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ABCG2-overexpressing S1-M1-80 cell xenografts in nude mice keep original biochemistry and cell biological properties.

Fang WANG ; Yong-Ju LIANG ; Xing-Ping WU ; Xiao-Dong SU ; Li-Wu FU

Chinese Journal of Cancer.2012;31(3):150-158. doi:10.5732/cjc.011.10310

S1-M1-80 cells, derived from human colon carcinoma S1 cells, are mitoxantrone-selected ABCG2-overexpressing cells and are widely used in in vitro studies of multidrug resistance(MDR). In this study, S1-M1-80 cell xenografts were established to investigate whether the MDR phenotype and cell biological properties were maintained in vivo. Our results showed that the proliferation, cell cycle, and ABCG2 expression level in S1-M1-80 cells were similar to those in cells isolated from S1-M1-80 cell xenografts (named xS1-M1-80 cells). Consistently, xS1-M1-80 cells exhibited high levels of resistance to ABCG2 substrates such as mitoxantrone and topotecan, but remained sensitive to the non-ABCG2 substrate cisplatin. Furthermore, the specific ABCG2 inhibitor Ko143 potently sensitized xS1-M1-80 cells to mitoxantrone and topotecan. These results suggest that S1-M1-80 cell xenografts in nude mice retain their original cytological characteristics at 9 weeks. Thus, this model could serve as a good system for further investigation of ABCG2-mediated MDR.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; Adenosine ; analogs & derivatives ; pharmacology ; Animals ; Antineoplastic Agents ; pharmacology ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; drug effects ; Cisplatin ; pharmacology ; Colonic Neoplasms ; metabolism ; pathology ; Diketopiperazines ; Doxorubicin ; metabolism ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Female ; Heterocyclic Compounds, 4 or More Rings ; Humans ; Inhibitory Concentration 50 ; KB Cells ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitoxantrone ; pharmacology ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; Neoplasm Transplantation ; Rhodamine 123 ; metabolism ; Topotecan ; pharmacology

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Functional roles and clinical values of insulin-like growth factor-binding protein-5 in different types of cancers.

Gökçe GÜLLÜ ; Sevgi KARABULUT ; Mustafa AKKIPRIK

Chinese Journal of Cancer.2012;31(6):266-280. doi:10.5732/cjc.011.10405

Insulin-like growth factor-binding proteins(IGFBPs) are critical regulators of the mitogenic activity of insulin-like growth factors (IGFs). IGFBP5, one of these IGFBPs, has special structural features, including a nuclear transport domain, heparin-binding motif, and IGF/extracellular matrix/acid-labile subunit-binding sites. Furthermore, IGFBP5 has several functional effects on carcinogenesis and even normal cell processes, such as cell growth, death, motility, and tissue remodeling. These biological effects are sometimes related with IGF (IGF-dependent effects) and sometimes not (IGF-independent effects). The functional role of IGFBP5 is most likely determined in a cell-type and tissue-type specific manner but also depends on cell context, especially in terms of the diversity of interacting proteins and the potential for nuclear localization. Clinical findings show that IGFBP5 has the potential to be a useful clinical biomarker for predicting response to therapy and clinical outcome of cancer patients. In this review, we summarize the functional diversity and clinical importance of IGFBP5 in different types of cancers.
Animals ; Apoptosis ; Cell Differentiation ; Cell Movement ; Humans ; Insulin-Like Growth Factor Binding Protein 5 ; genetics ; metabolism ; physiology ; Neoplasm Metastasis ; Neoplasms ; metabolism ; pathology ; Protein Binding ; RNA, Messenger ; metabolism ; Signal Transduction ; Somatomedins ; metabolism

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Long-term molecular changes in WHO grade II astrocytomas following radiotherapy.

Wei-Ying YUE ; Ke SAI ; Qiu-Liang WU ; Yun-Fei XIA ; Su-Huan YU ; Zhong-Ping CHEN

