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1.
Methods Mol Biol ; 1413: 403-21, 2016.
Article in English | MEDLINE | ID: mdl-27193863

ABSTRACT

Small molecule drugs that target microtubules (MTs), many of them natural products, have long been important tools in the MT field. Indeed, tubulin (Tb) was discovered, in part, as the protein binding partner of colchicine. Several anti-MT drug classes also have important medical uses, notably colchicine, which is used to treat gout, familial Mediterranean fever (FMF), and pericarditis, and the vinca alkaloids and taxanes, which are used to treat cancer. Anti-MT drugs have in common that they bind specifically to Tb in the dimer, MT or some other form. However, their effects on polymerization dynamics and on the human body differ markedly. Here we briefly review the most-studied molecules, and comment on their uses in basic research and medicine. Our focus is on practical applications of different anti-MT drugs in the laboratory, and key points that users should be aware of when designing experiments. We also touch on interesting unsolved problems, particularly in the area of medical applications. In our opinion, the mechanism by which any MT drug cures or treats any disease is still unsolved, despite decades of research. Solving this problem for particular drug-disease combinations might open new uses for old drugs, or provide insights into novel routes for treatment.


Subject(s)
Drug Discovery , Microtubules/metabolism , Tubulin Modulators/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Colchicine/chemistry , Colchicine/pharmacology , Colchicine/therapeutic use , Demecolcine/chemistry , Demecolcine/pharmacology , Demecolcine/therapeutic use , Furans/chemistry , Furans/pharmacology , Furans/therapeutic use , Humans , Ketones/chemistry , Ketones/pharmacology , Ketones/therapeutic use , Microtubules/chemistry , Protein Multimerization/drug effects , Stilbenes/chemistry , Stilbenes/pharmacology , Stilbenes/therapeutic use , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Taxoids/chemistry , Taxoids/pharmacology , Taxoids/therapeutic use , Tubulin Modulators/chemistry , Tubulin Modulators/therapeutic use , Vinca Alkaloids/chemistry , Vinca Alkaloids/pharmacology , Vinca Alkaloids/therapeutic use
2.
Int J Gynecol Cancer ; 14(4): 616-20, 2004.
Article in English | MEDLINE | ID: mdl-15304155

ABSTRACT

The purpose of the study was to determine whether paclitaxel inhibits the expression of heat shock protein 27 (HSP27) in two gynecologic cancer cell lines compared with other antineoplastic agents having different cytotoxic mechanisms. BG-1 ovarian cancer cells and HeLa uterine cancer cells were treated with a tubulin depolymerization inhibitor (paclitaxel), a topoisomerase-II inhibitor (etoposide), and two tubulin polymerization inhibitors (colcemid and vincristine). Cell kills were evaluated by counting the number of cells. Propidium iodide staining and flow cytometric analysis were applied for the determination of cell-cycle perturbation. HSP27 was stained by the indirect immunofluorescence technique and analyzed with a flow cytometer. In both BG-1 and HeLa cells, growth arrest and G2 / M accumulation were dependent on the dose of each cytotoxic agent. There were positive correlations between HSP27 overexpression and growth arrest and G2 / M accumulation when the cell lines were treated with etoposide, colcemid, or vincristine, but not with paclitaxel. Paclitaxel completely inhibited the expression of HSP27. The results of this study indicated that paclitaxel may possess unique mechanisms able to overcome drug resistance by inhibiting HSP27 expression.


Subject(s)
Antineoplastic Agents/therapeutic use , Heat-Shock Proteins/biosynthesis , Ovarian Neoplasms/drug therapy , Paclitaxel/therapeutic use , Uterine Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Cell Line, Tumor , Demecolcine/therapeutic use , Etoposide/therapeutic use , Female , Humans , Ovarian Neoplasms/metabolism , Uterine Neoplasms/metabolism , Vincristine/therapeutic use
3.
J Med Chem ; 28(9): 1204-8, 1985 Sep.
Article in English | MEDLINE | ID: mdl-4032423

ABSTRACT

Novel and known analogues of thiocolchicine were evaluated in vitro in a tubulin binding assay and in vivo in mice for acute toxicity and in the P388 lymphocytic leukemia assay. This evaluation included N-acyldeacetylthiocolchicines, N-(alkoxycarbonyl)deacetylthiocolchicines, thiodemecolcine and its methyl carbamate, and O-ethyl ethers of demethylthiocolchicines. Selective ether cleavage of thiodemecolcine with concentrated sulfuric acid at 50 degree C afforded the 2-demethyl congener, characterized as its N,O-diacetyl derivative. Several of the compounds showed high potency in the tubulin binding assay, matching the potency of colchicine. Several N-(alkoxycarbonyl)deacetylcolchicines (carbamates) exhibited strong binding affinity to tubulin but had only weak activities against the P388 tumor system, suggesting that other factors besides tubulin binding may be important for the biological effects. The compounds potent in the tubulin binding assay and in the P388 leukemia assay in mice were generally also toxic to mice in the acute toxicity test, showing thus a similar behavior of thiocolchicines to that observed earlier with colchicines. A considerable amount of data collected for 2-demethyl- and 3-demethylthiocolchicine suggests that the latter represents a broad-spectrum antitumor agent of considerable promise and possibly a less toxic substitute for colchicine.


