4'-Demethyl-epipodophyllotoxin thenylidene glucoside (VM 26), a podophyllum compound with a new mechanism of action.
TL;DR: The new podophyllotoxin glucoside derivative VM 26 was found to have a high cytostatic activity in cell cultures and inhibits entry of cells into mitosis or destroys cells preparing for mitosis, one of its biochemical effects is inhibition of thymidine uptake.
About: This article is published in European Journal of Cancer.The article was published on 1970-08-01. It has received 129 citations till now. The article focuses on the topics: Podophyllum.
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TL;DR: This review summarizes what is presently known about the biological activities of lignans and specifically inhibit certain enzymes in angiosperms and gymnosperms.
520 citations
TL;DR: The identification of both topoisomersase I and II as the specific targets of cancer chemotherapeutic drugs now provides a rational basis for the development of topoisomerase I poisons for possible clinical use and may lead to the identification of new therapies for treating cancer.
471 citations
TL;DR: Etoposide has been shown to be a highly schedule-dependent drug in clinical studies and there is no evidence of accumulation of etoposide and teniposide after multiple consecutive doses by the intravenous or oral routes.
Abstract: Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin and are increasingly used in cancer medicine. Teniposide is more highly protein-bound than etoposide, and its uptake and binding to cells is also greater. Etoposide and teniposide are phase-specific cytotoxic drugs acting in the late S and early G2 phases of the cell cycle. They appear to act by causing breaks in DNA via an interaction with DNA topoisomerase II or by the formation of free radicals. Teniposide is more potent as regards the production of DNA damage and cytotoxicity. Most studies show a biexponential decay following intravenous administration of etoposide and teniposide. The terminal elimination half-life of etoposide is less than that of teniposide, and the plasma and renal clearances of etoposide are greater. The peak plasma concentrations of drug and the area under the concentration versus time curve are linearly related to the intravenous dose of both drugs. Considerable interpatient variability of pharmacokinetic parameters exists following intravenous etoposide and teniposide. Various metabolites of etoposide and teniposide have been identified but their detection and quantitation are disputed. Approximately 30 to 70% of a dose of etoposide is accounted for by excretion, whereas the figure appears to be only 5 to 20% for teniposide. The bioavailability of oral etoposide is about 50% but its absorption is not linear with increasing dose within the range in clinical use. There is considerable inter- and intrapatient variability in the pharmacokinetics of oral etoposide. There is no evidence of accumulation of etoposide and teniposide after multiple consecutive doses by the intravenous or oral routes. The exact roles of the liver and kidney in metabolism and excretion of etoposide and teniposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This together with the phase-specific action of etoposide and teniposide and their increasingly widespread use in cancer medicine make the clinical pharmacology of these drugs of great clinical importance.
240 citations
TL;DR: In this article, 14 congeners of podophyllotoxin were evaluated for their ability to induce DNA breakage and inhibit growth of A549 human lung adenocarcinoma cells.
Abstract: Fourteen congeners of podophyllotoxin were evaluated for their abilities to induce DNA breakage and inhibit growth of A549 human lung adenocarcinoma cells. Among the congeners studied were VP16-213, VM26, alpha-peltatin, beta-peltatin, and picropodophyllotoxin. Alkaline elution methods were used to assess DNA break frequencies following 1-h exposure to different concentrations of the congeners. DNA breakage was dependent upon drug concentration and was detectable when cells were exposed for 1 h to concentrations of VM26 as low as 0.05 microM. DNA breaks formed rapidly in cells after addition of drug but increased little after 30 min of continuous exposure. Repair of drug-induced DNA breaks was equally rapid with repair of 90% of the breaks occurring within 1 h following removal of the drug. Relationships between the structures of the congeners and the resulting DNA breakage activities were obtained, which correlated well with the cytotoxicity. The data suggest that a free hydroxyl group at the 4'-position is essential for DNA breakage activity, epimerization at the 4-position of the podophyllotoxin rings enhances activity, glucosylation of the hydroxyl group at the 4-position diminishes activity, aldehyde condensation with the glucose moiety greatly enhances activity, and the structure of the group associated with the resulting acetal linkage influences DNA breakage activity. These studies present quantitative data supporting and expanding upon the structure-activity relationship first proposed by Loike and Horwitz [Loike, J. D., & Horwitz, S. B. (1976) Biochemistry 15, 5443-5448].
