HIV– positive anal cancer: an update for the clinician

Anal cancer used to be a rare cancer traditionally associated with elderly women. There are approximately 5260 cases per year in the U.S. (1). The onslaught of the Human Immunodeficiency Virus (HIV) virus has led to a change in anal cancer demographics. Anal cancer is on the rise in the U.S and the number of anal cases documented has quadrupled in the past 20 yrs correlating with the rise of the HIV epidemic. The incidence of anal cancer is 40 to 80 fold higher in the HIV positive (HIV+) population when compared to the general population (2). With the advent of highly active antiretroviral therapy (HAART), HIV+ patients are living longer as less are progressing to AIDS. As a consequence non AIDS defining cancers such as anal cancer are on the rise. Factors implicated in the etiology of anal cancer in HIV+ patients include (Human papillomavirus) HPV virus status, sexual habits, and a history of smoking. HPV 16 and receptive anal intercourse (RAI) increase the risk of anal cancer by 33% over the general population. In the general population, the rate of anal cancer is approximately 0.9 cases per 100,000. In patients with a history of RAI, the rate approaches 35 cases per 100,000 which is equivalent to the prevalence of cervical cancer (3). Smokers are eight times more likely to develop anal cancer. There has been much discussion about tailoring treatment decisions in HIV+ patients with anal cancer. This review focuses on squamous cell carcinomas of the anal canal which comprise 80 to 90% of all anal cancers diagnosed and highlight key issues in the management of HIV+ anal cancer patients including recent clinical trials.     

Antiangiogenics and immunotherapies in cervical cancer: an update and future’s view

Despite availability of primary and secondary prevention measures, cervical cancer (CC) persists as one of the most common cancers among women around the world, and more than 70% of cases are diagnosed at advanced stages. Although significant progress has been made in the treatment of CC, around 15–61% of patients develop a recurrence in lymph nodes or distant sites within the first 2 years of completing treatment and the prognosis for these patients remains poor. During the last decades, in an attempt to improve the outcome in these patients, novel agents as combination therapy that target known dysfunctional molecular pathways have been developed with the most attention to the inhibitors of the angiogenesis process. One therapeutic target is the vascular endothelial growth factor, which has been shown to play a key role in tumor angiogenesis, not only for growth of new tissue but also in tumor proliferation. Bevacizumab is recognized as a potent antiangiogenic agent in ovarian cancer but has also demonstrated encouraging antitumor activity in recurrent CC. Moreover, other antiangiogenic agents were recently under study including: sunitinib, sorafenib, pazopanib, cediranib and nintedanib with interesting preliminary results. Moreover, over the last few years there has been increasing interest in cellular immunotherapy as a strategy to harness the immune system to fight tumors. This article focuses on recent discoveries about antiangiogenic agents and immunotherapies in the treatment of CC highlighting on future’s view.     

β-Adrenergic Receptors : New Target in Breast Cancer

Preclinical studies have demonstrated that β-adrenergic receptor antagonists could improve the prognosis of breast cancer. However, the conclusions of clinical and pharmacoepidemiological studies have been inconsistent. This review was conducted to re-assess the relationship between beta-adrenoceptor blockers and breast cancer prognosis. Materials and Methods: The literature was searched from PubMed, EMBASE and Web of Nature (Thompson Reuters) databases through using key terms, such as breast cancer and betaadrenoceptor blockers. Results: Ten publications met the inclusion criteria. Six suggested that receiving betaadrenoceptor blockers reduced the risk of breast cancer–specific mortality, and three of them had statistical significance (hazard ratio (HR)=0.42; 95% CI=0.18-0.97; p=0.042). Two studies reported that risk of recurrence and distant metastasis (DM) were both significantly reduced. One study demonstrated that the risk of relapsefree survival (RFS) was raised significantly with beta-blockers (BBS) (HR= 0.30; 95% CI=0.10-0.87; p=0.027). One reported longer disease-free interval (Log Rank (LR)=6.658; p=0.011) in BBS users, but there was no significant association between overall survival (OS) and BBS (HR= 0.35; 95% CI=0.12–1.0; p=0.05) in five studies. Conclusions: Through careful consideration, it is suggested that beta adrenoceptor blockers use may be associated with improved prognosis in breast cancer patients. Nevertheless, larger size studies are needed to further explore the relationship between beta-blocker drug use and breast cancer prognosis.     

