共查询到20条相似文献,搜索用时 15 毫秒
1.
Lokeswari P. Tangella Michael E. Clark Elin S. Gray 《Biochimica et Biophysica Acta (BBA)/General Subjects》2021,1865(1):129736
BackgroundThe introduction of targeted therapies for the treatment of BRAF-mutant melanomas have improved survival rates in a significant proportion of patients. Nonetheless, the emergence of resistance to treatment remains inevitable in most patients.Scope of reviewHere, we review known and emerging molecular mechanisms that underlay the development of resistance to MAPK inhibition in melanoma cells and the potential strategies to overcome these mechanisms.Major conclusionsMultiple genetic and non-genetic mechanisms contribute to treatment failure, commonly leading to the reactivation of the MAPK pathway. A variety of resistance mechanisms are enabled by the underlying heterogeneity and plasticity of melanoma cells. Moreover, it has become apparent that resistance to targeted therapy is underpinned by early functional adaptations involving the rewiring of cell states and metabolic pathways.General significanceThe evidence presented suggest that the use of a combinatorial treatment approach would delay the emergence of resistance and improve patient outcomes. 相似文献
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Notoriously resistant malignant melanoma is one of the most increasing forms of cancer worldwide; there is thus a precarious need for new treatment options. The Wee1 kinase is a major regulator of the G(2)/M checkpoint, and halts the cell cycle by adding a negative phosphorylation on CDK1 (Tyr15). Additionally, Wee1 has a function in safeguarding the genome integrity during DNA synthesis. To assess the role of Wee1 in development and progression of malignant melanoma we examined its expression in a panel of paraffin-embedded patient derived tissue of benign nevi and primary- and metastatic melanomas, as well as in agarose-embedded cultured melanocytes. We found that Wee1 expression increased in the direction of malignancy, and showed a strong, positive correlation with known biomarkers involved in cell cycle regulation: Cyclin A (p<0.0001), Ki67 (p<0.0001), Cyclin D3 (p = 0.001), p21(Cip1/WAF1) (p = 0.003), p53 (p = 0.025). Furthermore, high Wee1 expression was associated with thicker primary tumors (p = 0.001), ulceration (p = 0.005) and poor disease-free survival (p = 0.008). Transfections using siWee1 in metastatic melanoma cell lines; WM239(WTp53), WM45.1(MUTp53) and LOX(WTp53), further support our hypothesis of a tumor promoting role of Wee1 in melanomas. Whereas no effect was observed in LOX cells, transfection with siWee1 led to accumulation of cells in G(1)/S and S phase of the cell cycle in WM239 and WM45.1 cells, respectively. Both latter cell lines displayed DNA damage and induction of apoptosis, in the absence of Wee1, indicating that the effect of silencing Wee1 may not be solely dependent of the p53 status of the cells. Together these results reveal the importance of Wee1 as a prognostic biomarker in melanomas, and indicate a potential role for targeted therapy, alone or in combination with other agents. 相似文献
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Blank CU Hooijkaas AI Haanen JB Schumacher TN 《Cancer immunology, immunotherapy : CII》2011,60(10):1359-1371
The treatment of human melanoma has progressed markedly in recent years. Building on the observation that immune recognition
is a frequent event in melanoma, a series of immunotherapeutic approaches have been evaluated in clinical trials, culminating
in the first phase III study improving overall survival of melanoma patients since 20 years. However, the response rates seen
upon immunotherapeutic interventions such as anti-CTLA4 treatment are often low. Furthermore, clinical responses can take
several weeks to develop, during which time stage IV melanoma patients often deteriorate. Recent advances in our understanding
of the genetic lesions in human melanoma now also allow the specific targeting of the signaling pathway alterations in this
disease. Such targeted therapies can lead to high response rates, although the duration of these responses is thus far relatively
short. We suggest that the combination of immuno and targeted therapy offers potential for synergy for both conceptual and
practical reasons. In this review, we will discuss the potential and possible limitations for such combination therapy, and
we describe the most promising combinations of targeted therapy and immunotherapy that can be tested in the clinic in the
coming years. The concept of induction therapy by small molecule administration and consolidation by immunotherapeutics also
has potential for the treatment of other human cancers. 相似文献
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Combination therapies aim to overcome the limitations of individual drugs by selecting diverse targets of action to enhance effectiveness synergistically. This article reviews the principles of combination therapy and its applications for benign prostatic hyperplasia and overactive bladder. It then examines pathophysiological, pharmacological, and clinical evidence for currently available drug and device combinations for erectile dysfunction that has not responded to first-line, single-agent therapy. 相似文献
