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Griseofulvin has been shown to block mitosis in the fungusBasidiobolus ranarum. A wide range of metabolic inhibitors were used to investigate the relationship between growth rate and mitotic index. On the basis of such experiments inhibitors could be divided into two groups; the first affect the cell during the interphase period, the second affect the cell during mitosis.

Mouse peritoneal macrophages were cultivated in vitro and treated with ethidium bromide (EB) or with cis-dichloro-diammine platinum (II) (cis-Pt). EB provokes strong cytological alterations and cell degeneration; cis-Pt was not toxic under our experimental contitions. EB-DNA complex penetrates into the macrophages, is liberated from DNA in vacuoles, then diffuses into the cell and is highly cytotoxic. Cis-Pt-DNA complex also penetrates into the cells, but cis-Pt cannot be released from DNA, cis-Pt-DNA complex accumulates inside cytoplasmic vacuoles but has no cytotoxic activity.

In vitro incubation of the isolated rabbit retina at elevated temperature results in the synthesis of a heat shock protein of M.W. 74,000 (hsp74). Recently we have demonstrated that this protein is associated with preparations of purified retinal microtubules and intermediate filaments. In order to examine the possibility that hsp74 synthesis is related to cytoskeletal stability, the effects of agents known to specifically affect microtubules were examined using an in vitro retinal system. Taxol, an antimitotic agent which stabilizes microtubules, was found to reduce the level of hsp74 synthesized in response to elevated temperature. Colchicine, a potent microtubule de-stabilizing agent, did not induce hsp74 synthesis in the absence of elevated temperature, however, under heat shock conditions, hsp74 synthesis was elevated in the presence of colchicine. Kinetics of microtubule assembly were similar in preparations isolated from cerebral hemispheres of control and hyperthermic animals however, microtubules from the latter were altered in appearance and exhibited a higher degree of crosslinking.

A method has been devised for obtaining viable cultures of normal sensory neurons and normal Schwann cells from rat dorsal root ganglia, using cytosine arabinoside and fluorodeoxyuridine for control of non-neuronal cell proliferation. These cultures were used to demonstrate (a) that Schwann cells could be generated and maintained in culture free of fibroblast contamination, (b) that Schwann cells could exist in either a quiescent or proliferative state, depending on the absence of neurons, (c) that sensory ganglia could be obtained that would provide an outgrowth of axons entirely free of non-neuronal cells even in the absence of antimitotic agents, and (d) that quiescent Schwann cells, induced to proliferate by 'bare' axons, could ensheath and, in time, myelinate some of these axons.

The management of acute leukemia has been transformed by the advent of major antimitotic agents. Intensive combination drug therapy has given excellent results for many patients, but in certain cases it remains dangerous (acute leukemia in elderly patients) or ineffective (refractory anemia with excess blasts (RAEB), secondary leukemia, leukemic relapse). Allogeneic bone marrow grafts are also limited by the particular conditions required (compatibility of MHC, age).

A ciliate protozoan (Tetrahymena pyriformis, amicronucleate strain GL), exposed to 5 mg/ml colchicine to prevent cell division, is able to overcome the initial inhibitory effect of the drug both in exponentially growing and in heat-shock synchronized cultures.

The response of sodium urate-induced paw welling in mice to various antimitotic and anti-inflammatory agents was studied. Antimitotics colchicine, vinblastine, vincristine and podophyllotoxin produced a significant suppression of paw swelling at similar dose levels. Desacetamidocolchicine, a more potent antimitotic agent than colchicine, was less active against paw swelling even when given in a 58-fold greater dose than colchicine. Anti-inflammatory agents prednisone and indomethacin inhibited paw swelling but phenylbutazone, even at lethal doses, was inactive in this respect.

The present experiments show that antimitotic agents commonly used in the treatment of neoplastic disorders do not behave uniformly with respect to the action on the blastic transformation of lymphocytes. Furthermore, their action differs according to the experimental procedure, namely whether they are administeredin vivo or added directly to the biological systemin vitro. It can be observed however, that a close relationship exists in thein vitro experiment between the inhibition of the blastic transformation and the antiproliferative effect, as measured by the inhibition of the uptake of tritiated thymidine. It is legitimate to believe that such agents are endowed with different degrees of immunological activity, which may be restrained or elicited according to the circumstances. Such effect should therefore be kept in mind, whenever these agents are given for a clinical treatment.