192 citations
Journal Article•
TL;DR: It is hoped that information gained from these animal models, which allow evaluation of many drugs within a relatively short period of time, will identify drugs effective in transitional cell carcinoma and lead to therapeutic trials in patients with bladder cancer.
Abstract: Summary Transitional cell carcinomas induced in syngeneic mice by the carcinogen N -[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) resemble their human counterpart both grossly and histologically and have been used in an animal model to evaluate antitumor drugs for activity in bladder cancer. In C3H/He mice, the first tumors are seen after 8 months on FANFT and an incidence of 70 to 100% is observed by 11 months. In the first of two long-term studies, single or combination chemotherapy was initiated after 10 months of FANFT. The drugs were administered for 3 weeks. Each treatment regimen was capable of producing a significant reduction in the mean bladder weight when compared to a group not receiving therapy (108 mg): cyclophosphamide (CY) (42.9); dactinomycin (49.6); cis -diamminedichloroplatinum(II) (56.4); and Adriamycin (69.5). The combination of CY with Adriamycin (37.3) or 5-fluorouracil (38.3) was superior to CY alone. In the second long-term study using this autochthonous tumor model, identical therapeutic regimens were initiated earlier in the carcinogenic process, after 5 or 7 months on FANFT. The regimens were: CY, 75 mg/kg; Adriamycin, 3 mg/kg, 2 times/week; CY + 5-fluorouracil, 45 mg/kg; CY + Adriamycin, 5 mg/kg; and Bacillus Calmette-Guerin 1 × 10 7 organisms. CY effected a significant reduction in the mean bladder weight, 30.8 mg at 5 months and 42.1 mg at 7 months (control, 44.6; p Bacillus Calmette-Guerin for either 3.5 or 5.5 months had a significant increase in the size of resulting tumors as indicated by the mean bladder weight. Intravesical chemotherapy was also evaluated by determining which drugs were capable of inhibiting the implantation of transitional tumor cells. A single-cell suspension of a transplantable FANFT-induced tumor is capable of implanting on the denuded murine urothelium. Since tumor cell implantation might be a factor in the high recurrence rate of human bladder cancer, irrigation with an effective cytotoxic agent might reduce this incidence. Intravesical Epodyl and epipodophyllotoxin significantly reduced the incidence of tumor cell implantation in the animal model. Thiotepa exhibited moderate antitumor activity. It is hoped that information gained from these animal models, which allow evaluation of many drugs within a relatively short period of time, will identify drugs effective in transitional cell carcinoma and lead to therapeutic trials in patients with bladder cancer.
189 citations
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TL;DR: H3-colchicine of high specific activity was prepared and based on the correlation between the time of first appearance of blocked mitoses and the radioactivity per cell, it is suggested that if a critical fraction of the sites are complexed, the cell is unable to form a functional mitotic spindle.
Abstract: H3-colchicine of high specific activity (2.5 curies per mM) was prepared in order to study the mechanism of colchicine inhibition of mitosis in cultures of human cells, strain K.B. No direct effects on the duration of the cell cycle or macromolecular synthesis were demonstrable at a concentration of colchicine which completely inhibited mitosis. The radioactive compound was bound to the cells at a rate proportional to colchicine concentration. The binding appeared to be reversible since the radioactivity of the cells reached a maximum value for a given concentration and was slowly lost after resuspension of the cells in fresh medium. A suitable exposure to colchicine produced accumulation of metaphase-blocked mitoses after the colchicine was removed from the medium. An exposure of 6 to 8 hours at 10-7 M was sufficient to block essentially all the cells in metaphase, thus indicating that colchicine is bound to the majority of interphase cells. The data are in quantitative agreement with a mechanism involving reversible binding of colchicine to a set of cellular sites. Based on the correlation between the time of first appearance of blocked mitoses and the radioactivity per cell, it is suggested that if a critical fraction (3 to 5 per cent) of the sites are complexed, the cell is unable to form a functional mitotic spindle.
384 citations
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