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Patricia M. Reynolds Roger L. Dawkins Michael J. Byrne 《Cancer immunology, immunotherapy : CII》1978,4(3):185-192
Summary The effects on the immune system of highdose cyclical combination chemotherapy were studied in nine patients with advanced malignant melanoma. Chemotherapy consisted of monthly cycles of dimethyl triazeno imidazole carboxamide 150 mg/m2 i.v. daily from days 1–5, cyclophosphamide 1000 mg/m2 i.v. on day 5, and vincristine 1.4 mg/m2 i.v. on day 5.Immunological testing was carried out prior to treatment and at weekly intervals during the first month.B, T and non-B, non-T cell numbers all tended to fall early in the cycle as did the phytohaemagglutinin(PHA)-induced transformation and PHA-induced cytotoxicity to chicken red cells. Although PHA-induced transformation and cytotoxicity usually returned to normal by day 29, B and T cell numbers often remained subnormal. In contrast, levels for antibody-dependent, cell-mediated cytotoxicity (ADCC) were relatively stable throughout the cycle. Two patients with subsequent tumour response to therapy had rebound supranormal PHA transformations between weeks 1 and 3 of the first cycle. No other changes correlated with prognosis in individual patients.Analysis of the temporal relationships between PHA transformation, PHA-induced cytotoxicity, and ADCC supported the concept that the three assays reflect the function of separate mononuclear cell subpopulations.The stability of ADCC is of particular interest in view of other work suggesting that this function may be important in immune responses to tumours, including melanoma.Work was supported by grants from the National Health and Medical Research Council and the Western Australian Arthritis and Rheumatism Foundation, and the Cancer Council of Western Australia 相似文献
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The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and 2 G protein-coupled receptor subtypes, ETAR and ETBR, promotes growth and progression of a variety of tumors, such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, lung, bladder, endometrial carcinoma, Kaposi's sarcoma, brain tumors, and melanoma. Acting on selective receptors, ET-1 regulates mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptors, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion, and metastatic dissemination. At the molecular level, endothelin receptor antagonists, besides providing ideal tools for dissecting the ET axis, have demonstrated their potential in developing novel therapeutic strategies. Emerging experimental and clinical data demonstrate that interfering with endothelin receptors provides an opportunity for the development of rational combinatorial approaches using endothelin receptor antagonists in combination with chemotherapy or molecularly targeted therapy. 相似文献
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Harbour JW 《Pigment cell & melanoma research》2012,25(2):171-181
Uveal melanoma is the second most common form of melanoma and the most common primary intraocular malignancy. Until recently, very little was known about the genetics of this aggressive cancer. Mutations in oncogenes and tumor suppressors that are common in other cancers are conspicuously absent in uveal melanoma. In recent years, however, uveal melanoma has begun to yield its secrets, and a fascinating picture is emerging of how it develops and progresses. Mutations in the G(q) alpha subunits, encoded by GNAQ and GNA11, appear to be early or perhaps initiating events that require further mutations for malignant transformation. On the other hand, mutations in the BRCA1-associated protein-1 (BAP1) appear to occur later and demarcate a molecular brink beyond which metastasis becomes highly likely. BAP1 mutations can also occur in the germline, leading to a distinctive cancer predisposition syndrome. These mutations appear to be key events that provide the potential for targeted therapy. This article will review the genetic findings in uveal melanoma over the past two decades and suggest important areas for future work. 相似文献
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A M Jordan T H Khan H Malkin H M Osborn A Photiou P A Riley 《Bioorganic & medicinal chemistry》2001,9(6):1549-1558
Evaluation of second generation prodrugs for MDEPT, by oximetry, has highlighted structural properties that are advantageous and disadvantageous for efficient oxidation using mushroom tyrosinase. In particular, a sterically undemanding prodrug bis-(2-chloroethyl)amino-4-hydroxyphenylaminomethanone 28 was synthesised and found to be oxidised by mushroom tyrosinase at a superior rate to tyrosine methyl ester, the carboxylic acid of which is the natural substrate for tyrosinase. The more sterically demanding phenyl mustard prodrugs 9 and 10 were oxidised by mushroom tyrosinase at a similar rate to tyrosine methyl ester. In contrast, tyramine chain elongation via heteroatom insertion was detrimental and the rate of mushroom tyrosinase oxidation of phenyl mustard prodrugs 21 and 22 decreased by 10 nanomol/min. 相似文献