1. 1. The antimitotic effects produced in tissue cultures of chick fibroblasts by certain mercaptoacetic derivatives of 1:4-naphthoquinone (S-(2-hydroxy-1:4-naphthoquinolyl-3) mercaptoacetic acid, called hydroxy-quo- mo , and S:S(1:4-naphthoquinolyl-2:3)- bis -mercaptoacetic acid, called quo- bis ) and by d -, l - and dl -methionine, is alleviated by applying a mixture of the mercaptoacetic adducts and the methionines to the growing cells. 2. 2. Total alleviation is obtained in the system d -methionine / quo- bis at a ratio d -methionine / quo- bis greater than 10:1. The system d -methionine / hydroxy-quo- mo gives complete alleviation at the ratio d -methionine / hydroxy-quo- mo 100:1. 3. 3. With l -methionine / quo- bis , only partial alleviation is achieved even at a ratio l -methionine / quo- bis 100:1. The mitotic inhibition is completely cancelled, but arrest in metaphase is only partially decreased and there is no inhibition of the chromosomal abnormalities. 4. 4. In the system d -methionine / quo- mo no alleviation has been found. 5. 5. d -Ethionine and d -leucine fail to antagonise the antimitotic effect of quo- bis . 6. 6. The increase of the mitotic count observed after application of the tetramercaptoacetic derivative of 1:4-benzoquinone remains unimpaired by d -methionine. 7. 7. It has been pointed out that the alleviation of the antimitotic action of certain sulphydryl adducts of 1:4-naphthoquinone by means of l -methionine, establishes a connection between the antimitotic effects of these compounds and “active methionine” (adenosine-methionine) and thus with the methyl donating properties of l -methionine.

DESACETYLMETHYLCOLCHICINE (Colcemide) is a natural alkaloid which differs from colchicine in that a methyl group replaces an acetyl group at the N position.1 It is a potent antimitotic agent, and over 30 papers have appeared in the foreign literature between 1953 and 1956 reporting its use in the treatment of chronic myelogenous leukemia.2 3 4 5 6 Recent reports have indicated that because of the rarity of gastrointestinal toxicity, it might be a more useful agent than colchicine and indeed might even replace it in the management of acute gouty arthritis.7 8 9 The case reported below illustrates an unusual and profound toxicity to the hematopoietic . . .

SUMMARYAntimitotic agents induce pathological alterations by suspension of the normal cellular renewal: it results the picture of the so called « aregenerative pathology ». Moreover, they induce cytological abnormalities, like cellular vacuolization, alterations of the enzymatic cellular pattern, cellular giantism, etc. These alterations constitute the « cytological dysplasia by antimitotic drugs ». They are easily recognizable in many organs, i.e. in the haemopoietic system, lungs and pancreas. Particularly evident is the cellular giantism in the labial epithelia: in some of these cells of gynecologically normal women two Barr bodies are observed.

The toxicity of 5-aziridino-2,4-dinitrobenzamide (CB 1954) in the rat at the LD50 dose level resembled the majority of antimitotic agents in causing enteritis, but there was less bone marrow depression than usual. At the minimum toxic dose both of these effects were absent, and the tissues affected were the urinary tract and the liver. In the urinary tract areas of transitional epithelium were replaced by a single layer of macronuclear cells. The main pathologic change in the liver was centrilobular venous thrombosis. With chronic dosage the most serious toxic effect was cataract formation which was associated with, but not necessarily the result of, destruction of lens epithelium.

SYNOPSIS To elucidate further the molecular events required for cytodifferentiation in Stentor coeruleus, the effects of several chemical metabolic inhibitors were tested on the outgrowth in situ of the membranellar cilia of the oral feeding organelle. The chemicals used included several inhibitors of cytoplasmic and mitochondrial protein synthesis (cycloheximide, emetine, and chloramphenicol), and an antimitotic agent (colchicine). Ciliary growth was affected only by colchicine, suggesting that a pool of “ciliary proteins” exists in interphase Stentor of sufficient size to permit complete reformation of the membranellar cilia. The implication of these observations to an understanding of the more complicated process of oral regeneration is discussed.

Taxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents.

Background Antimitotic chemotherapeutic agents target tubulin, the major protein in mitotic spindles. Tubulin isotype composition is thought to be both diagnostic of tumor progression and a determinant of the cellular response to chemotherapy. This implies that there is a difference in isotype composition between normal and tumor tissues. Methods To determine whether such a difference occurs in breast tissues, total tubulin was fractionated from lysates of paired normal and tumor breast tissues, and the amounts of β-tubulin classes I + IV, II, and III were measured by competitive enzyme-linked immunosorbent assay (ELISA). Only primary tumor tissues, before chemotherapy, were examined. Her2/neu protein amplification occurs in about 30% of breast tumors and is considered a marker for poor prognosis. To gain insight into whether tubulin isotype levels might be correlated with prognosis, ELISAs were used to quantify Her2/neu protein levels in these tissues. Results β-Tubulin isotype distributions in normal and tumor breast tissues were similar. The most abundant β-tubulin isotypes in these tissues were β-tubulin classes II and I + IV. Her2/neu levels in tumor tissues were 5–30-fold those in normal tissues, although there was no correlation between the Her2/neu biomarker and tubulin isotype levels. Conclusion These results suggest that tubulin isotype levels, alone or in combination with Her2/neu protein levels, might not be diagnostic of tumorigenesis in breast cancer. However, the presence of a broad distribution of these tubulin isotypes (for example, 40–75% β-tubulin class II) in breast tissue, in conjunction with other factors, might still be relevant to disease progression and cellular response to antimitotic drugs.

[formula: see text] A triply convergent, highly efficient second-generation synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on a 1-g scale.

Polo-like kinase 1 (PLK1) plays key roles during mitosis, prompting the development of PLK1 inhibitors for anticancer therapy. We recently determined that PLK1 is crucially required for entry into mitosis. Hence, we discuss the potential and limitations of PLK1 inhibition strategies to promote mitotic arrest and death of cancer cells.

The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian cells by interfering with proper assembly of α,β-tubulin heterodimers. They favor curved tubulin assemblies that destabilize microtubules and induce formation of spiral aggregates. Their binding energy profiles have been characterized by means of sedimentation velocity assays and the binding site of vinblastine at the interface between two tubulin dimers (α 1β 1-α 2β 2) has been ascertained by X-ray crystallographic studies on a complex of tubulin with the stathmin-like domain of protein RB3, albeit at relatively low resolution. Here we use molecular modeling and simulation techniques to build, refine and perform a comparative analysis of the three-dimensional complexes of vinblastine, vincristine, vinorelbine and vinflunine with a β 1α 2-tubulin interface in explicit water to rationalize the binding affinity differences in structural and energetic terms. Our results shed some more light into the binding determinants and the structure-activity relationships of these clinically useful agents.

Pharmacological blockade of fibroblastic proliferation after glaucoma filtration surgery by using antimitotic agents in different formulations (liposomes, nanospheres) is of great clinical interest. However, only limited comparative data are available on the effect of encapsulated drugs on intraocular pressure (IOP) after filtering surgery. Therefore we have studied the effect on IOP of liposomes, nanospheres and a solution of mitoxantrone (MTO), a well-known antimitotic, in rabbits before and after sclerectomy. MTO in solution form, as well as in a liposome formulation, improved the outcome of the surgery by reducing IOP when administered subconjunctivally just following surgery. This effect was similar to mitomycin-C application. In contrast, neither prior administration nor subconjunctival nanosphere injections induced a reduction in IOP. Liposome administration demonstrated no delayed action or promoting effect but reduced the occurrence of corneal opacity observed in groups treated with MTO in solution.