整合素β1(Integrinβ1)表达与脑胶质瘤恶性表型相关性研究

目的　探讨整合素 β1(integrinβ1)与脑胶质瘤恶性表型之间的关系。 方法　应用免疫组化SABC法和原位杂交检测integrinβ1在I～IV级脑胶质瘤中的表达。 结果　 5 3例I～IV级脑胶质瘤组织integrinβ1免疫组化阳性率分别为 36 .3%、38.5 %、72 .2 %和 81.8% ,III～IV级脑胶质瘤阳性率明显高于I～II级脑胶质瘤 ,差异显著 (P <0 .0 5 )。原位杂交显示integrinβ1mRNA表达 ,与integrinβ1蛋白表达结果相近。结论　integrinβ1高表达与脑胶质瘤组织分化程度低、侵袭强等恶性表型密切相关 ,并可能对这些恶性表型起正性调节作用。     

Commentary: Antioxidants for Cancer: New Tricks for an Old Dog?

Traditionally, the main focus of the importance of reactive oxygen species (ROS) in oncology is that these species induce DNA damage, leading to a predisposition to cancer. However, it has recently been shown that ROS may have an alternative activity, by modulating tumor cell signaling. Moreover, tumor cell signaling mediated by ROS is readily reversible upon treatment with antioxidants. This emerging evidence on the molecular effects of antioxidants on tumor cells, along with the evidence that the route of administration of antioxidants in earlier clinical trials for cancer could not achieve pharmacologically effective levels, suggests that antioxidants may serve as bona fide signal transduction modifiers for cancer. A re‐examination of the current evidence and further study is clearly warranted.     

Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression,an effect amplified by interleukin-1β

The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced.Conversely, the forced expression of Notch1ICD in naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation.In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium.     

Relationship between CCL5 and transforming growth factor-β1 (TGFβ1) in breast cancer

Purpose

Investigate circulating CCL5 in breast cancer patients and healthy controls, along with gene expression levels in corresponding tumour tissue and isolated primary stromal cells. Hormonal control of CCL5, and a potential relationship with TGFβ1, was also investigated.

Methods

Circulating levels of CCL5 and TGFβ1 were measured in 102 breast cancer patients and 66 controls using ELISA. Gene expression levels (CCL5, CCR5, TGFβ1, TGFβRII) were quantified in corresponding tumour tissue (n = 43), normal tissue (n = 16), and isolated tumour (n = 22) and normal (n = 3) stromal cells using RQ-PCR. CCL5 and circulating menstrual hormones (LH, FSH, Oestradiol, Progesterone) were analysed in serum samples from healthy, premenopausal volunteers (n = 60).

Results

TGFβ1 was significantly higher in breast cancer patients (Mean(SEM) 27.4(0.9) ng/ml) compared to controls (14.9(0.9) ng/ml). CCL5 levels decreased in the transition from node negative (59.6(3.7) ng/ml) to node positive disease (40.5(6.3) ng/ml) and increased again as the number of positive lymph nodes increased (?3 positive 50.95(9.8) ng/ml). A significant positive correlation between circulating CCL5 and TGFβ1 (r = 0.423, p < 0.0001) was observed, and mirrored at the gene expression level in tumour tissue from the same patients (r = 0.44, p < 0.001). CCL5, CCR5 and TGFβ1 expression was significantly higher in tumour compared to normal breast tissue (p < 0.001). A significant negative correlation was observed between circulating CCL5, Oestradiol and Progesterone (r = −0.50, r = −0.39, respectively, p < 0.05).

