Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.     

Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma

Background

Despite the availability of multiple treatment strategies, patients with advanced colon carcinoma (CC) have poor prognoses. The aim of this study was to evaluate the efficacy and safety of natural killer (NK) cell therapy in combination with chemotherapy in patients with locally advanced CC.

术中局部化疗对大肠癌患者预后影响的临床观察

目的：观察术中局部化疗对大肠癌患者的预后影响,探讨提高大肠癌患者临床疗效的辅助治疗方法。方法：选择DuckB期和DuckC期患者76例,根据自愿的原则均分为常规手术组和术中化疗组,常规手术组采取常规手术治疗,术中化疗组在常规手术过程中给予局部化疗治疗,比较两组患者术后第7d血常规、肝肾功能及两组患者术后并发症,并随访两组患者术后12个月和24个月局部复发情况。结果：两组患者在术后血常规、肝肾功能及术后并发症方面比较,差异无统计学意义（P〉0．05）;术后12个月和24个月局部复发病例比较,差异具有统计学意义①〈0．05）,术中化疗组显著少于常规手术组。结论：在DuckB期和DuckC期大肠癌患者外科手术治疗过程中．应积极采取术中化疗的治疗措施。     

乳腺癌CXCR1的表达特征及其与新辅助化疗疗效的相关性

目的:研究趋化因子受体CXCR1在乳腺癌组织中的表达特征,并探讨新辅助化疗前后其表达变化与化疗疗效的关系。方法:选取20例正常乳腺组织,20例乳腺纤维腺瘤,104例乳腺癌标本,免疫组化染色后统计每例标本CXCR1的阳性表达积分,分析不同乳腺疾病CXCR1的表达差异。统计新辅助化疗前后乳腺癌标本CXCR1的阳性表达积分的变化,分析其与化疗病理反应的关系。结果:CXCR1在正常乳腺组织、乳腺纤维腺瘤中低表达,在乳腺癌组织上高表达;其表达与患者的年龄、原发肿瘤的大小无关(P0.05),与病理分期、癌细胞的分化程度、淋巴结转移个数、激素受体状态及Her2表达情况相关,P0.05,有统计学意义。新辅助化疗后,癌组织中CXCR1的表达下降,下降幅度越大,其化疗疗效越好。结论:CXCR1的检测对于乳腺疾病的良恶性判断有指导意义,可辅助判断乳腺癌的恶性程度、侵袭性以及预后,CXCR1表达的下降与化疗疗效相关,抑制其表达可能可以提高化疗疗效。     

术中局部化疗对大肠癌患者预后影响的临床观察

目的:观察术中局部化疗对大肠癌患者的预后影响,探讨提高大肠癌患者临床疗效的辅助治疗方法。方法:选择DuckB期和DuckC期患者76例,根据自愿的原则均分为常规手术组和术中化疗组,常规手术组采取常规手术治疗,术中化疗组在常规手术过程中给予局部化疗治疗,比较两组患者术后第7d血常规、肝肾功能及两组患者术后并发症,并随访两组患者术后12个月和24个月局部复发情况。结果:两组患者在术后血常规、肝肾功能及术后并发症方面比较,差异无统计学意义(P>0.05);术后12个月和24个月局部复发病例比较,差异具有统计学意义(P<0.05),术中化疗组显著少于常规手术组。结论:在DuckB期和DuckC期大肠癌患者外科手术治疗过程中,应积极采取术中化疗的治疗措施。     

Models for the effect of toxicant in single-species and predator-prey systems

Models of single-species and predator-prey systems in a polluted closed environment are developed and partially analyzed. Three cases are considered: a single influx of toxicant, a constant influx of toxicant, and a periodic pollution of the environment. In the case of single-species growth we are able to determine some local and global dynamics. In the case of predator-prey systems, we investigate the existence of steady states for a small constant influx of toxicant.On leave from Department of Mathematics, Indian Institute of Technology, Kanpur, IndiaResearch partially supported by the Natural Sciences and Engineering Research Council of Canada, Grant No. NSERC A4823     

重离子辐射治疗进展

本文简略地回顾了重离子治疗的历史,更多的兴趣集中在重离子治癌的进展上。为了利用重离子的优越特性(例如：剂量局域性和高的生物效率),已经开发了几种技术。在临床试验中获得了令人鼓舞的治疗效果,广泛地提出了物理和辐射生物方面的临床结果和治疗技术,概要地分析了重离子治癌的前景。     

新辅助化疗与营养支持对老年结肠癌患者T 细胞，COX-2 及tM2-PK水平的影响

目的：探讨新辅助化疗与营养支持综合治疗对老年结肠癌患者血清肿瘤标记物水平、COX-2 及生活质量影响及临床意义。方法：选取我科收治的老年结肠癌患者80 例,根据治疗方案不同分为对照组与试验组。对照组常规行结肠癌根治切除术,试验组应用FOLFOX3 方案。比较两组患者血清肿瘤标记物CEA 及CA19-9 水平、COX-2 水平及CD4+、CD8+及tM2-PK 水平。结果：与治疗前相比,治疗后试验组和对照组CEA 及CA19-9 水平降低（P<0.05),COX-2、tM2-PK 水平降低（P<0.05),CD4+及CD4+/CD8+水平降低（P<0.05),CD8+水平升高（P<0.05)。与对照组比较,试验组COX-2、tM2-PK 水平、CD4+、CD8+水平改善明显优于对照组,差异具有统计学意义（P<0.05),而CEA 及CA19-9 水平组间比较,差异无统计学意义（P>0.05）。结论：新辅助化疗与营养支持综合治疗可杀伤老年结肠癌患者全身不可见转移肿瘤细胞,控制病情,临床疗效理想。     