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H Liu J Lu Y Hua P Zhang Z Liang L Ruan C Lian H Shi K Chen Z Tu 《Cell death & disease》2015,6(1):e1595
Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected epidermal growth factor receptor (EGFR) signaling cascades by markedly decreasing the levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support that EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found that the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, whereas SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Although SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited the growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of hematoxylin/eosin staining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assays, and immunohistochemistry staining of phosphorylated cyclin-dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR.Gastric cancer (GC) remains the fifth most common cancer worldwide, with an estimated 9 52 000 new cases (7% of total cancer incidence) and 7 23 000 deaths (9% of total cancer mortality) in 2012.1 As a highly aggressive and lethal malignancy, the aggressive nature of GC is linked to mutations in tumor suppressor genes, oncogenes, growth factors and their receptors, and so on.2 Till now, there are few effective treatment options for advanced patients with distant metastasis or recurrence.3 The detailed mechanisms that regulate GC are not yet fully understood; therefore, such situations underscore the persistent unmet need to identify therapeutics that target pathways involved in GC progression.Consequently, identification of key regulatory molecules in GC is of high priority for understanding the mechanism for tumor dissemination as well as the development of novel interventions. Aberrant expression and kinase activity of Src have been found in many different tumors, including GC.4, 5 Previous studies have shown that phosphorylated mammalian target of rapamycin (p-mTOR) was significantly overexpressed in advanced GC patients'' tumors and suggested that the PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mTOR) pathway is activated in GC with potential prognostic and predictive significance.6, 7 Aurora A overexpression has recently been reported in GC, and it was suggested to be associated with cancer progression and poor prognosis.8, 9, 10In our previous work, we conducted data mining meta-analyses integrating results from multiple small interfering RNA (siRNA) screens to identify gene targets, which are necessary for the growth of different cancer cells. Among those genes, we found that heat-shock protein 90 (HSP90) was one of the most vital proteins for cancer cell survival.11 As we know, HSP90 is involved in the regulation of numerous proteins important for GC pathogenesis, such as proteins important for cell adhesion (e.g., focal adhesion kinase), cell motility (e.g., epidermal growth factor receptor (EGFR), c-Src, phosphoinositide-dependent protein kinase 1 (PDK1)), and angiogenesis (e.g., hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor receptor (VEGFR)).12, 13, 14, 15 For these reasons, HSP90 has been of considerable interest as a therapeutic target in GC.As an ATP-dependent molecular chaperone protein, HSP90 conducts the proper folding of myriad proteins.12, 14 Abnormally high expression of HSP90 has been found in GC and been greatly considered as an independent prognostic marker of GC progression.16, 17, 18 HSP90 remains an attractive therapeutic target in a variety of cancers,19, 20, 21, 22 and inhibition of HSP90 showed potent growth inhibitory effects on GC in cell cultures and in mouse models.23, 24, 25 Ganetespib is a particularly promising second-generation HSP90 inhibitor that does not suffer from the toxicity issues associated with earlier-generation HSP90 inhibitors and exhibits increased potency compared with first- and other second-generation agents.11, 26, 27, 28, 29In this current study, using cell culture and xenograft mouse models, we sought to evaluate the effects of ganetespib treatments on GC cells, individually or in combination with other treatments. In addition, we searched for the possible mechanisms underlying the antitumor activities of ganetespib. And, our results suggested that, as a promising drug candidate, ganetespib has potent antitumor activities on GC, and it is worth being investigated further clinically for the molecularly targeted therapy of GC patients. 相似文献