Conclusion

CCL5 expression is elevated in the tumour microenvironment. The data support a role for hormonal control of circulating CCL5 and also highlight a potentially important relationship between CCL5 and TGFβ1 in breast cancer.     

肝癌组织中转化生长因子β1(TGF-β1)的表达及其临床病理学意义

随着肝癌二级预防研究的进展,早期病例检出率有了很大提高.然而小肝癌术后3年复发率为25.7%,5年复发率高达43.5%,肝癌组织中TCF-β1的表达增高.但TCF-β1与肝癌复发的关系尚未有报道 作者用免疫组化方法检测1992～1995年手术切除的52例小肝癌石蜡存档标本小肝癌中TGF-β2的免疫反应性并分析其与复发的关系.其中术后两年内复发者20例,无复发者32例.小肝癌指单个肿瘤直径小于等于5cm.均有明确的病理诊断,有门脉癌栓者17例,无门脉癌栓者35例,有肉眼或镜下TFPV者均判定为有门脉癌栓者,抗体为亲和层析纯兔抗人TG-β1多克隆抗体(其相关抗原源于用酸激活的完整的人TGF-β1肽链),使用     

Increased estrogen sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β-HSD1) following neoadjuvant aromatase inhibitor therapy in breast cancer patients

Aromatase inhibitors (AIs) are considered the gold standard for endocrine therapy of estrogen receptor (ER) positive postmenopausal breast cancer patients. The therapy may enhance therapeutic response and stabilize disease but resistance and disease progression inevitably occur in the patients. These are considered at least partly due to an emergence of alternative intratumoral estrogen production pathways. Therefore, in this study we evaluated effects of exemestane (EXE) upon the enzymes involved in intratumoral estrogen production including estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), and estrogen sulfotransferase (EST) and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). 116 postmenopausal patients with invasive ductal carcinoma, stage II/IIIa, were enrolled in JFMC34-0601 clinical trials between March, 2006 and January, 2008. EXE of 25 mg/day was administered according to the protocol. Pre- and posttreatment specimens of 49 cases were available for this study. Status of STS, EST, 17β-HSD1, ER, progesterone receptor (PgR), human epidermal growth factor receptor type 2 (Her2), and Ki67 in pre- and post-specimens were evaluated. Specimens examined before the therapy demonstrated following features; ER+ (100%), PgR+ (85.7%), and Her2+ (77.6%). After treatment, the number of Ki67, PgR, and ER positive carcinoma cells demonstrated significant decrement in clinical response (CliR) and pathological response (PaR) groups. Significant increment of 17β-HSD1 and STS immunoreactivity was detected in all groups examined except for STS in PaR. EST showed significant increment in nonresponsive groups. Alterations of Ki67 of carcinoma cells before and after therapy were subclassified into three groups according to its degrees. Significant alterations of intratumoral enzymes, especially 17β-HSD1 and STS, were correlated with Ki67 reduction after neoadjuvant EXE therapy. This is the first study demonstrating significant increment of STS and 17β-HSD1 following AI neoadjuvant therapy of postmenopausal ER positive breast carcinoma patients. This increment may represent the compensatory response of breast carcinoma tissues to estrogen depletion.     

Antitumor mechanisms and metabolism of the novel antitumor nucleoside analogues, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine and 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil

