肿瘤标记物与培美曲塞

0 引言 在肿瘤治疗领域,越来越多肿瘤生物标记物的研究给个体化治疗提供了更多的证据支持.而这些研究并不局限于靶向药物治疗,也包括化疗药物.     

Biomarkers for therapeutic efficacy

Depending on the tumour type, a larger or smaller number of cancer patients receive chemotherapy with systemic toxicity as the only effect. In that situation, an alternative, not necessarily medical, treatment would have been a better choice – and toxicity (and financial resources) could have been spared by withholding ineffective drugs. One of the reasons for this apparent paradigm is that the tumour cells of each cancer pa- tient may show different sensitivity/resistance towards different chemotherapeutic drugs, i.e. breast cancer or colorectal cancer is not only breast or colorectal cancer. With our increasing biological insight and understanding, it has become apparent that each patient's tumour tissue is unique and as a consequence, each patient's tumour cell sensitivity/resistance to- wards chemotherapeutic drugs may be different. As of today there is no method in routine clinical use to predict the sensitivity/resistance to chemotherapy in its broad sense in the individual patient. This chapter will describe several different DNA, RNA, protein and cell based assay methodologies and marker molecules that have been brought forward as potential predictive assays/markers to be used to select the most effective drugs for the individual cancer patient.     

Biomarkers for prostate cancer detection

Since its approval by the US FDA in 1986, prostate-specific antigen (PSA) has been employed to monitor men with a diagnosis of prostate cancer. In 1994, PSA was approved for use in prostate cancer screening and has been employed worldwide. However, due to the limited specificity of PSA for the disease, novel biomarkers are needed for detecting prostate cancer and for determining which cancers need to be treated. This review will discuss the development of new biomarkers for prostate cancer detection and disease prognostication, focusing on recent progress and particular topical issues related to the development and validation of these new markers.     

Biomarkers for neoplasmas in digestive organs

This review is concerned with the usefulness and the problem of biomarkers for cancer of digestive organs. Carcinoembryonic antigen (CEA) is a most popular and useful tumor marker for cancer of digestive organs. Squamous cell carcinoma (SCC) antigen and CYFRA have been reported as a useful tumor marker for esophageal cancer. CEA and CA 19-9 are a good prognostic factor in gastric cancer patients. The post-operative increase of serum CEA can be a predictive marker for the patients of colorectal cancer. Development of a radioimmunoassay for highly sensitive detection of tumor markers, they are considered to be useful for monitoring after treatment. But are not useful for the early diagnosis. The diagnosis of hepatocellular carcinoma (HCC) is based mainly on serological markers, such as alpha-fetoprotein and PIVKA-II. The two are useful complementary markers of HCC because they do not correlate with each other. But the problem of the false-positive rate for the patients with chronic hepatitis or liver cirrhosis is still remained. A typical marker of pancreatic and bile duct cancer is carbohydrate antigen, but the sensitivity of these markers is only 50%. Recent molecular biological analysis may be used as effective biomarkers in the diagnosis, prognosis, therapy, and risk assessment of digestive cancer.     

Biomarkers for Therapies Directed at Angiogenesis

Since 2004, six drugs with antiangiogenic properties—bevacizumab, sorafenib, sunitinib, pazopanib, temsirolimus, and everolimus—have been approved for clinical use in patients with advanced solid tumors, on the basis of their capacity to improve survival in phase 3 studies. Despite this enthusiasm in having these drugs approved, no significant predictive or prognostic factors have been identified for better patient selection with the aim of increasing the likelihood of clinical benefit. Biomarkers are understood as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Different kinds of biomarkers are available for clinical practice, including prognostic biomarkers associated with the risk of disease development, spread, or aggressiveness or with survival rates, as well as predictive biomarkers that provide us with information on the efficacy of a particular therapeutic option. Currently, several potential biomarkers have emerged from recently completed phase 1, 2, and 3 studies. These biomarkers are extensive in origin, depending on the source of the specimen (blood, serum, tumor tissue, circulating tumor cells, surrogate tissue), the type of analysis being done on the specimen (genomic—DNA or RNA—or proteomic), and sometimes whether the biomarker comes from clinical or radiologic data. Unfortunately, no validated predictive biomarkers of angiogenesis or antiangiogenesis are available for routine clinical use. Future anticancer drug research should run parallel to an ambitious biomarker development program to facilitate the selection of patients who would benefit most from these new targeted therapies, thereby providing more accurate benefit/safety and benefit/cost relationships.     

Biomarkers as surrogates for cancer development

Biomarkers are routinely applied in the management of chronic diseases to reduce morbidity and mortality through early diagnosis, as well as to assess the necessity for, and responsiveness to, applied interventions. Biomarkers yield mechanistic insights into layers of biologic organization from molecule to organelle, to cell, and finally to cellular organization and tissue. A step-wise approach to the development of tissue-based biomarkers is presented. These biomarkers may serve as molecular targets for scientific inquiry and intervention, as well as approvable endpoints for clinical trials.     

