组蛋白去乙酰酶抑制剂联合应用治疗肿瘤的研究进展

组蛋白去乙酰酶(histone deacetylase,HDAC)抑制剂可促进组蛋白乙酰化,调节染色质结构和基因转录。临床前研究,Ⅰ和(或)Ⅱ期临床试验都已证实,HDAC的小分子抑制剂能够有效地促进抑癌基因表达,抑制肿瘤生长并诱导细胞凋亡。在多种肿瘤中都已观察到,HDAC抑制剂与其他抗肿瘤药物联合应用,可在较低的剂量下产生更好的疗效,而不良反应减轻。     

Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies

Background and Purpose

In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested.

Experimental Approach

Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference.

Key Results

In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics.

Conclusion and Implications

Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug–drug interactions.

Linked Article

This article is commented on by Solary, pp 1555–1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12101     

Urinary excretion of albumin and transferrin in lithium maintenance treatment: daily versus alternate-day lithium dosing schedule

Urinary excretion of albumin and transferrin was determined by means of sensitive immunochemical methods in 40 manic-depressive patients prior to and following 6 months of daily or alternate-day lithium carbonate treatment. The median dose of lithium carbonate was 700 mg in the daily treatment group and 1200 mg in the alternate-day group, the corresponding median 12-h serum lithium concentration being 0.6 mmol l^–1 and 0.7 mmol l^–1, respectively. Urinary excretion of albumin and transferrin was significantly elevated in the lithium-treated patients as compared to a control group (Mann-Whitney). The change in urinary albumin: creatinine and transferrin: creatinine ratios between allocation and 6 months of treatment did not correlate significantly with the lithium dosing schedule (multiple linear regression), but did correlate with total lithium carbonate dose. In conclusion, the study provides no evidence of any difference in glomerular function (permeability) in the daily and alternate-day lithium dosing schedules, and lends no support to the hypothesis that alternate-day treatment diminishes the effect of lithium on renal function.     

Twelve-hour brain lithium concentration in lithium maintenance treatment of manic-depressive disorder: daily versus alternate-day dosing schedule

The 12-h brain lithium concentration was measured by lithium-7 magnetic resonance spectroscopy in ten manic-depressive patients receiving daily or alternate-day lithium carbonate treatment. The median dose of lithium carbonate was 800 mg in the daily treatment group and 1200 mg in the alternate-day group. Median 12-h serum lithium concentration in the two groups was 0.86 mmoll^–1 and 0.55 mmoll^–1, respectively, while the corresponding concentration in brain was 0.67 mmoll^–1 and 0.52 mmoll^–1, respectively. The 12-h brain lithium concentration was independent of lithium dosing schedule (multiple linear regression), but correlated significantly with the 12-h serum lithium concentration (P=0.003; B=0.53, 95% c.l. 0.24–0.82; =0.83). Thus at identical 12-h serum lithium concentrations the 12-h brain lithium concentration is similar with both treatment regimes. As the risk of manic-depressive relapse during alternate-day lithium treatment is in our experience 3-fold greater than with daily treatment (at similar mean 12-h serum lithium concentration), the findings suggest that the difference in the prophylactic efficacy of the two dosing schedules is unrelated to differences in the 12-h brain lithium concentration.     

Antiproliferative effects of ZD0473 (AMD473) in combination with 5-Fluorouracil or SN38 in human colorectal cancer cell lines

PURPOSE: ZD0473 (AMD473) [cis-amminedichloro(2-methylpyridine) platinum(II)] is a novel platinum agent of proven activity in vitro against a variety of human tumor-derived cell lines even with intrinsic or acquired resistance to CDDP. The aim of this study is to provide the basis for a rational design of ZD0473-based combination in colon cancer. EXPERIMENTAL DESIGN: We evaluated the cytotoxic effect of ZD0473 administered alone or in combination with 5-Fluorouracil (5FU) or SN38 in a panel of sensitive and 5FU-resistant colorectal cell lines (HT29/HT29-5FUR and LoVo/LoVo-5FUR). We analyzed four sequential schedules of administration: ZD0473 --> 5FU, 5FU --> ZD0473, ZD0473 --> SN38 and SN38 --> ZD0473. MTT-assay and isobologram analyses were performed to determine the synergism/antagonism. RESULTS: The pattern of response towards ZD0473, administered as single agent, was similar in all cases and independent of the 5FU-resistance phenotype (IC50 from 48.1 to 76.6 microM) and/or p53 status. No differences in sensitivity to ZD0473 alone or in combination were observed between DNA-mismatch repair-proficient (HT29/HT29-5FUR) and -deficient (LoVo/LoVo-5FUR) cells. ZD0473 administered prior to 5FU leads to synergistic/additive effect in all cell lines, while the 5FU --> ZD047 schedule was only synergistic in HT29 cells. Exposure to ZD0473 prior to SN38 leads to a synergistic/additive schedule in LoVo/LoVo-5FUR cells, while SN38 --> ZD0473 schedule was only synergistic in parental cell lines. CONCLUSIONS: The combinations of ZD0473 and 5FU or SN38 have shown to be active in sensitive and 5FU-resistant colorectal cell lines when a correct schedule of administration is applied. These results may be further exploited to promote new schedules of administration for advanced colorectal cancer treatment.     