The antitumor ribonucleoside analogues 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)uracil (EUrd), first synthesized in 1995, have strong antitumor activity against human cancer xenografts without severe side effects. Here, we studied the antitumor mechanisms of ECyd and EUrd using mouse mammary tumor FM3A cells in vitro and the mechanism of selective cytotoxicity of ECyd using human tumor xenografts in nude rats in vivo. In FM3A cells, ECyd and EUrd were rapidly phosphorylated to ECyd 5′-triphosphate (ECTP) and EUrd 5′-triphosphate (EUTP), which strongly inhibiting RNA synthesis. Cells treated with EUrd were later found to contain both EUTP and ECTP, and ECTP accumulated as the final product. Probably the uracil moieties of EUrd derivatives were efficiently converted to cytosine moieties in the cells. EUrd and its derivatives were minor metabolites in the cells treated with ECyd, so cytidine forms probably were not converted to uridine forms at the nucleoside or nucleotide stage. The ultimate metabolite of ECyd and EUrd, ECTP, is stable in cultured cells with a half-life of at least 3 days, so ECyd and EUrd are on a “closed” metabolic pathway to ECTP. These characteristics of ECyd and EUrd may be important for their antitumor activity. ECyd had strong and selective antitumor activity against the human tumor xenografts. ECyd-phosphorylating activity (uridine/cytidine kinase) in the xenografts was higher than that in the organs of the rats. This finding may account for the strong activity with mild side effects. ECyd and EUrd may be a new kind of antitumor nucleoside analogue for clinical use. Received: 8 June 1998 / Accepted: 5 November 1998     

Estrogen receptor α (ERα) mediates 17β-estradiol (E2)-activated expression of HBO1

Background

HBO1 (histone acetyltransferase binding to ORC1) is a histone acetyltransferase (HAT) which could exert oncogenic function in breast cancer. However, the biological role and underlying mechanism of HBO1 in breast cancer remains largely unknown. In the current study, we aimed to investigate the role of HBO1 in breast cancer and uncover the underlying molecular mechanism.

Methods

Immunohistochemistry was applied to detect HBO1 protein expression in breast cancer specimens (n = 112). The expression of protein level was scored by integral optical density (IOD) for further statistical analyses using SPSS. Real-time PCR was used to simultaneously measure mRNA levels of HBO1. The HBO1 protein expression in breast cancer cells was confirmed by western blot.

Results

HBO1 was highly expressed in breast cancer tissues and significantly correlated with estrogen receptor α (ERα) (p < 0.001) and progestational hormone (PR) (p = 0.002). HBO1 protein level also correlated positively with histology grade in ERα positive tumors (p = 0.016) rather than ERα negative tumors. 17β-estradiol (E2) could upregulate HBO1 gene expression which was significantly inhibited by ICI 182,780 or ERα RNAi. E2-increased HBO1 protein expression was significantly suppressed by treatment with inhibitor of MEK1/2 (U0126) in T47 D and MCF-7 cells.

Conclusions

HBO1 was an important downstream molecule of ERα, and ERK1/2 signaling pathway may involved in the expression of HBO1 increased by E2.     

原发性肝癌白细胞介素1β转换酶(ICE)基因治疗的研究

ICE基因被认为是调节哺乳动物细胞凋亡的关键基因,目前对其研究主要集中于其诱导细胞凋亡的机制方面,迄今尚未见到应用ICE进行肿瘤基因治疗方面的研究.     

Mechanism-based receptor-binding model to describe the pharmacokinetic and pharmacodynamic of an anti-α5β1 integrin monoclonal antibody (volociximab) in cancer patients

Purpose

Volociximab is a chimeric IgG₄ that is being developed as a novel first-in-class anti-angiogenic, α₅β₁ integrin inhibitor for the treatment of solid tumors. A mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to investigate the dynamic interaction between volociximab concentrations and free monocyte α₅β₁ integrin levels in cancer patients.

Methods

Twenty-one cancer patients from six dose cohorts (0.5, 1.0, 2.5, 5.0, 10, and 15 mg/kg) were included in the analysis. The fully integrated receptor-binding PK/PD model was developed and fit simultaneously to the PK/PD data. A Monte-Carlo parametric expectation-maximization method implement in S-ADAPT program was used to obtain estimates of population parameters and inter- and intra-subject variability.

Results

The PK/PD time profiles were well described by the model and the parameters were estimated with good precision. The model was used to simulate PK/PD time profiles for multiple dose regimens at various dose levels, and the results suggested that the monocyte α₅β₁ integrin binding was saturated (≤5% free) at week 16 in the majority of patients treated with volociximab doses ≥10 mg/kg IV every 2 weeks.