Chinese Journal of Cancer.2012;31(3):159-165. doi:10.5732/cjc.011.10149

Monitoring the long-term radiotherapy-associated molecular changes in low-grade gliomas (LGGs) facilitates the understanding of LGG response to radiotherapy. In this study, we used immunohistochemistry to analyze the expression of Ki-67, tumor protein P53 (TP53), P21, and P27 in 8 paired WHO grade II astrocytoma samples. The interval between radiotherapy (RT) and the second surgery was more than 3 months in all cases. The average Ki-67 labeling index (LI) was 5.3% in pre-RT samples and 11.54% in post-RT samples. Ki-67 LI was higher in the primary tumors that underwent malignant transformation observed at the second surgery after radiation. Post-RT Ki-67 LI decreased in 2 cases with an interval of less than 12 months between RT and the second surgery. TP53 expression was found in 3 out of 4 pre-RT samples with malignant transformation and in 1 out of 4 pre-RT samples without malignant transformation. Post-RT TP53 increased in 2 cases in which increased expression of P21 or P27 was also observed. Our study suggests that radiotherapy can inhibit WHO grade II astrocytoma proliferation as reflected by Ki-67 LI, but the effect attenuates with time. In addition, there is a tendency of malignant transformation for WHO grade II astrocytomas with a high Ki-67 level or TP53 expression in initial samples.
Adult ; Astrocytoma ; metabolism ; pathology ; radiotherapy ; surgery ; Brain Neoplasms ; metabolism ; pathology ; radiotherapy ; surgery ; Cell Proliferation ; radiation effects ; Cell Transformation, Neoplastic ; radiation effects ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; Cyclin-Dependent Kinase Inhibitor p27 ; metabolism ; Female ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; metabolism ; Male ; Middle Aged ; Neoplasm Grading ; Tumor Suppressor Protein p53 ; metabolism

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Nasopharyngeal carcinoma in Indonesia: epidemiology, incidence, signs, and symptoms at presentation.

Marlinda ADHAM ; Antonius N KURNIAWAN ; Arina Ika MUHTADI ; Averdi ROEZIN ; Bambang HERMANI ; Soehartati GONDHOWIARDJO ; I Bing TAN ; Jaap M MIDDELDORP

Chinese Journal of Cancer.2012;31(4):185-196. doi:10.5732/cjc.011.10328

Among all head and neck (H&N) cancers, nasopharyngeal carcinoma (NPC) represents a distinct entity regarding epidemiology, clinical presentation, biological markers, carcinogenic risk factors, and prognostic factors. NPC is endemic in certain regions of the world, especially in Southeast Asia, and has a poor prognosis. In Indonesia, the recorded mean prevalence is 6.2/100 000, with 13 000 yearly new NPC cases, but otherwise little is documented on NPC in Indonesia. Here, we report on a group of 1121 NPC patients diagnosed and treated at Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia between 1996 and 2005. We studied NPC incidence among all H&N cancer cases (n=6000) observed in that period, focusing on age and gender distribution, the ethnic background of patients, and the disease etiology. We also analyzed most prevalent signs and symptoms and staging of NPC patients at first presentation. In this study population, NPC was the most frequent H&N cancer (28.4%), with a male-to-female ratio of 2.4, and was endemic in the Javanese population. Interestingly, NPC appeared to affect patients at a relatively young age (20% juvenile cases) without a bimodal age distribution. Mostly, NPC initiated in the fossa of Rosenmuller and spreaded intracranially or locally as a mass in the head. Occasionally, NPC developed at the submucosal level spreading outside the anatomic limits of the nasopharynx. At presentation, NPC associated with hearing problems, serous otitis media, tinnitus, nasal obstruction, anosmia, bleeding, difficulty in swallowing and dysphonia, and even eye symptoms with diplopia and pain. The initial diagnosis is difficult to make because early signs and symptoms of NPC are not specific to the disease. Early-age Epstein-Barr virus (EBV) infection combined with frequent exposure to environmental carcinogenic co-factors is suggested to cause NPC development. Undifferentiated NPC is the most frequent histological type and is closely associated with EBV. Expression of the EBV-encoded latent membrane protein 1(LMP1) oncogene in biopsy material was compared between NPC patients of <30 years old and those of ≥30 years old, matched for sex and tumor stage. Higher LMP1 expression in patients of <30 years old was observed, which was related to more locoregional progressivity. Increased medical awareness of prevailing early stage signs and symptoms coupled to use of EBV-related diagnostic tumor markers may lead to down-staging and timely treatment to improve survival of patients with this aggressive disease.
Adolescent ; Adult ; Age Distribution ; Aged ; Child ; Epstein-Barr Virus Infections ; Female ; Herpesvirus 4, Human ; isolation & purification ; Humans ; Incidence ; Indonesia ; epidemiology ; ethnology ; Male ; Middle Aged ; Nasopharyngeal Neoplasms ; epidemiology ; ethnology ; pathology ; virology ; Sex Factors ; Viral Matrix Proteins ; metabolism ; Young Adult

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Prognostic value of the lymph node ratio in stage III colorectal cancer.

