聚乙二醇在化疗药物成药性研究中的应用——以阿霉素为例

多数抗肿瘤药物的水溶性差、系统毒性和多药耐药性已成为其临床应用所面临的主要问题,而利用聚乙二醇材料构建前药或合适的 递药系统来克服这些问题,备受广大药学研究者的关注。以具有良好抗肿瘤活性和分子荧光特性的阿霉素为例,综述聚乙二醇在化疗药物 前药和递药系统的构建及制备等成药性研究中的应用,为高效低毒抗肿瘤药品的进一步研究与开发提供参考。     

Adjuvant chemotherapy with melatonin for targeting human cancers: A review

Melatonin is a multifunctional hormone that has long been known for its antitumoral effects. An advantage of the application of melatonin in cancer therapy is its ability to differentially influence tumors from normal cells. In this review, the roles of melatonin adjuvant therapy in human cancer are discussed. Combination of melatonin with chemotherapy could provide synergistic antitumoral outcomes and resolve drug resistance in affected patients. This combination reduces the dosage for chemotherapeutic agents with the subsequent attenuation of side effects related to these drugs on normal cells around tumor and on healthy organs. The combination therapy increases the rate of survival and improves the quality of life in affected patients. Cancer cell viability is reduced after application of the combinational melatonin therapy. Melatonin does all these functions by adjusting the signals involved in cancer progression, re-establishing the dark/light circadian rhythm, and disrupting the redox system for cancer cells. To achieve effective therapeutic outcomes, melatonin concentration along with the time of incubation for this indoleamine needs to be adjusted. Importantly, a special focus is required to be made on choosing an appropriate chemotherapy agent for using in combination with melatonin. Because of different sensitivities of cancer cells for melatonin combination therapy, cancer-specific targeted therapy is also needed to be considered. For this review, the PubMed database was searched for relevant articles based on the quality of journals, the novelty of articles published by the journals, and the number of citations per year focusing only on human cancers.     

SIMS microscopy in the biomedical field.

We attempted to indicate the requirements for biomedical applications of SIMS microscopy. Sample preparation methodology should preserve both the structural and the chemical integrity of the tissue. Furthermore, it is often necessary to correlate ionic and light microscope images. This implies a common methodological approach to sample preparation for both microscopes. The use of low or high mass resolution depends on the elements studied and their concentrations. To improve the acquisition and processing of images, digital imaging systems have to be designed and require both ionic and optical image superimposition. However, the images do not accurately reflect element concentration; a relative quantitative approach is possible by measuring secondary ion beam intensity. Using an internal reference element (carbon) and standard curves the results are expressed in micrograms/mg of tissue. Despite their limited lateral resolution (0.5 microns) the actual SIMS microscopes are very suitable for the resolution of biomedical problems posed by action modes and drug localization in human pathology. SIMS microscopy should provide a new tool for metabolic radiotherapy by facilitating dose evaluation. The advent of high lateral resolution SIMS imaging (less than 0.1 microns) should open up new fields in biomedical investigation.     

A single, low, oral dose of a 5-carbon-linked trioxane dimer orthoester plus mefloquine cures malaria-infected mice

Four 5-carbon-linked trioxane dimer orthoesters (6a-6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally.     

Cancer chemotherapy induces cardiotoxicity by targeting cardiac stem cells

Overwhelming data indicate that cancer survivors are at higher risk of cardiovascular diseases because chemotherapy induces cardiotoxicity. Mechanistic explanation of this phenomenon is necessary to advise the clinical practice on the prevention of cardiotoxicity in cancer patients. Here we propose that chemotherapy induces cardiotoxicity by inadvertently interrupting the homeostasis of cardiac stem cells and depleting the resident cardiac stem cells pool. As a result, the heart loses the capability of regeneration and repair and demonstrates the cardiotoxicity symptoms. Our hypothesis is supported by several lines of emerging evidence: the high incidence of cardiotoxicity in paediatric cancer patients who still have more cardiac stem cells in the myocardium; the rescue of anthracycline cardiomyopathy by injection of cardiac stem cells; and the adverse cardiotoxicity induced by inhibitors of oncogenic kinases or pathways which target cardiac stem cells besides cancer cells. This may promote our growing appreciation that cardiac stem cells represent new targets of chemotherapy that contribute to cardiotoxicity and open up novel strategies for the preservation or expansion of the cardiac stem cells pool to overcome cardiotoxicity associated with chemotherapy.     

Cyclin A2 confers cisplatin resistance to endometrial carcinoma cells via up‐regulation of an Akt‐binding protein,periplakin

Although overexpression of cyclin A2 is reportedly an indicator of a poor prognosis of various malignancies including endometrial carcinoma, its molecular mechanism remains undetermined. To address this issue, we examined the effect of cyclin A2 on the development of resistance to chemotherapeutic drugs. The expression of cyclin A2 protein was increased in advanced‐stage and chemotherapy‐refractory stage endometrial carcinomas compared with that in early‐stage tumours. The expression levels of cyclin A2 in endometrial carcinoma cell lines correlated positively with the IC₅₀ for cisplatin. Endometrial carcinoma HHUA cells that overexpressed cyclin A2 showed increased resistance to cisplatin in vitro and in vivo, via the activation of a survival pathway, the inositol‐3 phosphate kinase (PI3K) cascade. The use of a cDNA microarray identified an Akt‐binding protein, periplakin, as a novel target of cyclin A2. The cyclin A2‐induced up‐regulation of periplakin was mediated via direct binding of Sp1 to the promoter that was activated by cyclin A2 along with chromatin remodelling involving CBP/p300, and the siRNA‐mediated silencing of periplakin suppressed the PI3K pathway. These results indicate cyclin A2 to be involved in the acquisition of aggressive behaviour of tumour cells through the activation of PI3K by cyclin A2‐induced periplakin, and to be a promising therapeutic target.     