Subject(s)
Colchicine/analogs & derivatives , Leukemia P388/drug therapy , Leukemia, Experimental/drug therapy , Tubulin/metabolism , Animals , Binding, Competitive , Chemical Phenomena , Chemistry , Colchicine/chemical synthesis , Colchicine/metabolism , Colchicine/therapeutic use , Colchicine/toxicity , Demecolcine/analogs & derivatives , Demecolcine/chemical synthesis , Demecolcine/therapeutic use , Drug Evaluation , Lethal Dose 50 , Mice , Structure-Activity Relationship
8.
Biull Eksp Biol Med ; 90(9): 357-9, 1980 Sep.
Article in Russian | MEDLINE | ID: mdl-7426742

ABSTRACT

Significant suppression of the entry of leukemic spleen cells in mitosis was found to be produced by the administration of colchamin (5 mg/kg) to mice with transplanted leukemia La. These data allow a conclusion that the duration of mitosis and the rate of mitotic activity in tissues cannot be determined by the colchamin method.


Subject(s)
Antineoplastic Agents , Demecolcine/pharmacology , Leukemia, Experimental/drug therapy , Mitosis/drug effects , Spleen/pathology , Animals , Demecolcine/therapeutic use , Leukemia, Experimental/pathology , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Transplantation, Homologous
11.
Biull Eksp Biol Med ; 85(2): 195-7, 1978 Feb.
Article in Russian | MEDLINE | ID: mdl-204377

ABSTRACT

The author studied the 24-hour changes in the number of normal and colchamine mitoses in the cells of Ehrlich's ascites carcinoma in mice after the injection of colchamine argainst the background of partial synchronization of cell division, obtained as a result of preliminary injection of dibutyryl cyclic 3',5'-AMP, and also in mice after the injection of colchamine alone or dibutyryl cyclic 3',5'-AMP. As shown, synchronization of cell division in the tumour led to the 2,6-fold increase in the number of tumour cells blocked by colchamine and also to the accelerated arrest of colchamine mitoses.


Subject(s)
Carcinoma, Ehrlich Tumor/drug therapy , Demecolcine/therapeutic use , Animals , Bucladesine/therapeutic use , Carcinoma, Ehrlich Tumor/pathology , Drug Therapy, Combination , Male , Mice , Mitosis , Time Factors
15.
Acta Neurochir (Wien) ; 35(1-3): 123-33, 1976.
Article in English | MEDLINE | ID: mdl-961496

ABSTRACT

Cellular synchronization using Colcemid as pretreatment for combined chemoradiotherapy was investigated. C6 rat brain tumour was cultured in RPMI medium containing 10(-5)-10(-7) Mol. of Colcemid for 24 hours. The basic cell kinetics were analysed with a Pulse Cytophotometer, which facilitated the analysis of tumour cell cycle phase distribution according to the DNA content. The effect of Colcemid depended on the concentration, and the minimal concentration showing continuous blocking during 48 hours after removal of the drug was 10(-6) Mol. G1 fraction of 2 C DNA content was reduced from 74% to 36%. G2-M phase of 4 C DNA content increased from 9% to 28%. S phase cells increased from 17% to 31%. Polyploid cells in the Tetraploid cell cycle could be recognized. The remaining 36% of cells within the GO + G1 peak of 2 C DNA content were considered to be diploid GO cells.


Subject(s)
Brain Neoplasms/drug therapy , Demecolcine/therapeutic use , Glioma/drug therapy , Premedication , Cell Division/drug effects , Cells, Cultured , Demecolcine/pharmacology , Humans , Neoplasms, Experimental , Time Factors
18.
Acta Radiol Ther Phys Biol ; 14(4): 376-84, 1975 Aug.
Article in English | MEDLINE | ID: mdl-1189971

ABSTRACT

The literature concerning the use of metaphase inducing agents as clinical sensitisers to radiation is briefly reviewed, and five cases are reported, which suggest that under ordinary clinical conditions, these agents are not likely to be of value. These results accord with animal experiments and a possible reason is suggested.


Subject(s)
Demecolcine/therapeutic use , Neoplasms/radiotherapy , Radiation-Sensitizing Agents/therapeutic use , Adenocarcinoma/radiotherapy , Adult , Aged , Anus Neoplasms/radiotherapy , Carcinoma, Squamous Cell/radiotherapy , Female , Humans , Lip Neoplasms/radiotherapy , Male , Middle Aged , Mitotic Index , Skin Neoplasms/radiotherapy , Stomach Neoplasms/radiotherapy
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