Jing-Qing REN ; Jian-Wei LIU ; Zhi-Tang CHEN ; Shao-Jie LIU ; Shi-Jie HUANG ; Yong HUANG ; Jing-Song HONG

Chinese Journal of Cancer.2012;31(5):241-247. doi:10.5732/cjc.011.10374

The nodal stage of colorectal cancer is based on the number of positive nodes. It is inevitably affected by the number of removed lymph nodes, but lymph node ratio can be unaffected. We investigated the value of lymph node ratio in stage III colorectal cancer in this study. The clinicopathologic factors and follow-up data of 145 cases of stage III colorectal cancer between January 1998 and December 2008 were analyzed retrospectively. The Pearson and Spearman correlation analyses were used to determine the correlation coefficient, the Kaplan-Meier method was used to analyze survival, and the Cox proportional hazard regression model was used for multivariate analysis in forward stepwise regression. We found that lymph node ratio was not correlated with the number of removed lymph nodes (r = -0.154, P = 0.065), but it was positively correlated with the number of positive lymph nodes (r = 0.739, P < 0.001) and N stage (r = 0.695, P < 0.001). Kaplan-Meier survival analysis revealed that tumor configuration, intestinal obstruction, serum carcinoembryonic antigen (CEA) concentration, T stage, N stage, and lymph node ratio were associated with disease-free survival of patients with stage III colorectal cancer (P < 0.05). Multivariate analysis showed that serum CEA concentration, T stage, and lymph node ratio were prognostic factors for disease-free survival (P < 0.05), whereas N stage failed to achieve significance (P = 0.664). We confirmed that lymph node ratio was a prognostic factor in stage III colorectal cancer and had a better prognostic value than did N stage.
Adult ; Aged ; Aged, 80 and over ; Carcinoembryonic Antigen ; blood ; Chemotherapy, Adjuvant ; Colectomy ; Colorectal Neoplasms ; blood ; drug therapy ; pathology ; surgery ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Lymph Node Excision ; Lymph Nodes ; pathology ; surgery ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Rectum ; surgery ; Retrospective Studies ; Young Adult

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Role of ABC transporters in cancer chemotherapy.

Yue-Li SUN ; Atish PATEL ; Priyank KUMAR ; Zhe-Sheng CHEN

Chinese Journal of Cancer.2012;31(2):51-57. doi:10.5732/cjc.011.10466

Multidrug resistance (MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality. The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette (ABC) transporters, which can increase efflux of drugs from cancer cells, thereby decreasing intracellular drug concentration. Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs. This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; metabolism ; Antineoplastic Agents ; therapeutic use ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Molecular Targeted Therapy ; Multidrug Resistance-Associated Proteins ; antagonists & inhibitors ; metabolism ; Nanomedicine ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; Neoplasms ; drug therapy ; metabolism ; Protein-Tyrosine Kinases ; antagonists & inhibitors

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Ex vivo expansion of tumor-infiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy.

Jia HE ; Xiao-Feng TANG ; Qiu-Yan CHEN ; Hai-Qiang MAI ; Zhou-Feng HUANG ; Jiang LI ; Yi-Xin ZENG

Chinese Journal of Cancer.2012;31(6):287-294. doi:10.5732/cjc.011.10376

Establishing Epstein-Barr virus(EBV)-specific cytolytic T lymphocytes(EBV-CTLs) from peripheral blood mononuclear cells(PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma(NPC). In the current study, we performed ex vivo expansion of tumor-infiltrating lymphocytes(TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody(OKT3), recombinant human interleukin(IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+ T cells, a variable percentage of CD3+CD8+ and CD3+CD4+ T cells, and less than 10% of CD3-CD16+ natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.
Biopsy ; CD3 Complex ; analysis ; CD4 Antigens ; analysis ; CD8 Antigens ; analysis ; Cells, Cultured ; Herpesvirus 4, Human ; immunology ; Humans ; Immunotherapy, Adoptive ; Interferon-gamma ; metabolism ; Interleukin-10 ; metabolism ; Interleukin-2 ; pharmacology ; Interleukin-4 ; metabolism ; Lymphocytes, Tumor-Infiltrating ; immunology ; virology ; Monocytes ; pathology ; Muromonab-CD3 ; pharmacology ; Nasopharyngeal Neoplasms ; immunology ; pathology ; therapy ; virology ; Receptors, IgG ; analysis ; T-Lymphocytes, Cytotoxic ; immunology ; virology ; Tumor Necrosis Factor-alpha ; metabolism

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Targeting proliferation and survival pathways in head and neck cancer for therapeutic benefit.

