overview of currently ongoing studies, and discuss future steps needed to advance research in this field. To date there have been several large (at least 7000 participants) trials testing the efficacy of antioxidant supplements in preventing cancer. The specific agents (diet-derived direct antioxidants and essential components of antioxidant enzymes) tested in those trials included β-carotene, vitamin E, vitamin C, selenium, retinol, zinc, riboflavin, and molybdenum. None of the completed trials produced convincing evidence to justify the use of traditional antioxidant-related vitamins or minerals for cancer prevention. Our search of ongoing trials identified six projects at various stages of completion. Five of those six trials use selenium as the intervention of interest delivered either alone or in combination with other agents. The lack of success to date can be explained by a variety of factors that need to be considered in the next generation research. These factors include lack of good biological rationale for selecting specific agents of interest; limited number of agents tested to date; use of pharmacological, rather than dietary, doses; and insufficient duration of intervention and follow-up. The latter consideration underscores the need for alternative endpoints that are associated with increased risk of neoplasia (i.e., biomarkers of risk), but are detectable prior to tumor occurrence. Although dietary antioxidants are a large and diverse group of compounds, only a small proportion of candidate agents have been tested. In summary, the strategy of focusing on large high-budget studies using cancer incidence as the endpoint and testing a relatively limited number of antioxidant agents has been largely unsuccessful. This lack of success in previous trials should not preclude us from seeking novel ways of preventing cancer by modulating oxidative balance. On the contrary, the well demonstrated mechanistic link between excessive oxidative stress and carcinogenesis underscores the need for new studies. It appears that future large-scale projects should be preceded by smaller, shorter, less expensive biomarker-based studies that can serve as a link from mechanistic and observational research to human cancer prevention trials. These relatively inexpensive studies would provide human experimental evidence for the likely efficacy, optimum dose, and long-term safety of the intervention of interest that would then guide the design of safe, more definitive large-scale trials.     

Plant-derived epigenetic modulators for cancer treatment and prevention

Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival. Massive deregulation of all components of the epigenetic machinery is a hallmark of cancer. These alterations affect normal gene regulation and impede normal cellular processes including cell cycle, DNA repair, cell growth, differentiation and apoptosis. Since epigenetic alterations appear early in cancer development and represent potentially initiating events during carcinogenesis, they are considered as promising targets for anti-cancer interventions by chemopreventive and chemotherapeutic strategies using epigenetically active agents. In this field, plant-derived compounds have shown promise. Here, we will give an overview of plant-derived compounds displaying anticancer properties that interfere with the epigenetic machinery.     

紫杉醇联合卡培他滨治疗Ⅳ期肺腺癌临床疗效及毒理研究

目的:探究紫杉醇联合卡培他滨方案治疗Ⅳ期肺腺癌的临床疗效及毒理研究。方法:选取我院肿瘤科收治的Ⅳ期肺腺癌患者62例,随机分为两组,其中对照组30例,给予卡培他滨口服常规治疗;实验组32例,在常规治疗的基础上加用紫杉醇治疗。对比两组有效率(RR)、疾病控制率(DCR)、中位进展时间(TTP)、中位生存期(MST)、血细胞分析情况、毒副作用发生率。结果:1实验组DCR高于对照组,差异具有统计学意义(P0.05);2实验组TTP、MST明显优于对照组,结果有统计学意义(P0.05);3两组患者血细胞各项指标无明显差异(P0.05);两组患者脱发、肝损害、恶心呕吐的发生率无明显差异(P0.05)。结论:紫杉醇联合卡培他滨方案可明显改善Ⅳ期肺腺癌患者的临床症状,延长患者的生存期,且毒副作用与单药治疗相比无差异,对临床具有指导意义,值得临床推广。     

他汀类药物对消化系统肿瘤作用的临床研究进展

他汀类药物作为一种降血脂药物在临床上大量应用,其药物种类多,并具有多效性。近年来许多体外及动物研究证明他汀类药物对肿瘤细胞具有抑制增殖、促进凋亡、增强放化疗效果的作用。随着体外及动物研究的不断深入,越来越多的临床研究相继展开,通过这些研究发现他汀类药物在人体中也可能具有阻断肿瘤的发生发展、辅助肿瘤放化疗的功效。本文对他汀类药物的作用机制及他汀类药物对不同消化系统肿瘤种类防治作用的临床研究进展进行综述。     

A deterministic approach to survival statistics

Survival functions of the form p(t) = exp[–(t)], > 0 can be generated by deterministic nonlinear, asymptotically stable (chaotic) dynamical systems. These systems thus provide an alternative to stochastic interpretations of failure time data. We use this approach to analyze cancer patient survival statistics. In this manner we are able to obtain fresh insights into the implications of negative and positive clinical trials.     