Posterior kV-CBCT scanning of the head and neck region minimizes doses to critical organs with sustained image quality

We evaluated the absorbed dose to critical organs, as well as the image quality, at different partial angles in kV-CBCT (Cone Beam Computed Tomography) scanning of the head and neck region. CBCT images of phantom from a 200° rotation were performed by using three different scanning paths, anterior, posterior, and right lateral with Catphan504 and RANDO phantoms. Critical organ dose was measured using TLD 100H in the RANDO phantom. The image quality of those phantoms was evaluated, using HU uniformity, HU linearity, contrast-to-noise ratio, low contrast visibility and spatial resolution with the Catphan504 dataset; and 5-point grading scales for the RANDO phantom dataset by five radiation oncologists. The image qualities from Catphan504 and RANDO phantom of every scanning path were comparable, with no statistically significant difference (p ≥ 0.05). However, there was a significant difference in the critical organ dose in all paths (p < 0.05), depending on the critical organ location and the scanning direction. Scanning directions show no effects on the image quality. Differences in absorbed dose to critical organs should were evaluated. The posterior scanning path for the CBCT was deemed preferable due because of considerably lower doses to several critical organs of the head and neck region.     

Correlation between lymphocyte-mediated auto-tumor reactivities and the clinical course

Summary T-cell-enriched lymphocyte populations of 69 lung carcinoma (44 squamous cell, 23 adeno-, and two large cell carcinoma) patients were investigated at the time of surgery for proliferative response to, and/or cytotoxic potential against, freshly separated autologous tumor cells. Tumor-free period and survival time of the patients were correlated with the reactivity obtained in the in vitro tests. The observation time varied between 20 and 78 months (mean 52). Tumor-free period and survival time were longer and survival rate higher in the group with lymphocyte reactivity toward their tumors. In the non-reactive group, all patients but one died within 3 years. Almost all patients had cytotoxic lymphocytes against K562, the three who did not belonging to the category with short survival time.     

The toxicity of azidothymidine (AZT) on human and animal cells in culture at concentrations used for antiviral therapy

AZT, a chain terminator of DNA synthesis originally developed for chemotherapy, is now prescribed as an antihuman immunodeficiency virus (HIV) drug at 500 to 1500 mg/person/day, which corresponds to 20 to 60 M AZT. The human dosage is based on a study by the manufacturer of the drug and their collaborators, which reported in 1986 that the inhibitory dose for HIV replication was 0.05 to 0.5 M AZT and that for human T-cells was 2000 to 20,000 times higher, i.e. 1000 M AZT. This suggested that HIV could be safely inhibited in humans at 20 to 60 M AZT. However, after the licensing of AZT as an anti-HIV drug, several independent studies reported 20-to 1000-fold lower inhibitory doses of AZT for human and animal cells than did the manufacturer's study, ranging from 1 to 50 M. In accord with this, life threatening toxic effects were reported in humans treated with AZT at 20 to 60 M. therefore, we have re-examined the growth inhibitory doses of AZT for the human CEM T-cell line and several other human and animal cells. It was found that at 10 M and 25 M AZT, all cells are inhibited at least 50% after 6 to 12 days, and between 20 and 100% after 38 to 48 days. Unexpectedly, variants of all cell types emerged over time that were partially resistant to AZT. It is concluded that AZT, at the dosage prescribed as an anti-HIV drug, is highly toxic to human cells.     

Potentiating effects of GHRH analogs on the response to chemotherapy

Growth hormone releasing hormone (GHRH) from hypothalamus nominatively stimulates growth hormone release from adenohypophysis. GHRH is also produced by cancers, acting as an autocrine/paracrine growth factor. This growth factor function is seen in lymphoma, melanoma, colorectal, liver, lung, breast, prostate, kidney, bladder cancers. Pituitary type GHRH receptors and their splice variants are also expressed in these malignancies. Synthetic antagonists of the GHRH receptor inhibit proliferation of cancers. Besides direct inhibitory effects on tumors, GHRH antagonists also enhance cytotoxic chemotherapy. GHRH antagonists potentiate docetaxel effects on growth of H460 non-small cell lung cancer (NSCLC) and MX-1 breast cancer plus suppressive action of doxorubicin on MX-1 and HCC1806 breast cancer. We investigated mechanisms of antagonists on tumor growth, inflammatory signaling, doxorubicin response, expression of drug resistance genes, and efflux pump function. Triple negative breast cancer cell xenografted into nude mice were treated with GHRH antagonist, doxorubicin, or their combination. The combination reduced tumor growth, inflammatory gene expression, drug-resistance gene expression, cancer stem-cell marker expression, and efflux-pump function. Thus, antagonists increased the efficacy of doxorubicin in HCC1806 and MX-1 tumors. Growth inhibition of H460 NSCLC by GHRH antagonists induced marked downregulation in expression of prosurvival proteins K-Ras, COX-2, and pAKT. In HT-29, HCT-116 and HCT-15 colorectal cancer lines, GHRH antagonist treatment caused cellular arrest in S-phase of cell cycle, potentiated inhibition of in vitro proliferation and in vivo growth produced by S-phase specific cytotoxic agents, 5-FU, irinotecan and cisplatin. This enhancement of cytotoxic therapy by GHRH antagonists should have clinical applications.