节律性化疗对多发性骨髓瘤患者血管生成的影响

目的 探讨低剂量环磷酰胺联合泼尼松节律性化疗对多发性骨髓瘤(MM)患者骨髓组织微血管密度(MVD)和外周血中血管内皮生长因子(VEGF)、血小板衍生生长因子BB(PDGF-BB)表达的影响.方法 54例难治或复发性MM患者给予低剂量环磷酰胺(50 mg/d) 联合泼尼松(15 mg/d)(CP方案) 持续口服.在治疗前和治疗后2、4、6个月分别取患者骨髓组织及外周血,应用免疫组织化学法分析患者的骨髓组织MVD,ELISA法检测外周血中VEGF和PDGF-BB表达水平.结果 在可评估的37例患者中,30例患者有效,有效率为81.08%.其余17例患者随访未达6个月或未能获得血清检测标本或失访.低剂量环磷酰胺联合泼尼松节律性化疗2、4、6个月后,有效组30例患者MVD计数分别为33.1±4.8/高倍视野(HP)、24.8±3.7/HP、19.7±2.1/HP;外周血VEGF水平分别为(394±57)、(268±32)、(217±20) ng/L;PDGF-BB水平分别为(304±31)、(274±31)、(196±22) ng/L.与治疗前相比,患者骨髓MVD和外周血VEGF、PDGF-BB表达水平显著降低(P\%值均<0.01).而无效组7例患者在化疗后2个月MVD为32.5±4.7/HP,外周血VEGF水平为(512±39) ng/L,PDGF-BB水平为(452±39) ng/L,与治疗前相比差异无统计学意义(P\%值均>0.05).结论 低剂量环磷酰胺联合泼尼松节律性化疗可明显降低MM患者骨髓组织MVD和血清VEGF、PDGF-BB表达水平.其在MM中的作用机制可能与抑制新生血管的生成有关.     

MEK in cancer and cancer therapy

The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is one of the best-characterized kinase cascades in cancer cell biology. It is triggered by either growth factors or activating mutations of major oncogenic proteins in this pathway, the most common being Ras and Raf. Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers. Targeting these kinases offers promise of novel therapies. MEK inhibitors (MEKi) are currently under evaluation in clinical trials and many have shown activity. In this review, we comprehensively examine the role of the MEK pathway in carcinogenesis and its therapeutic potential in cancer patients, with a focus on MEKi. We describe the clinical perspectives of MEKi in the two main models of Ras–ERK driven tumors, BRAF-mutant (“addicted” to the pathway) and KRAS-mutant (non-“addicted”). We also highlight the known mechanisms of resistance to MEKi and emerging strategies to overcome it.     

Cytokine therapy in cancer

Background: Cytokines provide important intercellular signals in inflammation, immunity and tumor and endothelial cell biology. Several cytokines have therapeutic potential when delivered exogenously alone or in combinations with chemotherapy or other biological agents. Objectives: To summarize current data on the biology and therapeutic use of human cytokines in malignancy. Methods: The review focuses on the most important physiological and pathological functions of each cytokine and a unifying concept for its potential role in human malignancy based on preclinical models and current published literature. Results/conclusions: Interleukin-2 is the model cytokine for the study of other cytokines that have similar or distinct properties with potential for superior therapeutic uses. Ongoing studies of cytokine networks involved in normal and pathological processes, along with enhanced knowledge of mechanisms of counterregulation and resistance, will guide future therapeutic strategies.     

Antisense oligonucleotide therapy in cancer

The sequencing of the human genome has highlighted some of the genes that are of importance in disease states. This has provided opportunities for the development of new therapeutics to target a wide range of human diseases. These new drugs are intended to be highly specific; antisense oligonucleotides (ONs) are one such class of new drugs. ONs are short pieces of DNA which hybridize to a specific target mRNA blocking its translation to protein, thereby inhibiting the action of the gene. Several genes known to be of importance in the regulation of apoptosis, cell growth, metastasis and angiogenesis provide a tantalizing prospect for the development of anticancer agents. The phosphorothioate antisense ONs are the current choice for antisense therapy. This article reviews the current strategies for antisense targets in cancer therapy.     

Sphingolipid targets in cancer therapy

Considerable progress has been made recently in our understanding of the role of ceramide in the induction of apoptotic cell death. Ceramide is produced by cancer cells in response to exposure to radiation and most chemotherapeutics and is an intracellular second messenger that activates enzymes, leading to apoptosis. Because of its central role in apoptosis, pharmacologic manipulation of intracellular ceramide levels should result in attenuation or enhancement of drug resistance. This may be achieved through direct application of sphingolipids or by the inhibition/activation of the enzymes that either produce or use ceramide. In addition, attention should be given to the subcellular location of ceramide generation, because this has been shown to affect the biological activity of sphingolipids. This review summarizes the sphingolipid biosynthetic pathway, as it relates to the identification of important targets for drug discovery, and the development of novel agents capable of enhancing chemotherapy.     