奥利沙铂、多西紫杉醇化疗方案联合同步三维适形放疗治疗晚期非小细胞癌的近期临床疗效观察

目的:观察并探讨奥利沙铂(Oxaliplatin,L-OHP)与多西紫杉醇(Docetaxel,DXL)化疗方案联合同步三维适形放疗(three dimensional conformal radiotherapy,3DCRT)治疗晚期局限性非小细胞肺癌(non-small cell lung cancer,NSCLC)的近期临床效果并安全性。方法:将2010年1月-2012年2月间入选的94例局限性NSCLC患者随机单盲分为观察组(48例)与对照组(46例),观察组给予L-OHP、DXL化疗方案并联合同步3DCRT治疗方案,对照组予3DCRT治疗方案,对比两组治疗后临床疗效、生命质量改善情况及治疗期间毒副反应。结果:①两组患者疗效构成不同,观察组完全缓解率(12.5%)与总有效率(81.3%)均高于对照组(6.5%、58.7%),且后者差异具有统计学意义(X2=5.713,P=0.017);②观察组、对照组治疗后生活质量改善比例分别为56.6%、33.3%,两组生活质量具有显著性差异(Z=-2.101,P=0.036);③治疗期间观察组、对照组分别死亡2例(4.2%)、1例(2.2%),观察组骨髓抑制、胃肠道反应、末梢神经损害、放射性肺损伤发生率高于对照组(P0.05)。结论:L-OHP与DXL化疗联合同步3DCRT放疗治疗NSCLC可提高后者对原发病灶的近期控制率、改善患者生活质量,但也应注意对联合放化疗期间出现毒副反应的对症处置。     

海洋中药牡蛎肉的现代临床实验研究进展．

牡蛎作为一种广泛分布的海洋药用动物,其软体部分及其提取物在其药理研究、临床应用、药用价值等方面获得了广泛研究。牡蛎肉营养丰富,含有多种不饱和脂肪酸和糖类,尤其是锌的舍量较高。在对鹌鹑、小鼠、兔子等多种实验动物的体内实验及多种肿瘤细胞的体外增殖实验中发现,牡蛎肉较突出的作用为降血糖血脂,抗血栓,抗氧化,免疫增强,抗肿瘤,保肝护肝等。本文对其古籍记载,化学成分和临床实验研究进行了综述,为进一步深入地研究和拓宽其临床应用范围提供了坚实的科学依据。     

Cancer prevention by carotenoids

Various natural carotenoids seem to be valuable for cancer prevention, and these carotenoids may be more suitable in combinational use, rather than in single use. In fact, we have proven that combinational use of natural carotenoids resulted in significant suppression of liver cancer. Patients of viral hepatitis with cirrhosis were administered with β-cryptoxanthin-enriched Mandarin orange juice, in addition to capsules of carotenoids mixture. Cumulative incidence of hepatocellular carcinoma development was compared with that in the group treated with carotenoids mixture capsules alone, or in the group without treatment (control group). In the data analysis at year 2.5, cumulative incidence of liver cancer in β-cryptoxanthin-enriched orange juice with carotenoids mixture capsules-treated group was lower than that in the control group (p = 0.05). Cumulative incidence of liver cancer in the group treated with carotenoids mixture capsules alone was also lower than that in the control group, but not statistically significant.     

Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States

Modern medicine has been relatively slow to apply chronotherapeutic principles to standard oncologic practice. Despite the impressive body of evidence supporting the use of chronochemotherapy, with only a rare exception most oncology clinics in the United States lack the expertise and capability to implement it. At the same time, American medicine has increasingly come to recognize the importance of toxicity mitigation, cytoprotection, and quality of life for patients undergoing cancer treatment. However, toxicity mitigation strategies such as chronomodulated infusional chemotherapy and novel cytoprotective agents are not widely embraced by U.S. physicians. This article explores some reasons why this situation exists, including the influence of non-medical biases that may affect management decisions on the application of chemotherapy. The author conducted a survey of U.S. companies representing the three private insurance payers available (HMO, PPO, Indemnity) as well as representatives of Medicare and Medicaid. Responses to the survey confirmed that U.S. insurers do not at present officially reimburse for chronotherapy; however, changes will come about through educational efforts aimed at increasing awareness among insurers as to the clinical benefits and cost-effectiveness of this mode of treatment. At this juncture, the outlook for cancer chronotherapy as a first-line approach to the treatment of metastatic cancer in the United States remains uncertain. Under the current method of insurance reimbursement, the advancement of chronotherapy in the United States is threatened despite evidence that such treatment is both therapeutically sound and cost-effective.     

Cannabinoids and Gliomas

Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances—the endocannabinoids—that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Δ⁹-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.     

颗粒溶素的研究进展

颗粒溶素具有溶细胞作用和杀菌活性,其作用对象包括肿瘤细胞、细菌、真菌和寄生虫。颗粒溶素是T淋巴细胞、单核细胞和其他炎性细胞的化学刺激物,可以激活许多细胞因子的表达,包括调节激活T细胞表达和分泌（RANTES）、单核细胞化学引诱物蛋白（MCP）1、MCP3、巨噬细胞炎性蛋白1（MP）、白介素（IL）-10、IL-1、IL-6和干扰素（IFN）-α。颗粒溶素与感染、癌症、移植、自身免疫、皮肤和生殖疾病等多种疾病相关。基于颗粒溶素的多功能性,本文针对其作用机制和与临床常见疾病关系做一综述。     

Effectiveness as an outcome measure for treatment trials in psychiatry

There is at present some confusion about the relative value of clinical trials performed to investigate efficacy vs. those designed to investigate effectiveness. This is particularly challenging when studies performed as experiments for regulators by companies are used to shape and inform clinical practice, especially if studies conducted under more real life conditions fail to support predicted benefits. We review the field in relation to the new antipsychotics, in particular. Other indications, including mood disorders, which are also briefly touched upon, have so far received less definitive attention, but are likely to encounter the same difficulties. We conclude that, where the results of efficacy trials are positive and an effectiveness trial is negative, one should not necessarily prefer the effectiveness trial – it may simply have failed. Where efficacy trials and effectiveness trials point to similar conclusions, then the findings are mutually supportive.