Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44+ cancer stem cells

Cis-diamminedichloridoplatinum(II)(CDDP)-based combination chemotherapy is frequently used in gastrointestinal cancer. The synergistic mechanism of all-trans retinoic acid (ATRA), cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear. Despite their potent antitumor properties, resistance to CDDP and 5-FU develops frequently in tumors. To clarify this mechanism, we determined the sensitivity to each drug and their combination in two gastrointestinal cancer stem cells (CSCs) subpopulation.Here, we report the identification and separation of CD44⁺ cells from human gastric carcinoma (AGS) and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines by magnetic activated cell sorting (MACS). We allowed the CD44^± cells to grow 6 days at a subtoxic concentration of ATRA and then treated with different concentration of CDDP and 5-FU for 24 h. The cytotoxicity was examined by cell proliferation MTT assay. Additionally, AO/EB staining was used for detection of apoptotic cells. In order to determine whether the growth inhibition was also associated with changes in cell cycle distribution, cell cycle analysis was performed using flow cytometry.Low concentration of ATRA (1 μM, 6days) followed by 5-FU and CDDP was found to be more effective than either drugs alone, thus resulting in synergistic cytotoxicity in Kyse-30 and AGSCD44^± cells. Furthermore, there was an indication that the combination of ATRA with 5FU and CDDP caused an increase in cell cycle arrest in G2/M and G0/G1.We conclude that low concentration of ATRA enhances the cytotoxicity of CDDP and 5FU by facilitating apoptosis and cell cycle arrest in gastrointestinal CSCs and provide a rational basis for the design of novel, well-tolerated CDDP- and 5FU-based chemotherapy in human gastrointestinal carcinoma.     

Sequence-dependent Termination of Mammalian DNA Polymerase Reaction by a New Platinum Compound, (–)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) Monohydrate

We examined the mechanisms of the inhibition of DNA synthesis by a new platinum compound, (-)-( R )-2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) monohydrate (DWA-2114R), a derivative of the antitumor drug cis- diamminedichloroplatinum(II) (CDDP), using prokaryotic and eukaryotic DNA polymerases. Preincubating activated DNA with CDDP or DWA-2114R reduced its template activity for prokaryotic and eukaryotic DNA polymerases in a dose-dependent manner. DWA2114R required six times greater drug concentration and two times longer incubation time to show the same decrease of the template activity compared to CDDP. Treatment of primed pUC118 ssDNA templates with the two drugs followed by second-strand synthesis by prokaryotic and eukaryotic DNA polymerases revealed that DWA2114R bound to DNA in a similar manner to CDDP and these adducts blocked DNA elongation by DNA polymerases of eukaryotes as well as of prokaryotes. With these two drugs, the elongations by E. coli DNA polymerase I (Klenow fragment), T7 DNA polymerase and calf thymus DNA polymerase α were strongly arrested at guanine-guanine sequences (GG). Stop bands were also observed at adenine-guanine sequences (AG) guanine-adenine-guanine sequences (GAG) and mono-guanine sequence (G). Calf testis DNA polymerase β was also arrested efficiently at AG, GAG and G, but much more weakly at GG. This pattern was common to DWA2114R and CDDP.     

泰素蒂加顺铂治疗进展期NSCLC的临床研究

目的观察泰素蒂加顺铂方案治疗进展期非小细胞肺癌的临床疗效、毒副作用。方法收集可评价疗效的进展期非小细胞肺癌50例,以泰素蒂加顺铂方案进行化疗,泰素蒂75 mg/m2静脉滴注,第1天;顺铂25 mg/m2～30 mg/m2静脉滴注,第2天～第5天,每3周为一个周期,2～3周期后评价疗效和毒副反应并随访。结果50例患者中,总有效率为50.0 %,其中初治病例为53.1 %,复治病例为44.4 %,初复治病例间差异无显著性(P >0.05)。中位缓解期为5个月。中位生存期为9.5个月,1年生存率为61.0 %。毒副反应主要为骨髓抑制,白细胞下降达Ⅲ度、Ⅳ度者52.0 %,血小板下降达Ⅲ度、Ⅳ度者为14.0 %。血红蛋白下降不严重。其他毒副反应还有脱发、过敏反应、水钠潴留、静脉炎、末梢神经炎、口腔炎、腹泻等,但发生率均较低。结论泰素蒂加顺铂方案治疗进展期非小细胞肺癌,特别是复发病例,临床疗效比较满意,毒副反应能够耐受。辅以G蛳CSF可防治重度的骨髓抑制,有较好的临床应用价值。     

