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Second-Generation Antimitotics in Cancer Clinical Trials.

Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA's effectiveness. With the desire to overcome some of the MTA's limitations, mitotic and SAC components have attracted great interest as promising microtubule

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… Until now, no small molecule has been approved for clinical use, and MTAs still remain the antimitotic agents with the best therapeutic benefit. …

Disruption of p53 function in immortalized human cells does not affect survival or apoptosis after taxol or vincristine treatment.

In the present study, we report our findings on the impact of p53 disruption on the sensitivity of human cell lines to the antimitotic agents Taxol and vincristine. Comparisons of cell survival and apoptosis were made with y-irradiation and, in some cases, several other DNA-damaging chemotherapeutic agents. Studies in eight Burkitt's lymphoma and lymphoblastoid cell lines (four wild-type p53 and four mutant p53 cell lines) revealed that the DNA-damaging agents assayed tended to exhibit less growth inhibition in the mutant p53 cell lines compared to the wild-type p53 cell lines. In contrast, no…

The Chemical Composition and Antimitotic, Antioxidant, Antibacterial and Cytotoxic Properties of the Defensive Gland Extract of the Beetle, Luprops tristis Fabricius.

The unpredictable invasion of the Mupli beetle, Luprops tristis Fabricius (Coleoptera: Tenebrionidae), makes areas uninhabitable to humans. These beetles produce a strong-smelling, irritating secretion as a defence mechanism, which causes blisters on contact with human skin. In the current study, gas chromatography high-resolution mass spectrometry (GC-HRMS) analysis of the defensive gland extract of the Mupli beetle revealed the presence of compounds such as 2,3,dimethyl-1,4-benzoquinone, 1,3-dihydroxy-2-methylbenzene, 2,5-dimethyl hydroquinone, tetracosane, oleic acid, hexacosane, pentacosan

[Fertility in women after cancer therapy].

In children and young women, antimitotic chemotherapy and radiotherapy can provoke premature ovarian failure, as well as chromosomal or genic mutations potentially responsible of pregnancy wastage, congenital malformations or genetic diseases in the progeny. After an abdominal radiotherapy, the long term sequelae of uterine irradiation can induce pregnancy wastage, prematurity or low birth-weight. Irreversible ovarian damages are mainly due to alkylating agents and abdominal radiotherapy. The gradual depletion of the follicular pool accounts for the apparent increasing ovarian sensitivity: in

The Mechanisms of Action of Tumor Treating Fields.

Tumor treating fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While antimitotic effects were the first recognized biological anticancer activity of TTFields, data have shown that tumor treating fields achieve their anticancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different

An Expedient Total Synthesis of Chivosazole F: an Actin-Binding Antimitotic Macrolide from the Myxobacterium Sorangium Cellulosum.

A unified strategy for the chemical synthesis of the chivosazoles is described. This strategy is based on two closely related approaches involving the late-stage installation of the isomerization-prone (2Z,4E,6Z,8E)-tetraenoate motif, and an expedient fragment-assembly procedure. The result is a highly convergent total synthesis of chivosazole F through the orchestration of three mild Pd/Cu-mediated Stille cross-coupling reactions, including the use of a one-pot, site-selective, three-component process, in combination with controlled installation of the requisite alkene geometry.

Selective antimicrotubule activity of N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5) against kinetoplastid parasites.

Analogs of the antimitotic herbicide oryzalin (3,5-dinitro-N4,N4-di-n-propylsulfanilamide) were recently prepared that were more potent in vitro than the parent compound against the kinetoplastid parasite Leishmania donovani (Bioorg Med Chem Lett 12:2395-2398, 2002). In the present work, we show that the most active molecule in the group, N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5), is a potent, selective antimitotic agent against kinetoplastid parasites. GB-II-5 possesses IC50 values of 0.41 and 0.73 microM in vitro against two strains of the related parasite Trypanosoma br

Recent advancements of coumarin-based anticancer agents: An up-to-date review.

Heading the list of the critical health-related issues worldwide, cancer continues to be a one of the most serious life-threatening diseases … such as alkylating agents, topoisomerase inhibitors, hormone antagonists, angiogenesis inhibitors, antimitotic agents, apoptosis inducers, human carbonic anhydrase inhibitors, telomerase inhibitors and other mechanisms. Accordingly, medicinal chemists and drug design scientists embarked on exploring diverse coumarin-based derivatives comprehending their potential t …

Verrucas. Guidelines for management.

Most people will experience infection with human papilloma virus (HPV) at some point in their life. Diagnosis, based on clinical examination, is usually straight forward. Treatment can, however, be challenging. Indications for treatment include pain, interference with function, cosmetic embarrassment, and risk of malignancy. Clearance rates are highest in young, healthy individuals with short duration of infection. Treatment may be with destructive agents (keratolytics, cryotherapy, curettage and cautery, laser, photodynamic therapy), with antimitotic agents (podophyllin, bleomycin, retinoids)…

APC(Cdc20) suppresses apoptosis through targeting Bim for ubiquitination and destruction.

