卷 14, 编号 5 (2014)
- 年: 2014
- 文章: 15
- URL: https://kld-journal.fedlab.ru/1871-5206/issue/view/14263
Oncology
Editorial (Thematic Issue: Treatment of Cancer in the Elderly)
637-638
Targeted Anti-HER2 Cancer Therapy in Elderly Women Diagnosed with Breast Cancer
摘要
Trastuzumab or lapatinib treatment with chemotherapy or hormonotherapy are the gold standard treatments for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (early breast cancer or metastatic breast cancer). Older patients have been largely underrepresented in clinical trials, and few data on trastuzumab or lapatinib efficacy and toxicity have been reported for this subgroup. This article has reviewed the main articles that have analyzed these items.
639-645
Erlotinib and Gefitinib for Elderly Patients with Advanced Non-small-cell Lung Cancer
摘要
Erlotinib and gefitinib are tyrosine kinase inhibitors (TKI) associated with the EGFR, which is involved in cell proliferation, growth, migration, invasion and survival, and has been found to be overexpressed in non-small-cell lung cancer. Erlotinib was the first target agent approved for the treatment of NSCLC in second- and third line, in patients unselected for EGFR mutations; gefitinib was the first EGFR tyrosine kinase inhibitor approved for the treatment of NSCLC in all lines of setting in patients harbouring EGFR mutations. In elderly patients, with a poor prognosis, and different co-morbidities, erlotinib and gefitinib could be considered as valid therapeutic options. This paper reviews the role of both drugs, in the management of elderly patients affected by advanced NSCLC based on an update analysis of randomised and non-randomised clinical trials.
646-650
Tools For Decision-Making In Older Cancer Patients. Role Of The Comprehensive Geriatric Assessment
摘要
Approximately 60% of cancer incidence and 70% of cancer mortality occurs in individuals older than 65 years. The optimal approach to cancer therapy in older adults is often unclear. Historically, advanced age has been an exclusion criterion in clinical cancer trials, and older adults have been consistently underrepresented. As a result, there is a lack of information about treatment efficacy and tolerability in this population. Comprehensive Geriatric Assessment (CGA) is one of the most useful tools for the oncologist to make decisions related to older patients diagnosed with cancer. This tool has proved to be very useful to detect many deficits, tolerance to chemotherapy and survival in such patients. In this review, we analyze the role of CGA in decision making in geriatric oncology.
651-656
New Drugs for Follicular Lymphoma in Older Adults
摘要
Follicular lymphoma is essentially a disease of the elderly, and the aging of the population in developed countries will increase patient numbers in coming years. Significant achievements have been made for treatment, but better understanding of the disease and major progress in biology now facilitate the development of many new drugs, which may have improved toxicity profiles making them appropriate for treatment of older adults. However, the increasing number of treatment possibilities, can also increase the toxicity risks, and unexpected toxicities specific to older adults may be encountered. Consequently, specific studies of older patients should be considered, using appropriate evaluation tools such as comprehensive geriatric assessment. This review will described the development of these new drugs, in the context of the treatment of older-adults with follicular lymphoma.
657-664
Oral Chemotherapy in Elderly Women with Metastatic Breast Cancer
摘要
Life expectancy has significantly increased over the past 30 years, with a greater prevalence of diverse disease states, especially cancer. As older persons are a very heterogeneous group with an increased prevalence of comorbidities and a relative inability to tolerate the adverse effects of chemotherapy, the treatment of cancer in the elderly is particularly demanding. The principles of its management are similar to those in younger patients but with special considerations linked to comorbidities and clinical status. The objective of chemotherapeutic treatment in metastatic breast cancer has historically been primarily palliative. The introduction of newer approaches with improved or at least equivalent efficacy and reduced toxicity is highly desirable. Such approaches may include the use of less toxic drugs, more convenient routes of administration (e.g., oral) and home-based (outpatient) rather than hospital-based therapies. The available oral cytostatic drugs include vinorelbine and capecitabine. In this review, we analyze oral cytostatic drugs in the elderly patient diagnosed with metastatic breast cancer.