多希紫杉醇联合顺铂治疗晚期非小细胞肺癌疗效观察

目的观察和评价多希紫杉醇联合顺铂(DP方案)治疗晚期非小细胞肺癌的疗效和毒性。方法将我科近几年收治的48例晚期非小细胞肺癌患者随机分为治疗组和对照组。治疗组采用多希紫杉醇联合顺铂(DP方案),对照组采用长春瑞滨联合顺铂(NP方案)。2周期化疗后进行疗效、毒性对比研究。结果治疗组和对照组近期有效率分别为45.5%和37.5%,疾病进展时间(TTP)分别为6.3和5.9个月,中位生存期分别为10.1和9.0个月,1年生存率分别为45.8%和39.4%,两组间比较差异均无显著性(P>0.05)。治疗组在恶心呕吐、骨髓抑制等毒性反应发生率方面低于对照组,差异有显著性(P<0.05)。结论多希紫杉醇联合顺铂治疗晚期非小细胞肺癌与NP方案相比较,疗效相似,但毒性反应低于NP组,患者更易耐受,可广泛应用于临床。     

Chemo-endocrine therapy in patients with stage D2 prostate cancer

There have only been a few studies of chemo-endocrine therapy compared with endocrine therapy alone in newly diagnosed prostate cancer patients. We assessed the effects of these two therapies by comparing long-term survival rates. One hundred and twenty-nine patients were entered in this study between November 1977 and March 1992. Seventy-seven patients were treated with endocrine therapy alone. Other 52 patients received chemo-endocrine therapy, which included orchiectomy and/or diethylstilbestrol diphosphate (DES-DP) plus Cisplatin, with or without other cytotoxic agents. All patients had bone metastasis at the beginning of the study. There was a significant difference in survival between patients who received endocrine therapy and chemo-endocrine therapy (P = 0.0078). That is, survival rate was superior for the chemoendocrine therapy patients throughout the entire follow-up period. These data suggest that early chemo-endocrine therapy containing Cisplatin, with or without maintenance chemotherapy, is a potentially effective treatment for newly diagnosed metastatic prostate cancer and is worth further investigation via a randomized trial.     

顺铂对结直肠癌肿瘤浸润淋巴细胞杀伤活性的影响

为在临床选择有效的免疫化疗方案提供一定的理论依据，作者以结直肠癌肿瘤浸润淋巴细胞（ＴＩＬ）和顺铂（ＣＤＤＰ）为研究对象，对１６名手术治疗的结直肠癌患者，分别观察ＣＤＤＰ体内注射及体外预处理ＴＩＬ和Ｒａｊｉ细胞对ＴＩＬ表面标志和杀伤活性的影响。流式细胞仪检测结果显示，静脉注射ＣＤＤＰ能增加结直肠癌ＴＩＬ中ＣＤ３＋／ＣＤ４＋和ＣＤ３＋／ＣＤ８＋细胞含量，同时增强ＴＩＬ体外杀伤Ｒａｊｉ细胞的活性；而体外以ＣＤＤＰ处理Ｒａｊｉ细胞能增强其对结直肠癌ＴＩＬ杀伤的敏感性。作者认为，对于联合应用ＴＩＬ和ＣＤＤＰ治疗结直肠癌的临床效果有必要进一步研究。     

Cisplatin-induced long-term dynorphin A-immunoreactivity in cell somata of rat area postrema neurons

We evaluated long-term dynorphin A-immunoreactivity in the rat area postrema (AP) after the administration of cisplatin. First, rats were given 1, 5 and 10 mg/kg body weight cisplatin (i.p.) and their behavior was monitored for 72 h. We observed a delayed increase in pica 24-72 h after injection, compared to the 24 h before injection. We attributed this to the cisplatin injection. Pica was defined as an increase in the intake of non-nutritional matter such as kaolin. Administration of 1, 5 and 10 mg/kg cisplatin led to an increase in kaolin intake on day 1. Administration of 5 and 10 mg/kg of cisplatin led to decreased intake of laboratory chow (MF) on days 1–3, but 10 mg/kg cisplatin causes an excessive aggravation of their condition. Following this behavioral experiment, we immunohistochemically examined the induction of dynorphin A in the AP at 24, 48 and 72 h post-administration of 1 and 5 mg/kg cisplatin. Administration of 5 mg/kg cisplatin caused dynorphin A to accumulate gradually in the neurosoma of the AP neurons, and the numbers of positive AP neurosomata at 48 and 72 h post-administration were higher than following an equal dosage of 0.9% NaCl. These findings suggest that dynorphin A increases in the central nervous system for a long time following administration, and causes certain behavioral and clinical changes, including those related to appetite and nausea.     