Anaphase-promoting complex Cdc20 (APC(Cdc20)) plays pivotal roles in governing mitotic progression. By suppressing APC(Cdc20), antimitotic agents activate the spindle-assembly checkpoint and induce apoptosis after prolonged treatment, whereas depleting endogenous Cdc20 suppresses tumorigenesis in part by triggering mitotic arrest and subsequent apoptosis. However, the molecular mechanism(s) underlying apoptosis induced by Cdc20 abrogation remains poorly understood. Here, we report the BH3-only proapoptotic protein Bim as an APC(Cdc20) target, such that depletion of Cdc20 sensitizes cells to ap…

The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells.

Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2

[Accidents of chemotherapy involving the upper limb].

Subcutaneous extravation of antimitotic agents in the upper limb is a rare complication of chemotherapy. The functional integrity of the limb can be compromised due to severe skin damage. Extensive soft tissue necrosis is difficult to manage and cannot always be repaired without sequellae. Based on an analysis of a series of patients and a review of the literature, we report the main pathophysiological features and clinical signs of such accidents as well as the still debated therapeutic management. Two points are essential: the emergency situation created by these accidents requiring adequate…

Successful desensitization to brentuximab vedotin after hypersensitivity reaction.

Monoclonal antibodies (mAb) have become the standard of care for numerous diseases. However, side effects including infusion and hypersensitivity reactions experienced by patients continue to be a limiting factor in their use. In the therapy of cancer, treatment choices are frequently limited and minimizing side effects of a life-saving or life-prolonging therapy becomes of the utmost importance. We report the successful use of a rapid desensitization protocol in a patient with NHL, treated with a novel antibody-drug conjugate, chimeric monoclonal antibody linked to the antimitotic agent monom

Toxin-Producing Endosymbionts Shield Pathogenic Fungus against Micropredators.

The fungus Rhizopus microsporus harbors a bacterial endosymbiont (Mycetohabitans rhizoxinica) for the production of the antimitotic toxin rhizoxin. Although rhizoxin is the causative agent of rice seedling blight, the toxinogenic bacterial-fungal alliance is, not restricted to the plant disease. It has been detected in numerous environmental isolates from geographically distinct sites covering all five continents, thus raising questions regarding the ecological role of rhizoxin beyond rice seedling blight. Here, we show that rhizoxin serves the fungal host in fending off protozoan and metazoan

Multiple modes of action of eribulin mesylate: Emerging data and clinical implications.

Eribulin mesylate (eribulin) is a synthetic analogue of the marine-sponge natural product halichondrin B. Eribulin exhibits potent antiproliferative activities against a variety of human cancer cell types in vitro and in vivo, and is used for the treatment of certain patients with advanced breast cancer or liposarcoma who are refractory to other treatments. The antiproliferative effects of eribulin have long been attributed to its antimitotic activities. Unlike other microtubule-targeting agents, eribulin inhibits microtubule polymerization through specific plus end binding, thus interfering w

Haemolytic-uraemic syndrome complicating long-term mitomycin C and 5-fluorouracil therapy for gastric carcinoma.

Three cases of acute renal toxicity in patients receiving long-term therapy with mitomycin C and 5-fluorouracil are reported. Two of the pat … ty that mitomycin C may sensitise the kidneys to minor mismatches. With the increasing use of these antimitotic agents, great vigilance should be exercised with regard to renal function and haemolytic status.

Identification of antimitotic sulfonamides inhibiting chromosome congression.

The discovery of new small-molecule inhibitors is essential to enhancing our understanding of biological events at the molecular level and driving advancements in drug discovery. Mitotic inhibitors have played a crucial role in development of anticancer drugs. Beyond traditional microtubule inhibitors, various inhibitors targeting specific mitotic factors have been developed. This study aimed to develop novel mitotic inhibitors targeting chromosome alignment. We established a cell-based screening method using Cell Division Cycle Associated 5 (CDCA5) and kinesin-5 as markers, designed to effici

Cytogenetics of acute and chronic schistosomiasis mansoni.

Schistosomiasis mansoni patients with acute were examined for genetic damage using the conventional cytogenetic method to assess the frequency of chromosomal aberration (CA) in the cultured blood cells. A non-significant difference was noticed in the frequency of CA between patients (acute & chronic) and control (n = 15), but on treatment of blood cultures with bleomycin (a radiomimetic agent with a DNA alkylating effect), the percentage of induced breakage and fragmentation increased significantly 2 and 3 folds in acute and chronic patients respectively, indicating increased chromosomal fragi

A new class of cytotoxic agents targets tubulin and disrupts microtubule dynamics.

Despite the advances in treatment strategies, cancer is still the second leading cause of death in the USA. A majority of the currently used cancer drugs have limitations in their clinical use due to poor selectivity, toxic side effects and multiple drug resistance, warranting the development of new anticancer drugs of different mechanisms of action. Here we describe the design, synthesis and initial biological evaluation of a new class of antimitotic agents that modulate tubulin polymerization. Structurally, these compounds are chalcone mimics containing a 1-(1H-imidazol-2-yl)ethan-1-one moie…