Vinflunine: drug safety evaluation of this novel synthetic vinca alkaloid

Introduction: Vinca alkaloid agents have been widely used in several different types of malignancies. However, cancer cells, ultimately, develop resistance to these agents. Therefore, the development of new agents with improved efficacy is warranted. Recently, a new synthetic vinca alkaloid, vinflunine, was developed through the addition of two fluor molecules by superacidic chemistry.

Areas covered: The authors describe the development of the new vinca alkaloid vinflunine from preclinical studies to the late-stage clinical trials, highlighting the most important clinical and safety data of vinflunine. In vitro and in vivo studies have shown a superior efficacy of vinflunine over other vinca alkaloids and with an improved safety profile. Early clinical trials have demonstrated a significant activity of vinflunine against different malignancies. Phase III trials showed that vinflunine increases survival in patients with advanced transitional cell carcinoma of the urothelium (TCCU) tract treated in the second-line and is as effective as docetaxel in second-line NSCLC.

Expert opinion: Vinflunine is currently approved in Europe for the treatment of second-line TCCU and is currently being developed in other malignancies. It has been shown to have predictable and manageable adverse effects, such as neutropenia, anemia, constipation and fatigue.     

A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors

BACKGROUND:

E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids).

METHODS:

In a phase 1 study, E7974 was given intravenously over a 2‐ to 5‐minute infusion on day 1 of every 21‐day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose‐limiting toxicity (DLT).

RESULTS:

Twenty‐eight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m², 0.27 mg/m², 0.36 mg/m², 0.45 mg/m², and 0.56 mg/m²) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m², where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression‐free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95‐147.93 L), slow clearance (2.23‐7.15 L/h), and moderate to slow elimination (time to half‐life, 10.4‐30.5 hours).

CONCLUSIONS:

This study shows that E7974 once every 21‐day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m². Cancer 2012. © 2012 American Cancer Society     

Antitubulin agents

Microtubules are dynamic filamentous cytoskeletal proteins that are an important therapeutic target in patients with tumors. Microtubule binding agents have been part of the pharmacopoeia of cancer for decades, and until the advent of targeted therapy microtubules represented the only alternative to DNA as a therapeutic target in cancer. There are currently a variety of available vinca alkaloids and taxanes and other agents, such as ixabepilone and eribulin, have also been approved. Maytansinoids have been used for the production of immunoconjugates, monoclonal antibodies covalently bound to antimitotic molecules. The screening of a variety of botanical species and marine organisms continues to yield promising new antitubulin agents with novel properties. Enhanced tumor specificity, reduced neurotoxicity, and insensitivity to chemoresistance mechanisms are the three main objectives in the current search for novel microtubule binding agents.     

微管蛋白抑制剂SUD-35固体分散体的制备、鉴定及初步体外药效学研究

目的将难溶性微管蛋白抑制剂SUD-35制备成固体分散体,以增加其溶解度及溶出速率。方法以聚乙二醇6000为载体,溶剂-熔融法制备SUD-35固体分散体。采用差示扫描量热分析与X-射线衍射观察药物在载体中的存在状态,并进行溶解度和体外溶出度研究。采用MTT法对SUD-35固体分散体对小鼠白血病L1210细胞药效进行测定。结果 SUD-35固体分散体中SUD-35的溶解度和溶出速率相对原料药和物理混合物均有明显提高,差示扫描量热分析与X-射线衍射结果显示SUD-35以无定型状态存在于固体分散体中,细胞药效结果显示SUD-35固体分散体对小鼠白血病L1210细胞增殖抑制率强于SUD-35纯药。结论聚乙二醇6000为载体制备SUD-35固体分散体,可显著提高SUD-35的溶解度及溶出速率。     

Design,synthesis, and biological evaluation of a new class of benzo[b]furan derivatives as antiproliferative agents,with in silico predicted antitubulin activity

A new series of 3‐benzoylamino‐5‐(1H‐imidazol‐4‐yl)methylaminobenzo[b]furans were synthesized and screened as antitumor agents. As a general trend, tested compounds showed concentration‐dependent antiproliferative activity against HeLa and MCF‐7 cancer cell lines, exhibiting GI₅₀ values in the low micromolar range. In most cases, insertion of a methyl substituent on the imidazole moiety improved the antiproliferative activity. Therefore, methyl‐imidazolyl‐benzo[b]furans compounds were tested in cell cycle perturbation experiments, producing cell cycle arrest with proapoptotic effects. Their core similarity to known colchicine binding site binders led us to further study the structure features as antitubulin agents by in silico protocols.     

3‐Arylindanones and related compounds as antiproliferative agents against colorectal cancer

Diverse benzylidene indanones and their derivatives were synthesized as anticancer agents. Two of the analogues, that is 7 and 22, exhibited significant antiproliferative activity against several human cancer cell lines. Both the compounds possessed antimitotic activity and induced apoptosis in DLD1 colorectal adenocarcinoma cells through activation of caspase pathways. In cell cycle analysis, both the compounds induced predominantly G2/M phase arrest in DLD1 cells. Molecular docking studies revealed that compound 7 occupies colchicine binding pocket of β‐tubulin. Both the compounds were safe in acute oral toxicity in rodents. Both the compounds are further being optimized for better efficacy.     

Kinesin spindle protein Inhibitors as anticancer agents

Kinesin spindle protein (KSP), or Hs Eg5, is a member of the kinesin superfamily of molecular motor proteins that utilise the energy generated from the hydrolysis of ATP to transport vesicles, organelles and microtubules. KSP plays essential roles in mitotic spindle function and its inhibition prevents normal bipolar spindle formation, leading to mitotic arrest and subsequently to apoptosis of cells. Therefore, KSP inhibitors have potential as novel anticancer therapeutics. Since the discovery of monastrol in 1999, many types of KSP inhibitors have been reported. This review describes the mechanism of action and development of different types of KSP inhibitors.     

Antitubulin activity of vinblastine and vincristine

Summary The antitubulin activity of vinblastine and vincristine was compared by means of the radial segmentation test. Vinblastine was found to have antitubulin activity at least 6 times higher than that of vincristine. It is concluded that, if the differential indications for vinblastine or vincristine are balanced, it may be decisive for clinical treatment that more antitubulin activity can be administered as vinblastine than as vincristine.     

贵州民族药提取物A-3抗H22肿瘤细胞生长作用机制的初步研究

目的：对贵州民族药提取物A-3抗肿瘤作用机制进行初步研究。方法：研究A-3对小鼠皮肤迟发型超敏反应、肿瘤细胞凋亡、肿瘤血管生成及微管蛋白聚合解聚活性等四个方面的影响,初步探讨药物的抗肿瘤作用机制。结果：A-3能明显刺激正常小鼠和荷瘤小鼠的脾脏及胸腺增生,促进DTH反应。每天给予50mg／kg和100mg／kgA-3能见到明显促进H22肿瘤细胞凋亡的作用,但两剂量对H22肿瘤血管生成均无显著影响。浓度为0．1mmol／L时,A-3对兔脑微管蛋白体外的聚合解聚平衡反应无明显影响。结论：A-3可能通过提高机体免疫功能及促进肿瘤细胞凋亡等作用来抑制肿瘤生长。