Daniel E JOHNSON

Chinese Journal of Cancer.2012;31(7):319-326. doi:10.5732/cjc.011.10404

Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. Recent studies have elucidated a key signaling axis, the EGFR-STAT3-Bcl-XL signaling axis, that is aberrantly activated in a majority of HNSCC and contributes to the proliferation and survival of malignant cells. Considerable effort is being placed on developing highly specific inhibitors of different components of this pathway. This review highlights the progress that is being made towards achieving potent inhibition of the EGFR-STAT3-Bcl-XL signaling axis in HNSCC and the promising therapeutic strategies that are currently under development for this disease.
Animals ; Antibodies, Monoclonal ; pharmacology ; Antineoplastic Agents ; pharmacology ; Apoptosis ; Biphenyl Compounds ; pharmacology ; Cell Proliferation ; Head and Neck Neoplasms ; metabolism ; pathology ; Humans ; Nitrophenols ; pharmacology ; Piperazines ; pharmacology ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; STAT3 Transcription Factor ; antagonists & inhibitors ; metabolism ; Signal Transduction ; drug effects ; Sulfonamides ; pharmacology ; bcl-X Protein ; antagonists & inhibitors ; metabolism

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Reversing multidrug resistance by tyrosine kinase inhibitors.

Miao HE ; Min-Jie WEI

Chinese Journal of Cancer.2012;31(3):126-133. doi:10.5732/cjc.011.10315

Recently, a large number of tyrosine kinase inhibitors(TKIs) have been developed as anticancer agents. These TKIs can specifically and selectively inhibit tumor cell growth and metastasis by targeting various tyrosine kinases and thereby interfering with cellular signaling pathways. The therapeutic potential of TKIs has been hindered by multidrug resistance(MDR), which is commonly caused by overexpression of ATP-binding cassette(ABC) membrane transporters. Interestingly, some TKIs have also been found to reverse MDR by directly inhibiting the function of ABC transporters and enhancing the efficacy of conventional chemotherapeutic drugs. In this review, we discuss ABC transporter-mediated MDR to TKIs and MDR reversal by TKIs.
ATP-Binding Cassette Transporters ; antagonists & inhibitors ; physiology ; Antineoplastic Agents ; pharmacology ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors

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Increased pretreatment levels of serum LDH and ALP as poor prognostic factors for nasopharyngeal carcinoma.

Guo LI ; Jin GAO ; Ya-Lan TAO ; Bing-Qing XU ; Zi-Wei TU ; Zhi-Gang LIU ; Mu-Sheng ZENG ; Yun-Fei XIA

Chinese Journal of Cancer.2012;31(4):197-206. doi:10.5732/cjc.011.10283

Serum enzymes that play potential roles in tumor growth have recently been reported to have prognostic relevance in a diverse array of tumors. However, prognosis-related serum enzymes are rarely reported for nasopharyngeal carcinoma(NPC). To clarify whether the level of serum enzymes is linked to the prognosis of NPC, we reviewed the pretreatment data of lactate dehydrogenase(LDH), alkaline phosphatase (ALP), and glutamyl transferase (GGT) in 533 newly diagnosed NPC patients who underwent radical radiotherapy between May 2002 and October 2003 at Sun Yat-sen University Cancer Center. Patients were grouped according to the upper limit of normal values of LDH, ALP, and GGT. The Kaplan-Meier method and log-rank test were used for selecting prognostic factors from clinical characteristics and serum enzymes, and the chi-square test was applied to analyze the relationships of clinical characteristics and serum enzymes. Finally, a Cox proportional hazards model was used to identify the independent prognostic factors. We found that increased levels of LDH had poor effects on both overall survival and distant metastasis-free survival (P = 0.009 and 0.035, respectively), and increased pretreatment level of serum ALP had poor effects on both overall survival and local recurrence-free survival (P = 0.037 and 0.039, respectively). In multivariate analysis, increased LDH level was identified as an independent prognostic factor for overall survival. Therefore, we conclude that increased pretreatment serum LDH and ALP levels are poor prognostic factors for NPC.
Adolescent ; Adult ; Aged ; Alkaline Phosphatase ; blood ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Child ; Cisplatin ; administration & dosage ; Female ; Fluorouracil ; administration & dosage ; Humans ; Kaplan-Meier Estimate ; L-Lactate Dehydrogenase ; blood ; Male ; Middle Aged ; Nasopharyngeal Neoplasms ; blood ; drug therapy ; pathology ; radiotherapy ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Prognosis ; Proportional Hazards Models ; Radiotherapy, Computer-Assisted ; Radiotherapy, Conformal ; Radiotherapy, Intensity-Modulated ; Survival Rate ; Young Adult ; gamma-Glutamyltransferase ; blood

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