Safety considerations with combination therapies for psoriasis

ABSTRACT

Introduction: Psoriasis is a chronic inflammatory skin disease that waxes and wanes, and long-term remission can be difficult to achieve regardless of disease severity. Currently, numerous treatment options are available for psoriasis including steroid and non-steroid topical agents, phototherapy, oral systemic agents, and biologics, with many more therapeutic agents under development.

Areas covered: This article will review various combination therapy strategies such as rotational therapy and sequential therapy and describe a variety of safe and effective combination therapies for the treatment of psoriasis. Two or more agents with different mechanisms of action and safety profiles can be used to achieve and/or maintain adequate disease control while minimizing the toxicity of treatments. Combination therapy can also be used when a single agent is not enough for treating recalcitrant disease. Choosing a combination regimen that maximizes safety and efficacy while considering patient usability and compliance can be a challenge.

Expert opinion: Given the various treatment options currently available for psoriasis and more agents under development, combination therapy will continue to be a valuable treatment strategy for any patient with psoriasis. It is crucial for clinicians to carefully consider the fine balance between safety and efficacy when combining various therapeutic agents.     

Diverse array-designed modes of combination therapies in Fangjiomics

In line with the complexity of disease networks, diverse combination therapies have been demonstrated potential in the treatment of different patients with complex diseases in a personal combination profile. However, the identification of rational, compatible and effective drug combinations remains an ongoing challenge. Based on a holistic theory integrated with reductionism, Fangjiomics systematically develops multiple modes of array-designed combination therapies. We define diverse “magic shotgun” vertical, horizontal, focusing, siege and dynamic arrays according to different spatiotemporal distributions of hits on targets, pathways and networks. Through these multiple adaptive modes for treating complex diseases, Fangjiomics may help to identify rational drug combinations with synergistic or additive efficacy but reduced adverse side effects that reverse complex diseases by reconstructing or rewiring multiple targets, pathways and networks. Such a novel paradigm for combination therapies may allow us to achieve more precise treatments by developing phenotype-driven quantitative multi-scale modeling for rational drug combinations.     

The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats

Although it has been demonstrated that many of the behavioral responses to psychomotor stimulants are gender dependent and hormonally sensitive, few studies have examined the possibility that the estrous cycle interacts with drug reinforcement in laboratory animals. The present experiment assessed the effect of the estrous cycle on two aspects of cocaine self-administration behavior: the breaking point on a progressive ratio (PR) schedule and the rate of cocaine intake on a fixed ratio one (FR1) schedule. On the PR schedule, the first lever response produced a drug infusion. Subsequent response requirements escalated with each injection until the behavior extinguished. Breaking points were defined as the final ratio completed. On a FR1 schedule, the estrous cycle had no effect on the rate of drug intake. On a PR schedule, female rats reached higher breaking points during estrus than during other stages of the estrous cycle. Furthermore, female rats displayed higher breaking points than male rats. It appears that the estrous cycle influences an animal's motivation to self-administer cocaine.     

The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies

Introduction: Type 2 diabetes (T2D), a multifactorial and chronic disease, requires in an elevated percentage of patients the association of several antidiabetic drugs to achieve optimal glycemic control. Dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium–glucose cotransporter inhibitors (SGLT2i) are new classes of oral antidiabetic drugs developed over the last years.

Areas covered: This paper summarizes the safety of DPP-4i and SGLT2i combination therapies. Relevant studies were identified through searches in PubMed.