Targeted therapy in colorectal cancer

Advances in chemotherapeutic agents have led to improved outcomes for patients with metastatic colorectal cancer (CRC). Chemotherapies, however, are limited by their toxicities and lack of specificity. Aberrations in the regulation and expression of growth factors have been implicated in the development of CRC, and this understanding has led to the development of targeted agents. In 2004, two novel agents, bevacizumab and cetuximab, were approved by the US Food and Drug Administration for the treatment of metastatic CRC. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, and cetuximab, a human-mouse chimeric monoclonal antibody to the epidermal growth factor receptor, have changed the field dramatically. Bevacizumab appears to augment the efficacy of combination chemotherapy regimens for the treatment of metastatic CRC in both the first- and second-line settings, and the role of bevacizumab as part of adjuvant treatment is the subject of ongoing trials. However, because of the increased incidence of serious arterial thromboembolic events, gastrointestinal perforations, bleeding complications, and hypertension associated with bevacizumab, this agent is probably not indicated in all circumstances. Combination treatment with cetuximab and irinotecan appears appropriate in patients with advanced CRC who have failed irinotecan. Patients who are unable to receive additional irinotecan may be treated with cetuximab monotherapy. Positive epidermal growth factor receptor status by immunohistochemistry of a tumor specimen is presently mandated to determine candidacy for this therapy, although this assay appears to be suboptimal and newer assessment techniques to determine suitability for therapy must be developed. Phase III trials should shed light on the role of cetuximab in the first-line metastatic and adjuvant settings. Multitargeted strategies in CRC combining chemotherapy with bevacizumab and cetuximab are currently being explored. Further advances in the treatment of CRC are expected through continued scientific investigation and well-designed clinical trials.     

Molecular therapy in lung cancer

Every year more than 370,000 new cases of lung cancer occur in Europe. About 70% of the patients are not curable because of local or distant spread of tumor cells. Despite the use of chemotherapy, median survival of these patients is less than one year In the last two decades, important advances in cancer research have been achieved. This led to the development of a new class of potential anti-cancer agents, selectively targeting molecules which are important for the growth and the spread of tumor cells. Focussing on lung cancer, this review presents compounds that are furthest in clinical development, covering epidermal growth factor receptor inhibitors, receptor tyrosin kinase inhibitors, anti-angiogenic agents, matrix metalloproteinase inhibitors, gene therapy and antisense therapy.     

Radiation therapy in childhood cancer

OBJECTIVES: To review treatment-related issues and acute and late side effects of radiation therapy for the treatment of childhood malignancies. DATA SOURCES: Research and review articles, oncology textbooks, and clinical experience. CONCLUSIONS: Radiation therapy is a key component in the treatment of childhood malignancies. Children receiving radiation have special nursing care needs that are dependent on growth and developmental issues. IMPLICATIONS FOR NURSING PRACTICE: Nurses play an important role in the education of families and children receiving radiation therapy. In addition, nurses are key in the management of acute and late toxicities from childhood radiation therapy.     

BRAF inhibitors in cancer therapy

Activating BRAF mutations, leading to constitutive activation of the MAPK signaling pathway, are common in a variety of human cancers. Several small molecule BRAF inhibitors have been developed during the last years and shown promising results in clinical trials, especially for metastatic melanoma, while they have been less effective in colon cancer. Two inhibitors, vemurafenib and dabrafenib, have been approved for treatment of melanoma. Unfortunately, in most patients who initially respond the tumors eventually develop acquired resistance to the BRAF inhibitors. So far, a number of resistance mechanisms have been identified, including secondary NRAS mutations and BRAF alternative splicing, leading to reactivation of the MAPK pathway. Other alterations, both upstream and downstream of BRAF can have the same effect, and activation of alternative pathways can also play a role in resistance to BRAF inhibitors. In addition, intra-tumor heterogeneity with the presence of clones of tumor cells lacking BRAF mutations needs to be considered, since wildtype BRAF can be activated by inhibitors designed to target mutated BRAF. Combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib has significantly prolonged progression free survival compared to dabrafenib alone in metastatic melanoma. Combination treatments of BRAF inhibitors with other agents may not only circumvent or delay resistance, but may also lead to fewer side effects, such as development of secondary squamous tumors. Several clinical trials are underway for many different BRAF mutation positive cancers with BRAF inhibitors alone or in combination with other small molecule inhibitors, immunotherapies or conventional chemotherapy.     