665-672
Advances in the Researches on the Biological Activities and Inhibitors of Phosphatidylinositol 3-kinase
摘要
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway, being important in apoptosis hence cancer such as breast cancer and non-small-cell lung cancer. It signaling axis controls cell proliferation and survival and has achieved major importance as a target for cancer therapy. The serine/threonine kinase Akt (also known as protein kinase B or PKB), since its initial discovery as a protooncogene, has become a major focus of attention because of its critical regulatory role in diverse cellular processes, including cancer progression and insulin metabolism. The Akt cascade is activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors, G protein coupled receptors and other stimuli that induce the production of phosphatidylinositol 3,4,5 triphosphates (PtdIns(3,4,5)P3) by phosphoinositide 3-kinase (PI3K). Therefore, PI3K plays an important role in in numerous cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. In this review, we introduced the structure of the PI3K, and then focused on its biological activities. In addition, we reviewed the advances in the researches of PI3K as well as related inhibitors over the last couple of decades. Finally, we also discussed the prospect and developmental trend of phosphatidylinositol 3-kinase as antitumor agents.
673-687
α-Methylene-γ-lactones as a Novel Class of Anti-leukemic Agents
摘要
Natural products are important leads in drug discovery. In recent years, the anti-leukemic properties of natural compounds isolated from plants, containing an α-Methylene-γ-lactones skeleton, have attracted a lot of attention. Extensive research has been carried out to characterize their molecular mechanisms of action and potential chemotherapeutic application in different types of cancer, including leukemias. Sesquiterpene lactones, a group of α-Methylene-γ-lactones are plant-derived compounds, mostly of the Compositae family, used in traditional medicine especially for the treatment of inflammation. However, they exhibit a broad spectrum of other biological effects, including cytotoxic, anti-bacterial, anti-helminthic, and anti-tumor activity. Recently, a sesquiterpene lactone, parthenolide, and several other compounds containing an α-methylene-γ-lactone skeleton have become topics of interest as potential antileukemic agents. The recent research emphasizes their selective activity against leukemia cells while the normal hematopoietic cells remain unaffected. In this review, we give a brief description of natural α-Methylene-γ-lactones isolated from plants and their derivates with minor chemical modifications that possess anti-leukemic activity. We also discuss molecular mechanisms of action of these compounds, in particular, their selectivity against leukemia cells.
688-694
The Potential of Acridine Carboxamide Pt Complexes as Anti-Cancer Agents : A Review
摘要
There has been a concerted attempt to produce more effective anti-tumour agents based on the widely-used cancer chemotherapeutic agent, cisplatin. One interesting approach is to attach a DNA-affinic chemical group to the cisplatin molecule. This could result in a more efficient binding to the biological target, DNA, and produce a different spectrum of Pt-DNA crosslinks that may permit an agent to overcome cisplatin resistance. Acridine Pt complexes, have activity against cisplatin-resistant cells, have a differing DNA sequence selectivity compared to cisplatin and hence, are strong candidates for development as anti-tumour agents. The properties of acridine Pt analogues, especially 9-aminoacridine carboxamide Pt complexes, are reviewed here and the sequence specific interaction of acridine carboxamide Pt complexes with DNA is explored. The 9-aminoacridine carboxamide Pt complexes have a reduced reaction at runs of consecutive guanine nucleotides compared with cisplatin, and form adducts at novel DNA sequences, especially 5'-CGA. The activity of the 9-aminoacridine Pt complexes against cisplatin-resistant cell lines is due to their ability to escape the DNA repair capacity of the cells, through the production of variant DNA adducts. The future prospects for development of acridine carboxamide Pt complexes as cancer chemotherapeutic agents are discussed.