Therapeutic effect of adipose-derived mesenchymal stem cells on Cisplatin induced testicular damage in adult male albino rat

Infertility represents a major medical, economic, and psychological problem. Stem cells therapy for infertility has a great interest nowadays especially for cancer survivors at pre-reproductive and reproductive age.

 Thirty-two adult male albino rats were used, divided equally into four groups; Group I (Control group) received isotonic saline intraperitoneally (i.p.) as vehicle. Group II (Cisplatin-treated group) received Cisplatin (i.p.) at a single dose of 7 mg/kg, and then were sacrificed after 5 days. Group III (Stem-cell-treated group) received Cisplatin (i.p.) at a single dose of 7 mg/kg, then after 5 days received adipose-derived mesenchymal stem cells (ADMSCs) (1 × 10⁶). Cells were injected in the rete testis, then after 60 days, the animals were sacrificed. Group IV (Auto healing group) received Cisplatin (i.p.) at a single dose of 7 mg/kg, and then left for 65 days then the animals were sacrificed. Cisplatin administration resulted in degenerative changes in the testicular architecture in the form of thickened irregular BM of seminiferous tubules. The germinal epithelium showed disorganization and marked reduction in the thickness, associated with Sertoli cells preservation. Features of apoptosis assured by elevated caspase-3 expression were noticed. The interstitium showed cellular infiltration and distorted Leydig cells. Injection of (ADMSCs) resulted in great improvement of testicular architecture and increase in the testosterone level associated with strong immune reaction of the CD-44. ADMSCs are recommended as a new treatment modality for male infertility.

Abbreviation: i.p.: intraperitoneally; BM: basement membrane; ADMSCs: adipose-derived mesenchymal stem cells; WHO: World Health Organization; MSCs: mesenchymal stem cells; DMEM: Dulbecco modified eagles media; PBS: phosphate-buffered saline; FACS: fluorescence-activated cell sorting; ELISA: enzyme-linked immunosorbent assay; CP: Cisplatin; ROS: reactive oxygen species; CAT: catalase; SOD: superoxide dismutase; OS: oxidative stress; SSCs: spermatogonia stem cells; GCs: germ cells; UCMSCs: umblical cord mesenchymal stem cells; TGFb1: transforming growth factor beta-1; BMP4: Bone morphogenic protein 4; BMP8b: bone morphogenic protein 8b.     

A Randomized Study of Epithelial Ovarian Cancer: Is Chemotherapy Useful after Complete Remission?

Objective. The aim of this study is to verify whether consolidation chemotherapy with Cisplatin improves disease-free survival and/or overall survival in patients affected by epithelial ovarian cancer.Methods. A multicenter study examined 122 randomized patients in complete remission as judged by laparoscopy or laparotomy following first-line chemotherapy consisting of ACy (Adriamycin + Cyclophosphamide), PCy (Cisplatin + Cyclophosphamide), or Mitoxantrone + Carboplatin. Sixty-one of these patients were treated with 3 cycles of 5-Fluorouracil (FU) 500 mg/m2 for 5 days followed by Cisplatin at 100 mg/m2 on the 6th or 7th day every 28 days; the other 61 received no further treatment (nihil group).Results. Sixty patients in the Cisplatin arm were evaluable. There were 36 relapses in the FU+Cisplatin arm and 30 in the nihil arm. Peritoneal relapses were 25% for Cisplatin treatment vs. 16.4 % for nihil. There were 29 deaths in the Cisplatin arm vs. 27 for nihil. Median overall survival time (95 months with Cisplatin vs. 96 months in the nihil group) and median disease-free survival (66 months with Cisplatin vs. 73 in the nihil group) were similar in both arms (p=0.66 and p=0.41, respectively). There were no significant differences in tumor stage and grade between the two arms. Seven patients presented a second neoplasm during follow-up: six in the nihil arm, but only one patient in the Cisplatin arm. Death in these patients was due to the second neoplasm and not to progression of ovarian cancer.Conclusion. Three courses of additional platinum+FU treatment after five cycles of first-line chemotherapy without FU produced no increase in overall survival or disease-free survival.