胃癌干细胞标志物

分离鉴定胃癌干细胞需要借助某些特异性的表面标志,包括正常胃干细胞标志、通用的肿瘤干细胞标志和间充质标志等.目前除常见的CD133和CD44分子外,已研究出许多新的胃癌干细胞标志物,对其进行联合检测有望分离出胃癌干细胞,为推进胃癌的治疗提供依据.     

Biomarkers for responses to heavy metals

Biomarkers for pathophysiological responses to heavy metals are described with special reference to immunotoxic responses to them. Autoantibody induction in animals by exposure to cadmium is exemplified and discussed on its relevance to pathogenesis of cadmium-induced renal disease. The availability of autoantibodies as a mechanism-oriented biomarker is discussed further in association with cases of autoantibody induction in heavy metal workers.     

Biochemotherapy for melanoma

Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine (DTIC) alone or a multiagent combination chemotherapy, and biologic therapy with recombinant interferon-a and/or interleukin-2. However, none of these treatment options has produced long-term control of the disease except on rare occasions. Combined chemo-immunotherapy (biochemotherapy) has shown high objective response rates (approximately 50%) and a significant though small proportion of long-term complete responders in metastatic melanoma. It has, however, been associated with greater toxicity. Overall results of sequential versus concurrent biochemotherapy are similar, but the toxicity appears to be less severe in patients treated with the concurrent regimen. At this time, biochemotherapy is under evaluation in a well-designed prospective, randomized trial to identify whether there is benefit to this strategy, compared with chemotherapy alone.     

Vaccination for melanoma

Our knowledge of the immune system has grown tremendously in the 50 years since Coley used bacteria in an attempt to create a vaccine for cancer. The strategy for cancer vaccines has developed in that time as well. Both clinical and laboratory evidence suggests that melanoma is the more immunogenic of solid tumors. If treated early, melanoma can be controlled with surgery, but many patients continue to die from it. With our increased understanding of the immune system’s interaction with melanoma, many clinical trials of melanoma vaccines are now underway. Vaccines designed to treat metastatic melanoma have shown some evidence of clinical effectiveness. This article outlines the current status of melanoma vaccination.     

Circulating circRNAs as Potential Biomarkers for Cancers

Cancers are diseases with a high mortality rate worldwide. In order to better diagnose and improve the survival rate, many studies have been conducted. In recent years, the role of non-coding RNAs in cancers has been confirmed, and circular RNAs (circRNAs) have attracted much attention. CircRNAs are involved in the occurrence and development of cancers with high stability. Experiments have shown that they can exist stably in peripheral blood. Therefore, the expression of circulating circRNAs can be detected to help diagnose cancers and reflect tumor progression. In this review, we summarized the role of circulating circRNAs in cancers and discussed their potential as biomarkers.     

Biomarkers for Evaluation of Prostate Cancer Prognosis

Prostate cancer, with a lifetime prevalence of one in six men, is the second cause of malignancy-related deathand the most prevalent cancer in men in many countries. Nowadays, prostate cancer diagnosis is often basedon the use of biomarkers, especially prostate-specific antigen (PSA) which can result in enhanced detectionat earlier stage and decreasing in the number of metastatic patients. However, because of the low specificityof PSA, unnecessary biopsies and mistaken diagnoses frequently occur. Prostate cancer has various featuresso prognosis following diagnosis is greatly variable. There is a requirement for new prognostic biomarkers,particularly to differentiate between inactive and aggressive forms of disease, to improve clinical managementof prostate cancer. Research continues into finding additional markers that may allow this goal to be attained.We here selected a group of candidate biomarkers including PSA, PSA velocity, percentage free PSA, TGFβ1,AMACR, chromogranin A, IL-6, IGFBPs, PSCA, biomarkers related to cell cycle regulation, apoptosis, PTEN,androgen receptor, cellular adhesion and angiogenesis, and also prognostic biomarkers with Genomic tests fordiscussion. This provides an outline of biomarkers that are presently of prognostic interest in prostate cancerinvestigation.     

预测贝伐珠单抗抗肿瘤治疗效果的生物学标记物

贝伐珠单抗已被用于多种恶性肿瘤的治疗,但仍没有一个公认的普遍适用的疗效预测指标.目前除了以影像学、副反应作为预测因子外,很多研究集中在对生物学标记物的筛选上.循环标记物中血管内皮生长因子(vascular endothelial growth factor,VEGF)水平对疗效的预测没有定论,而治疗前高水平可溶性血管内皮生长因子受体(soluble vascular endothelial growth factor receptor,sVEGFR)及低水平m管细胞间粘附因子-1、E-选择素、血管紧张素-2预示着治疗反应更好.肿瘤组织免疫组化方面,研究发现治疗前磷酸化VEGFR2与VEGFR2比值高或低表达碳酸酐酶9(carbonicanhydrase9,CA9)、CD31-微m管密度(CD31-microvesseldensty,CD31-MVD)患者的疾病控制率高.另外基因方面的研究显示含有VEGF-634CC和VEGF-1498TT者副反应较少,而携带VEGFR2H472Q变异型基因者出现副反应的几率高.综上,要找到合适的生物学标记物来预测贝伐珠单抗抗肿瘤治疗的效果,需要进一步的基础研究去发现更特异的作用位点及更大规模的临床试验去验证.