695-705
Statins and Cancer
摘要
Statins have pleiotropic properties and might exert an effect even in the field of cancer. Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid. Specifically, inhibition of HMG-CoA reductase by statins has been proved to prevent the synthesis of mevalonic acid, a precursor of non-steroidal isoprenoids, which are lipid attachment molecules for small G proteins, such as Ras, Rho and Rac. Thus, statins may inhibit the synthesis of isoprenoids and thereby suppress the activation of small G proteins. In addition, statins exert pro-apoptotic, anti-angiogenic, and immunomodulatory effects, which may prevent cancer growth. Statins may inhibit the growth of a variety of cancer cell types, including breast, gastric, pancreatic, and prostate carcinoma, neuroblastoma, melanoma, mesothelioma and acute myeloid leukemia cells. They exert pro-apoptotic effects in a wide range of cancer cell lines, but with many differences in the sensitivity to statin-induced cell death among different cancer cell types. Regarding anti-angiogenic effects, multiple statin effects on blood vessel formation by inhibition of angiogenesis through down-regulation of pro-angiogenic factors, such as vascular endothelial growth factor, inhibition of endothelial cell proliferation and inhibition of adhesion to extracellular matrix by blocking intercellular adhesion molecules have been suggested. The molecular mechanisms of statin immunomodulation often implicate multiple pathways, regarding the regulation of genes encoding key molecules, which are involved in antigen presentation and subsequent immunomodulation. Another mechanism involves the down-regulation of the nuclear factor-kappa-B, which is responsible for the transcription of many genes involved in immunologic mechanisms, such as interferon-inducible protein-10, monocyte chemo-attractant protein 1 and cyclooxygenase-2. Statins have been associated with a significantly lower risk of breast, colorectal, ovarian, pancreatic, lung cancers and lymphoma in several observational studies. On the other hand, other studies, including meta-analyses have raised concerns about the safety of statins among elderly patients. A recent study upon the relationship between statin use (prior to cancer diagnosis) and cancer-related mortality in the entire Danish population from 1995-2009 in adults > 40 years of age has been conducted. As compared to statin non-users, patients using statins prior to cancer diagnosis were 15% less likely to die from any cause or cancer specifically. Further investigation is needed to elaborate on their mode of action as well as their true significance on cancer prevention and perhaps as an adjuvant to cancer chemotherapy.
706-712
Physiological Modulation Approaches to Improve Cancer Chemotherapy : A Review
摘要
The success of anticancer therapy is limited due to the resistance caused by tumor cells to cytotoxic agents, which interfere with the effectiveness of various chemotherapeutic agents. Several mechanisms for decreased effectiveness of anti-cancer drugs have been examined however the most widely studied mechanism is the efflux of cytotoxic drugs from the cell due to P-gp overexpression. However, the role of P-gp inhibitors in improving chemotherapy is limited due to the existence of other mechanisms of resistance such as activation of glutathione mediated detoxification, blockade of DNA repair, apoptotic pathways, TK signaling pathways and altered tumor microenvironment. Alternative strategies to overcome factors responsible for reduced efficacy of cancer therapy have also been considered such as inhibition of the detoxification system like glutathione, targeting Tks and DNA repair pathways, combination of angiogenic inhibitors, RNAi mediated inhibition of targeted genes etc. Additionally, preventing the onset of resistance can be targeted via siRNA strategy and nanoparticle strategy. In this review, we describe detailed mechanisms involved in decreasing effectiveness of anticancer drugs as well as the strategies used to modulate these mechanisms for effective cancer treatment.
713-749
Damnacanthal: A Promising Compound as a Medicinal Anthraquinone
摘要
The Noni fruit, or scientifically known as Morinda citrifolia can be found in various parts of the world, especially in the pacific region. It is a small evergreen bushy-like tree originated from the Rubiaceae family. The plant has been used by polynesians as a medicinal herb for more than 2000 years. A substantial amount of phytochemicals can be found in the roots of this plant. Among all, damnacanthal has been found to be the most interesting, versatile and potent compound. Damnacanthal or chemically known as,3- hydroxy-1-methoxyanthraquinone-2-caboxaldehyde (C16H10O5), appears as pale yellow crystals with a melting point of 210-211 °C. This compound is of particular interest due to its striking pharmacological properties. Damnacanthal was shown to inhibit the oncogene Ras, p56lck tyrosine kinase, NF-KB pathway and induce apoptosis in vitro. This review aims to discuss the biological properties of damnacanthal, specifically on its anti-cancer activity that has been reported.