非头颈部恶性肿瘤并发放射性口腔黏膜炎患者口腔菌群和细胞免疫功能变化

探讨非头颈部恶性肿瘤并发放射性口腔黏膜炎（ROM）患者口腔菌群和细胞免疫功能的变化。

选择2020年1月至2022年3月在我院口腔科接受放化疗治疗的非头颈部恶性肿瘤并发ROM患者30例为ROM组,选择在同期接受放化疗治疗但未发生ROM的30例患者为非ROM组。将1～2级ROM患者纳入轻症组,将3～4级ROM患者纳入重症组。患者均在放化疗治疗结束当天禁食禁水,静卧于床上,使用一次性无菌棉签采集口腔、软腭、硬腭、两侧颊黏膜等部位黏膜样本。采用Illumina测序仪进行16S rRNA基因测序,使用贝叶斯算法对OTU在各个分类水平上的群落组成进行统计。采用流式细胞术检测所有研究对象CD4⁺/CD8⁺、B细胞和NK细胞水平。

ROM组和非ROM组患者在性别、年龄、肿瘤分期、肿瘤类型和合并糖尿病方面差异均无统计学意义（均P＞0.05）。相比非ROM组,ROM组患者口腔菌群Chao1指数和Shannon指数均较低,Simpson指数、链球菌属、放线菌属和普雷沃菌属相对丰度均较高（均P＜0.05）。ROM组患者外周血CD4⁺/CD8⁺、B细胞和NK细胞水平均低于非ROM组（均P＜0.05）。重症组患者口腔菌群Chao1指数和Shannon指数均低于轻症组,Simpson指数、链球菌属、放线菌属和普雷沃菌属相对丰度均高于轻症组（均P＜0.05）。重症组患者外周血CD4⁺/CD8⁺、B细胞和NK细胞水平均低于轻症组（均P＜0.05）。

ROM患者口腔菌群多样性表现为Chao1指数和Shannon指数降低,Simpson指数升高,其中链球菌属、放线菌属和普雷沃菌属相对丰度显著变化。此外,ROM患者细胞免疫功能显著降低。

     

Neo-adjuvant chemo-(immuno-)therapy of advanced squamous-cell head and neck carcinoma: a multicenter, phase III, randomized study comparing cisplatin + 5-fluorouracil (5-FU) with cisplatin + 5-FU + recombinant interleukin 2

We carried out an open, randomized, phase III, multicenter clinical trial to compare, in neo-adjuvant setting, the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c. recombinant interleukin-2 (rIL-2) in patients with advanced (stage III–IV) head and neck squamous-cell carcinoma (HNSCC). Regimen A was the classical Al Sarraf treatment: 100 mg/m² cisplatin i.v. on day 1 plus 1000 mg m⁻² day⁻¹ 5-FU on days 1–5 as a continuous infusion. Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c. on days 8–12 and 15–19. Treatment was repeated every 3 weeks for three cycles. A total of 33 patients were enrolled in the study; 30 were evaluable for toxicity and 28 for response. Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients (20%) of group A and 4 (31%) of group B had a complete response, 9 patients (60%) of group A and 6 (46%) of group B had a partial response, with an overall response rate of 12 patients (80%) for group A and 10 patients (77%) for group B. Two patients (13%) of group A and 3 patients (23%) group B had stable disease; 1 patient (7%) of group A had progressive disease. Thus, there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the standard chemotherapy. Both regimens were well tolerated. There were 2 toxic deaths (6.7%), 1 from hematological causes in group A and 1 from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity, mainly nausea/vomiting and stomatitis, were the most frequent toxicities. The calculated number of patients for the sample has not yet been reached; however, the projection of our present results suggests that it is highly improbable that a clinically significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved. Received: 9 April 1998 / Accepted: 30 June 1998     

Simultaneous color‐coded imaging to distinguish cancer “stem‐like” and non‐stem cells in the same tumor

In this study, we demonstrate that the differential behavior, including malignancy and chemosensitivity, of cancer stem‐like and non‐stem cells can be simultaneously distinguished in the same tumor in real time by color‐coded imaging. CD133⁺ Huh‐7 human hepatocellular carcinoma (HCC) cells were considered as cancer stem‐like cells (CSCs), and CD133^? Huh‐7 cells were considered as non‐stem cancer cells (NSCCs). CD133⁺ cells were isolated by magnetic bead sorting after Huh‐7 cells were genetically labeled with green fluorescent protein (GFP) or red fluorescent protein (RFP). In this scheme, CD133⁺ cells were labeled with GFP and CD133^? cells were labeled with RFP. CSCs had higher proliferative potential compared to NSCCs in vitro. The same number of GFP CSCs and the RFP NSCCs were mixed and injected subcutaneously or in the spleen of nude mice. CSCs were highly tumorigenic and metastatic as well as highly resistant to chemotherapy in vivo compared to NSCCs. The ability to specifically distinguish stem‐like cancer cells in vivo in real time provides a visual target for prevention of metastasis and drug resistance. J. Cell. Biochem. 111: 1035–1041, 2010. © 2010 Wiley‐Liss, Inc.