The aim of this study was to establish the capacity of thermoresponsive poly(N-isopropylacrylamide) copolymer films to deliver bioactive concentrations of an antimitotic agent to human vascular smooth muscle cells (HASMC) over an extended period of time. Copolymer films were prepared using a 50:50 (w/w) ratio of N-isopropylacrylamide (NiPAAm) monomer to the more hydrophobic N-tert-butylacrylamide (NtBAAm) and loaded with the antimitotic agent colchicine (0.1 μmol per film) at room temperature. Colchicine release from films was sustained over a 14-day period. At 24 h postloading, the concentration of colchicine in the medium overlying films was 2.12 ± 0.16 μM; this fell to 0.20 ± 0.01 μM at 7 days and decreased further to 0.12 ± 0.01 μM after 14 days. Colchicine released from copolymer films inhibited proliferation when subsequently placed on HASMC: at 0.1 μM, released colchicine reduced proliferation to 18.5 ± 0.8% of control cells (p < 0.001, n = 9). The antiproliferative effect of released colchicine was comparable to that of native colchicine, as observed in separate experiments. Furthermore, colchicine released from 50:50 polymer films inhibited the proliferation of cells grown in the same environment as the copolymer. Inhibition of cell proliferation was not due to the release of cytotoxic particles from the copolymer because medium incubated with copolymer for 5 days and then applied to HASMC did not alter cell viability. In conclusion, this study demonstrates that 50:50 NiPAAm:NtBAAm copolymers can deliver bioactive concentrations of the antimitotic agent colchicine to human vascular cells over an extended period of time. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 67A: 667–673, 2003

Summary The authors studied the clinical and histological effects of cyclosporine instilled after filtering surgery. Its efficacy and variety of advantages compared to other antimitotic agents encourage its use.

Razoxane [ICRF 159, 1,2-bis(3,5-dioxopiperazin-I-yl) propane] is an oral antimitotic agent, which is very effective in the treatment of psoriasis (Atherton et al., 1980). Its efficacy in psoriasis is related to its effect on the increased epidermopoiesis and on the abnormal dermal microvasculature. Razoxane arrests the cell cycle progression only during the late pre-mitotic (G2) or the early mitotic (M) phase of the cell cycle.

Tubulin, the protein subunit of microtubules, is considered a target for antimitotic agents such as colchicine, maytansine and the vinca alkaloids vincristine and vinblastine. Of these agents, only vincristine and vinblastine have been found to have clinical utility for treatment of human neoplastic disease. The basis for therapeutic selectivity was examined in a comprehensive model in which human rhabdomyosarcomas were grown as xenografts in mice. This model has allowed a detailed examination of differences between neoplastic and non-neoplastic tissues with respect to binding, retention and metabolism of vinca alkaloids. Of note is that in tumor tissue, vincristine is tenaciously bound whereas vinblastine is not. In non-neoplastic tissue, retention of both agents is poor. The mechanisms responsible for differential retention between vinca alkaloids and between neoplastic and non-neoplastic tissues were examined. Results suggest that guanosine 5-triphosphate may be implicated in the formation and stability of vinca-tubulin complexes in tissue cytosols. Two models consistent with the data are proposed, and the significance to therapeutic efficacy is discussed.

A method of treating psoriasis without the use of corticosteroids or antimitotic agents is described. A special technique incorporating the use of anthralin is employed with results which are better than any so far published. As well as being effective and inexpensive, the technique is safe, with no systemic side effects. It has been adopted as the standard therapeutic procedure in a number of centers in England and Europe.

Tracer experiments prove that the antimitotic agent narciclasine (6) is biosynthesised from O-methyl-norbelladine (1) by para–para coupling followed by late elimination of two carbon atoms.

A new hydroquinone compound, the internal salt of 2,5-bis-ethylenimino-hydroquinone, has a multiform antimitotic effect and a potent tumor-inhibiting action on a wide spectrum of inoculated tumors of mice and rats. On the other hand, normal tissues undergoing intensive cell division do not appear to be affected adversely from the histological standpoint.

In previous studies (1, 2, 3, 4, 5, 6, 7) local administration of 5-Fluorouracil' (5-FL) was found to have a marked effect upon the natural course of single and multiple basal cell cpitheliomas and solar keratoses as well as secondary tumors in the skin. The variables that appeared to influence the effects of 5FU and other topically administered antimitotic agents upon the tumors included: concentration of the agent; use of occlusive dressings; duration of application and nature of the vehicle containing the agent. Comparisons of the effects of preparations containing various concentrations of 5-FL upon large confluent areas of superficial basal cell epitheliomatosis have been reported (3). This report presents a more systematic study to compare the effects of different concentrations of 5-FU concurrently administered by inunction to multiple, superficial, basal cell carcinomas in the same patient.