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Non-small cell lung cancer (NSCLC) is an intractable disease for which effective treatment approaches are urgently needed. The ability to induce antigen-specific immune responses in patients with lung cancer has led to the development of immunotherapy as a novel concept for the treatment of NSCLC. Adoptive cellular therapy (ACT) represents an important advancement in cancer immunotherapy with the utilization of tumor infiltrating lymphocytes, cytokine-induced killer cells, natural killer cells and γδ T cells. In this study, we review recent advances in ACT for NSCLC in clinical trials and provide a perspective on the improvement in ACT and potential therapeutic approaches using engineered T cell therapy for NSCLC. 相似文献
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The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib has been approved for years as a first-line therapy for patients harboring EGFR-sensitizing mutations. With the promising implementation of immunotherapeutic strategies for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize immune approaches in the context of conventional or targeted therapies. Tumor cells are known to evade immune attack by multiple strategies, including undergoing phenotypic plasticity via a process designated as the epithelial–mesenchymal transition (EMT). As signaling through EGFR is a major inducer of EMT in epithelial cells, we have investigated the effect of EGFR inhibition with erlotinib on tumor phenotype and susceptibility to immune attack. Our data shows that short-term exposure of tumor cells to low-dose erlotinib modulates tumor plasticity and immune-mediated cytotoxicity in lung cancer cells harboring a sensitizing EGFR mutation, leading to a remarkable enhancement of tumor lysis mediated by innate NK cells and antigen-specific T cells. This effect positively correlated with the ability of short-term EGFR blockade to modulate tumor phenotype towards a more epithelial one, as well as to increase susceptibility to caspase-mediated apoptosis. The effect, however, was lost when erlotinib was utilized for long periods of time in vitro or in vivo, which resulted in gain of mesenchymal features and decreased (rather than increased) tumor lysis in response to immune effector mechanisms. Our data provides rationale for potential combinations of erlotinib and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.Lung cancer is the leading cause of cancer related deaths in the world, with the majority of cases (~85%) corresponding to the non-small cell lung cancer (NSCLC) type.1 Frequently, proliferation and survival of NSCLC is driven by the oncogene epidermal growth factor receptor (EGFR), which results deregulated in tumors by means of mutation or gene amplification.2 The frequency of EGFR deregulation in NSCLC has led to the development of several EGFR-targeted therapies, including erlotinib, an approved EGFR tyrosine kinase inhibitor (EGFR-TKIs) that is widely used for the treatment of NSCLC.3, 4 Presence of EGFR-sensitizing mutations, mainly deletions in exon 19 or the L858R substitution in exon 21 of EGFR, has shown to best predict responses to erlotinib and other EGFR-TKIs in patients;5 however, despite a remarkable tumor debulking caused by EGFR signaling blockade, tumor relapse is seen in almost 100% of treated patients, resulting in very low long-term survival rates.6Given the high mortality rate of NSCLC, there is a pressing call for novel therapeutic approaches that could circumvent the therapeutic resistance seen in the clinic thus far.7 In recent years, immunotherapeutic strategies have become recognized means to stimulate the destruction of tumor cells by manipulating or enhancing anti-tumor immune responses. However, there is still a need for further improvement of immune-mediated approaches for the treatment of NSCLC.8 One aspect for consideration in this regard is the ability of tumor cells to evade immune responses by an array of strategies,9, 10 including their ability to undergo profound phenotypic plasticity via a process designated as the epithelial–mesenchymal transition (EMT).11, 12 This phenomenon is now recognized as a mechanism of progression in carcinomas,13, 14, 15 where it promotes tumor cell migration, invasion and metastasis, as well as the acquisition of resistance to a variety of anti-cancer therapeutics, including resistance to immune-mediated cytotoxic lysis.16, 17, 18, 19Accumulating evidence links the EGF/EGFR axis to the phenotypic plasticity of solid tumors. In multiple reports in different cancer types, signaling through this axis has been described as a driver of tumor EMT20, 21 and given these observations, blockade of EGFR signaling has been explored and shown to revert the phenotype of tumor cells from a mesenchymal-like to an epithelial one.20, 22 Interestingly, long exposure to EGFR-TKIs, resulting in the acquisition of tumor resistance and relapse, has been linked to the acquisition of mesenchymal properties in tumor cells, as mesenchymal-like cells are less sensitive to the cytotoxic effects of EGFR inhibition.23, 24, 25, 26Although the effect of EGFR-TKIs in cancer signaling and clinical outcome are well established, the potential of blocking EGFR signaling as a means to facilitate tumor targeting by anti-tumor immune effector cells has not been thoroughly investigated. In this study, EGFR inhibition