Expert opinion: DPP4i and SGLT2i are antidiabetic drugs that lower blood glucose without causing hypoglycaemia or weight increase. More importantly, cardiovascular trials have clearly demonstrated the cardiovascular safety of DPP4i and a reduction in cardiovascular events with SGLT2i (empagliflozin and canagliflozin). Therefore, the association of both therapeutic groups could be an attractive option to achieve optimal blood glucose control in T2D because of their complementary mechanism of action. Clinical trials evaluating the combination of SGLT2i and DPP4i show that the co-administration of these drugs in fixed-dose combinations in comparison to separate tablets does not carry additional safety concerns that each individual drug, but increases therapeutic effects. Therefore, this antidiabetic combination is a safe and effective therapy for patients with T2D.     

The efficacy of topical tazarotene monotherapy and combination therapies in psoriasis

Tazarotene (Tazorac^®, Allergan, Inc.) is the first topical retinoid approved for the treatment of plaque psoriasis. It has a similar onset of action compared to potent topical steroids and has the advantage of a longer remission. The common side effects associated with the drug include skin irritation (including pruritus), erythema and a burning sensation. To overcome some of these shortcomings, it has been used in combination with steroids, calcipotriene and phototherapy. Combination therapy not only results in a decrease in adverse side effects, but also enhanced efficacy. Clinical study data have shown that combination therapy is just as important as tazarotene monotherapy, if not more.     

Honokiol induces paraptosis and apoptosis and exhibits schedule-dependent synergy in combination with imatinib in human leukemia cells

Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, has been shown to inhibit growth and induce apoptosis in different cancer cell lines. This study shows that honokiol can induce a cell death distinct from apoptosis at lower concentrations. The death was characterized by cytoplasmic vacuolization with the endoplasmic reticulum swelling and accompanied by apoptosis at higher concentrations in NB4 and K562 cells. The two death processes may be in sequence at lower concentrations and in parallel with the increase of honokiol concentration. Membrane-associated cytotoxicity was involved in honokiol-induced paraptosis and apoptosis. Furthermore, honokiol inhibited concentration-dependent cell adhesion to extracellular matrix for NB4 cells. In addition, the cytotoxicity of honokiol combined treatment with imatinib was schedule- and concentration-dependent and the sequential administration of honokiol before imatinib appeared to be more beneficial in K562 cells. Taken together, the data suggest that honokiol induced a novel cell death pathway and there was cross-talk between apoptotic and non-apoptotic programmed cell death caused by honokiol in leukemia cells. Moreover, honikiol exhibited schedule-dependent synergy in combination with imatinib and sequential administration of imatinib followed by honokiol could be the optimal sequence to combine these two drugs in K562 cells.     

The combination of sulfinosine and 8-Cl-cAMP induces synergistic cell growth inhibition of the human neuroblastoma cell line in vitro

Summary To identify purine analogs that could be effective in treating neuroblastomas, we tested the anticancer properties of sulfinosine, 8-Cl-cAMP and 8-Cl-adenosine in the SK-N-SH cell line. First we examined the effects of these three agents on cell growth inhibition and cell viability by the BrdU and Sulforhodamine B assay. Treatment of SK-N-SH cells with increasing concentrations of these compounds led to a significant inhibition of cell proliferation and decrease of cell viability in a time- and dose-dependant manner at micromolar concentration (<10 μM). Treatment with a combination of sulfinosine and 8-Cl-cAMP resulted in synergistic effects on growth inhibition, cell cycle arrest and induction of apoptosis. Flow-cytometric analysis showed that 8-Cl-cAMP arrested the cells in the G0/G1 phase and sulfinosine blocked cell cycle progression at the G2/M stage, in contrast to the combined effects of both agents that did not arrest growth at any particular phase of the cell cycle. Further analysis of apoptosis induction demonstrated an increase from 17 to 24% of both early and late apoptotic cells and a very low percentage of necrotic cells. These results indicate that apoptosis was the predominant type of cell death after treatment of SK-N-SH cells with both substances, as well as with their combinations.     

Phase I evaluation of chlorozotocin (NSC-178248): weekly schedule

Summary A phase I trial of chlorozotocin was completed for a weekly times four dose schedule repeated every 8 weeks. Thrombocytopenia was the acute dose limiting toxicity. Nausea and vomiting were moderate to severe and dose related. Two cases of possible drug related irreversible nephrotoxicity were seen. Transient elevations of serum creatinine and mild proteinuria were noted. Also, transient elevations in SGOT were observed. One patient with a carcinoid tumor had a 60% reduction in his 5HIAA level after one course of therapy. The recommended dose for phase II clinical studies of chlorozotocin is 40 mg/m² IV weekly for four weeks, repeated every 8 weeks.     

An overview on Vadimezan (DMXAA): The vascular disrupting agent

Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone‐acetic acid‐based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5‐HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL‐6, GCSF, KC, IP‐10, and MCP‐1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed.     