750-755
East-West FusionNecrosis and Apoptosis Acting in Concert by Demethylcantharidin-Integrated Platinum Complexes
摘要
The different types of cell death occurring in HCT116 colorectal cancer cell after the treatment of cisplatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(demethylcantharidin:DMC) and Pt(R,R-1,2-diaminocyclohexane: DACH)(DMC) were examined. Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) are the two DMC-integrated platinum complexes:Pt(R,R-DACH)(DMC) with the same Pt moiety as oxaliplatin and Pt(NH3)2(DMC) akin to carboplatin. Using the light scattering properties of cells combined with propidium iodide (PI) red fluorescence to distinguish between early apoptotic and necrotic cells, the results confirmed that apoptosis, which triggered by cisplatin, carboplatin and oxaliplatin, was the major type of cell death, while the major DMC-induced cell death type was necrosis. The increase in the necrotic cell population was observed after Pt((NH3)2(DMC) treatment when compared with carboplatin; therefore, the DMC ligand in Pt(NH3)2(DMC) contributing to cell death was demonstrated. However, the DMC ligand in Pt(R,RDACH)( DMC) failed to elevate the necrotic cell population significantly in contrast to oxaliplatin, thus Pt(R,R-DACH) in Pt(R,RDACH)( DMC) dominantly contributed to cell death. The IC50 value (antiproliferative activity) reflects the net effect of drugs on cell proliferation resulting from inhibition of cell growth and division, and induction of cell death. The sub-G1 populations representing the sum of the amounts of late apoptotic cells and necrotic cells after the treatment of cispatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) were found to be not correlated with the corresponding IC50 values;therefore, the rate of cell growth and division inhibition rather than the rate of induction of cell death dictated to the IC50 values. This combined analysis of IC50 values and the sub-G1 population data also reveals that the platinum compounds containing R,R-DACH are most efficient in inhibiting cell growth and division, while carboplatin induces cell death most rapidly. When the Pt-DNA adducts are believed to be major cytotoxic species, the combined analysis of the IC50 values and the sub-G1 population data infers that the R,R-DACH-Pt-1,2-d(GpG) intrastrand cross-links caused by oxaliplatin treatment are more effective in inducing cell growth and division inhibition, while the (NH3)2Pt-1,3- d(GpXpG) intrastrand cross-links caused by carboplatin treatment can trigger cell death more rapidly. The rate of cell growth and division inhibition and the cell death rate induced by the main cisplatin-DNA adducts:(NH3)2Pt-1,2-d(GpG) intrastrand cross-links lie in between.
756-761
Steroidal Cardiac Na+/K+ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo
摘要
Sodium potassium pump (Na+/K+ATPase) is a validated pharmacological target for the treatment of congestive heart failure. Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promote Na+/K+ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and are considered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitors showed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remained unknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity in vitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumor panels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3- pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, was selectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na+/K+ATPase inhibitors have potent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development.
762-770
3-Bromopyruvic Acid, A Hexokinase II Inhibitor, is an Effective Antitumor Agent on the Hepatoma Cells : in vitro and in vivo Findings
摘要
Over-expressed in cancer cells, hexokinase II (HK II) forms a mitochondrial complex, which promotes cancer survival. 3- Bromopyruvic acid (3-BrPA) dissociates HK II from this complex, causing cell death, and thus, having an anti-tumor effect. The design of this study was to first analyze the expression of HK II in the hepatoma cell line, BEL-7402, then investigate the effects of 3-Br-PA on these cells, and finally, discuss its potential for clinical usage. HK II expression was detected in BEL-7402 cells by immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). In vitro treatment of cells with 3-BrPA significantly inhibited their growth, as evaluated by MTT assay and adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA). To analyze the in vivo function and safety of this drug, a tumor model was established by subcutaneously implanting hepatic cancer cells into nude mice. 3-BrPA treatment (50 mg/kg ip. daily, 6 days/week for three weeks) was effective in the animal model by attenuating tumor growth and causing tumor necrosis. Toxic signs were not observed. The acute toxicity study provided an LD50 of 191.7 mg/kg for 3-BrPA. Taken together, our in vitro and in vivo analyses suggest that 3-BrPA exerts anti-hepatoma effects, and may be an effective pharmacological agent for the treatment of hepatocellular carcinoma.
771-776