has been explored both in vitro and in vivo with xenografts of EGFR-mutated NSCLC cells, in terms of its ability to modulate epithelial versus mesenchymal features and to improve tumor sensitivity to immune-mediated attack. Our data demonstrate that short-term, low-dose erlotinib modulates immune-mediated cytotoxicity of NSCLC cells, leading to a remarkable enhancement of tumor cell lysis. This effect positively correlated with the ability of short-term blockade of EGFR signaling to modulate tumor phenotype towards a more epithelial one. The effect, however, was lost when erlotinib was utilized for long periods of time (⩾72 h both in vitro or in vivo), which resulted in tumor mesenchymalization and decreased tumor lysis in response to immune effector mechanisms. The data presented here thus provide rationale for potential combinations of erlotinib and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term treatment with an EGFR-TKI. 相似文献
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B S Larsson B Larsson A Roberto 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》1989,2(4):356-360
Previous studies have shown that some thioamides, e.g., thiouracil, are incorporated as false precursors into melanin during its synthesis. If boronated analogs of the thioamides share this property, the melanin of melanotic melanomas offers a possibility for specific tumoural uptake and retention of boron as a basis for neutron capture therapy. We report on the synthesis of boronated 1H-1,2,4-triazole-3-thiol (B-TZT), boronated 5-carboxy-2-thiouracil (B-CTU), and boronated 5-diethylaminomethyl-2-thiouracil (B-DEAMTU) and the localization of these substances in melanotic melanomas transplanted to mice. The distribution in the mice was studied by boron neutron capture radiography. B-TZT and B-CTU showed the highest tumour:normal tissue concentration ratios, with tumour:liver ratios of about 4 and tumour:muscle ratios of about 14; B-DEAMTU showed corresponding ratios of 1.4 and 5, respectively. The absolute concentration of boron in the tumours, however, was more than three times higher in the mice injected with B-TZT, compared with B-CTU. The results suggest that B-TZT may be the most promising compound of the three tested with regard to possible therapy of melanotic melanomas. 相似文献
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Ozgur Sahin Qingfei Wang Samuel W Brady Kenneth Ellis Hai Wang Chia-Chi Chang Qingling Zhang Preety Priya Rui Zhu Stephen T Wong Melissa D Landis William J Muller Francisco J Esteva Jenny Chang Dihua Yu 《Cell research》2014,24(5):542-559
Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors by-passed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment. 相似文献
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V Vicente M Gomez M M Ochotorena A Cremades M Canteras 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》1990,3(1):1-7
We studied, by means of quantitative histopathological methods, the changes that took place in B16 melanoma implanted into C57BL/6J mice after combination treatment of hyperthermia, melphalan, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). The studies were made on animals sacrificed on days 11, 18, and 25 after implantation. Tumors in treated animals showed a progressive delay in growth, a noticeably reduced number of metastases, and diminution of proliferative capacity. However, this treatment did not affect necrosis, stroma, capsule, or cell infiltration. Ultrastructurally, signs of cell damage were constantly present. 相似文献
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Moldvay J 《Magyar onkologia》2007,51(3):191-196
Lung cancer is the leading cause of cancer death worldwide, and it is responsible for 20-25% of all cancer deaths. In Hungary, more than 4,000 lung cancer patients receive chemotherapy every year, and of them 3,000 suffer from non-small cell lung cancer. Despite the rapid development in antitumor treatment options, the response rates of chemotherapies in non-small cell lung cancer still remain between 15-35%. Recently, EGFR tyrosine kinase inhibitor therapy has been introduced with a response rate of 15% when used in unselected patients. However, this ratio may increase up to 70% when only patients with tumors containing EGFR mutation are treated. Therefore, results of translational research that could help pulmonologists and oncologists to apply tailored therapy in lung cancer patients are of great importance. The purpose of our work was to establish a model in order to study the relevance of immunohistochemical and molecular biological analyses of tumor specimens in treatment and patient selection, and to investigate their cost-sparing effects. We concluded that the most cost-effective type of patient selection could be achieved with EGFR mutation status analysis of the tumor tissue. Our results may help to determine the most cost-effective way of patient selection in case of non-small cell lung cancer patients requiring second line therapy; moreover, they might serve as a basis for further economic analyses. 相似文献