Natural polyphenols in cancer therapy

Natural polyphenols are secondary metabolites of plants involved in defense against different types of stress. Extracts containing these compounds have been used for thousands of years in traditional eastern medicine. Polyphenols act on multiple targets in pathways and mechanisms related to carcinogenesis, tumor cell proliferation and death, inflammation, metastatic spread, angiogenesis, or drug and radiation resistance. Nevertheless, reported effects claimed for polyphenols are controversial, since correlations between in vitro effects and in vivo evidence are poorly established. The main discrepancy between health claims versus clinical observations is the frequent use of nonphysiologically relevant concentrations of these compounds and their metabolites in efficacy and mechanistic studies. The present review will discuss how in vivo administration correlates with polyphenol metabolism, toxicity, and bioavailability. Analysis of the general application of polyphenols in cancer therapy will be complemented by potential applications in the therapy of specific tumors, including melanoma, colorectal and lung cancers. Possible pharmaceutical formulations, structural modifications, combinations, and delivery systems aimed to increase bioavailability and/or biological effects will be discussed. Final remarks will include recommendations for future research and developments.     

Preoperative therapy in esophageal cancer

Progress has been made in the treatment of locally advanced esophageal cancer. Preoperative and postoperative chemotherapy also appears to improve survival in gastroesophageal junction adenocarcinoma compared to surgery alone. Adding radiotherapy to preoperative chemotherapy enhances rates of curative resection, achieves measurable rates of pathologic complete response, and recent trials indicate a survival benefit for preoperative chemoradiotherapy compared to surgery alone in esophageal cancer. Given the achievement of pathologic complete responses with combined chemoradiotherapy in esophageal cancer, recent trials have evaluated the contribution of surgery after chemoradiotherapy. With currently available systemic therapy for squamous cancers of the esophagus that respond to combined chemoradiotherapy, there is no clear survival benefit for the addition of surgery after chemoradiotherapy despite improvements in local tumor control with the addition of surgery. Surgery may salvage nonresponding patients with biopsy-positive residual disease. For adenocarcinoma of the esophagus, a histology with consistently lower rates of pathologic complete response than squamous cell cancer, surgery appears to play a greater role. Trials are now evaluating the use of newer chemotherapy agents combined with radiotherapy, including taxanes, irinotecan, and oxaliplatin. Response on postiron emission tomography early on during induction chemotherapy may be a strong prognostic measure of outcome. Targeted agents, including monoclonal antibodies that target the epidermal and vascular endothelial growth factor receptors, are in active development in phase II and III trials.     

Endocrine therapy in cancer.

A proportion of cancers in endocrine target tissues can show the presence of specific receptors for either steroid or polypetide hormones. Manipulation of the controlling hormones does not guarantee regression. A third of cancers in endocrine target organs (breast, uterine endometrium, and prostate) show a 50% reduction in size of lesions after hormonal therapy. If regression resulting from an aggressive form of therapy lasts a short while and the tumor reactivates by the time the unpleasant effects of the therapy wear off, the treatment is not palliative. Endocrine therapy in prostatic cancer is palliative but there is no evidence that is increases survival. 11 different progestational agents in endometrial cancer therapy in the past 25 years resulted in a 30-35% response. Response must be maintained by continual treatment and may last from 12 months to 7-8 years. In breast cancer, tumors with a significant level of estrogen receptor (ER+) have about a 60% chance of regression vs. tumors without estrogen receptors (ER-), 10%. Advanced cancers of the thyroid of the papillary or follicular type regress when the patient is treated by thyroxine, .3 mg daily. Leukemia and lymphoma are frequently treated, with varying degrees of success with corticosteroid therapy, which may also predispose the patient to intercurrent infection. Renal cancer has been often treated by medroxyprogesterone acetate or testosterone propionate, with little success.     

Molecular targets in cancer therapy

OBJECTIVES: To review selected pharmacologic agents that target key cellular processes along with their mechanisms of action and adverse events. Nursing implications including what patients and families need to know, administration issues, and management of common toxicities will be reviewed. DATA SOURCES: Research articles, clinical trials, abstracts, and book chapters. CONCLUSION: Knowledge of complex biology and biochemistry regulating normal and abnormal cellular function obtained over the past 30 years is starting to be used clinically for new therapies to treat cancer. By targeting what makes cancer unique, these therapies are able to spare more healthy or normal cells than the standard treatments, such as radiation and chemotherapy. Several molecular targeting agents are now in use and even more are under study as cancer treatments. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses must understand the principles underlying targeted treatments and their potential benefits to provide adequate patient education and care.     

Molecular target therapy in cancer

Many molecular target drugs have been developed based on the progress in the study of molecular biology. Majority of treatment for common malignancy include molecular target drugs. Patients selection has become possible by pharmacogenomical tests in some molecular target therapy. Development of active molecular target therapy will enable the increment of curative populations even in advanced malignancies. Intensive proof of principle study will open doors for the identification of new molecular targets.