Intravenous self-administration of acetaldehyde in the rat as a function of schedule,food deprivation and photoperiod

The present series of experiments were conducted to discover whether rats would self-administer acetaldehyde (AcH) intravenously. The first study establishes the basic parameters for AcH self-injection in rats at 80% reduced body weight on a fixed-time 1 min (FT-1) food delivery schedule tested in the dark phase of a 12:12 light/dark cycle. The results show a dose-dependent effect with 1.3% AcH being the preferred dose as measured by the number of infusions. In the second experiment rats were on 100% free-feeding and at 80% reduced body weight, both conditions either with or without the influence of a FT-1 min schedule. The findings indicate that an interaction between dose, food deprivation and a FT-1 min schedule appears to initiate and maintain high levels of AcH self-injection in the dark. In a further experiment using 1.3% AcH the self-injection rates of animals at 80% body weight with a FT-1 min schedule reveal that the time of day of testing may be an important variable for inducing AcH intake. The results suggest that under altered environmental conditions AcH may have both an aversive and reinforcing effect.     

Pharmacokinetic considerations for use of artemisinin-based combination therapies against falciparum malaria in different ethnic populations

Introduction: Artemisinin-based combination therapy (ACT) is used extensively as first-line treatment for uncomplicated falciparum malaria. There has been no rigorous assessment of the potential for racial/ethnic differences in the pharmacokinetic properties of ACTs that might influence their efficacy.

Areas covered: A comprehensive literature search was performed that identified 72 publications in which the geographical origin of the patients could be ascertained and the key pharmacokinetic parameters maximum drug concentration (C_max), area under the plasma concentration-time curve (AUC) and elimination half-life (t_½β) were available for one or more of the five WHO-recommended ACTs (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine and artesunate-sulfadoxine-pyrimethamine). Comparisons of each of the three pharmacokinetic parameters of interest were made by drug (artemisinin derivative and long half-life partner), race/ethnicity (African, Asian, Caucasian, Melanesian, South American) and patient categories based on age and pregnancy status.

Expert opinion: The review identified no evidence of a clinically significant influence of race/ethnicity on the pharmacokinetic properties of the nine component drugs in the five ACTs currently recommended by WHO for first-line treatment of uncomplicated falciparum malaria. This provides reassurance for health workers in malaria-endemic regions that ACTs can be given in recommended doses with the expectation of adequate blood concentrations regardless of race/ethnicity.     

Drug therapies for polymyalgia rheumatica: a pharmacotherapeutic update

Introduction: Polymyalgia rheumatica (PMR), a common disease in individuals older than 50 in the western world, is characterized by bilateral inflammatory pain involving the shoulder girdle and less commonly the neck and pelvic girdle. The main goals of the currently available treatment are to induce remission and prevent relapse.

Areas covered: This review briefly presents the main epidemiological and clinical features of PMR and discusses in depth both its classical management as well as new therapies used in PMR.

Expert opinion: In general, patients with isolated PMR experience a rapid response (in less than seven days) to 12.5–25 mg/prednisone/day. Methotrexate is the conventional disease-modifying antirheumatic drug most commonly used for disease management, especially for relapses of the disease. However, this agent often yields a modest effect. Randomized controlled trials do not support the use of antitumor necrosis factor agents in PMR. Several case series and retrospective studies have highlighted the efficacy of the anti-interleukin-6 receptor antibody tocilizumab in PMR. However, controlled trials are needed to fully establish the efficacy of this biologic agent in PMR. The potential beneficial effect of the Janus-kinase inhibitors remains to be determined.     

头颈鳞癌的分子靶向药物治疗

头颈鳞癌（HNSCC）是全球的第六种最常见的恶性肿瘤。尽管极力提高各种治疗方式的水平,但晚期病例死亡率仍高。因此,寻找更有效的分子靶向药物和联合应用不同治疗方法势在必行。抗EGFR单克隆抗体,西妥昔单抗（Cetuximab）是第一个治疗HNSCC的靶向药。现已证明局部晚期HNSCC患者用Cetuximab＋放射治疗（P．T）有生存期益处,并增强局部区域控制。对铂耐药的转移性HNSCC患者单用Cetuximab有临床效果。Ⅲ期试验用Cetuximab和标准的铂为基础的方案第一线治疗复发转移HNSCC患者证明有生存期益处。其他靶向治疗方法也在研究中,正在对各期HNSCC患者进行的临床试验将进一步确定靶向治疗作用