Conclusions

The developed model is useful for anticipating the drug exposures and extent of volociximab binding to peripheral monocyte α₅β₁ integrin in untested regimens and for optimizing the design of future clinical trials.     

Antitumor Effect of the New Rhodium(II) Complex: Rh2 (Form)2 (02 CCF3)2 (H20)2 (Form = N,N’-di-p-tolylformamidinate)

Summary

The new rhodium(II) complex Rh₂(Form) (0₂CCF₃)₂(H₂0)₂ (Form = N, N’ — di-p-tolyl formamidinate) was evaluated for its toxicity on the rat and for its efficacy against two tumors of this animal: the Yoshida ascites sarcoma and the T8 sarcoma of Guérin.

The rhodium(II) formamidinate shows very low toxicity: in fact 150 mg/kg (the highest quantity of drug soluble in 4 ml of dimenthyl sulfoxide) is not toxic for rats. We were unable to establish the lethal dose or the highest nontoxic dose since larger mounts of complex require a dose of dimethyl sulfoxide (DMSO) that is itself toxic and the compound is insoluble in other solvents such as water or Tween.

Doses of rhodium(II) formamidinate, varying from 3 to 30 mg/kg, were administered once by i.p., i.v., i.m. and intratumor (i.t.) route from 1 to 7 days after i.p. injection of 10⁶ Yoshida ascites sarcoma cells and subcutaneous (s.c.) implantation of ? 300 mg (corresponding to 2-3 × 10⁷ living tumor cells) of T8 sarcoma of Guérin. The compound is active when administered i.p. 24 hours after Yoshida ascites sarcoma at the smallest dose tested (3 mg/Kg), increasing the average life span of 62.3% and allowing the survival of 50% of the rats. It is also active when administered i.p. at the highest dose tested (30 mg/Kg) 7 days after tumor cell challenge, increasing the average life span in 43.8% and allowing survival in 20% of the rats; it is not active after i.v. or i.m administration. The title complex exhibits anticancer activity against T8 sarcoma of Guérin, increasing significantly the average life span of 17% and 25.9% of rats if administered by i.v. and i.m. routes respectively at the dose of 30 mg/Kg the day following implantation of the neoplasia, and of 12.2% of rats by i.t. route at the dose of 10 mg/Kg five days after tumor challenge.

A comparison between the therapeutic properties of the title complex with those of the complexes Rh₂(O₂CCH₃)₄ and cis-Pt(NH₃)₂Cl₂(CDDP) reveals that the rhodium(II) formamidinate derivative exhibits the same antitumor activity associated with considerably reduced toxicity.     

A new nitrosourea derivative TA-077, 1-(2-Chloroethyl)-3-isobutyl-3-(β-maltosyl)-1-nitrosourea

Summary A new water-soluble nitrosourea derivative, 1-(2-chloroethyl)-3-isobutyl-3-(-maltosyl)-1-nitrosourea (TA-077), was tested for antitumor activity against murine tumors and a human mammary carcinoma (MX-1) implanted in athymic mice, and the results were compared with those obtained with five other nitrosourea derivatives currently in clinical use: 1-(2-chloroethyl)-3-(methyl--d-glucopoyranos-6-yl)-1-nitrosourea (MCNU), 1-(2-chloroethyl)-3-(-d-glucopyranosyl)-1-nitrosourea (GANU), 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), chlorozotocin, and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU).The results indicated that TA-077 had a unique optimal treatment schedule different from other nitrosoureas. With daily IV treatments for 5 days, TA-077 showed the highest antitumor activity of all against the advanced Lewis lung carcinoma, defined by tumor weight and the survival of tumor-bearing mice. Furthermore, TA-077 given according to this treatment schedule was successful in inducing an apparent cure (complete regression and no recurrence) in all the athymic mice bearing MX-1, which the other five nitrosoureas could not. In addition, TA-077 possessed higher therapeutic indices (optimal dose/ILS₂₅) against L1210 and P388 leukemias than MCNU, which possessed the highest therapeutic index against L1210 leukemia among the five nitrosourea derivatives.