Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Podophyllotoxin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed1987

Mitochondrial matrix localization of a protein altered in mutants resistant to the microtubule inhibitor podophyllotoxin.

Specific antibodies to a protein designated P1 (Mr approximately equal to 63,000), which is specifically altered in mutants resistant to the microtubule inhibitor podophyllotoxin, bind to mitochondria in cells of various vertebrate and invertebrate species (Eur. J. Cell Biol. 44, 278-285 (1987); Can. J. Biochem. Cell Biol. 63, 489-502 (1985)). To investigate the relationship of this protein to mitochondria, rat liver mitochondria have been purified and immunoblot analysis with these provide evidence that the P1 protein is a major component of mitochondria. Two-dimensional gel electrophoretic analysis of mitochondrial proteins from Chinese hamster ovary (CHO) cells also show the P1 protein to be a major mitochondrial component. Subfractionation of rat liver mitochondria into various compartments indicates that the P1 protein is mainly associated with the matrix fraction. Effect of treatment of CHO cells with mitochondrial inhibitors on the synthesis of P1 protein was also investigated. Treatment with the K+ ionophores nonactin and valinomycin, which abolish mitochondrial membrane potential, inhibited synthesis of the mature forms of the P1 protein as well as a number of other mitochondrial proteins, as seen by two-dimensional gel electrophoresis of labeled polypeptides. Treatment of the podophyllotoxin-resistant mutant of CHO cells with the above inhibitors affected both the wild-type and the mutant forms of the P1 protein in a similar manner. Concomitant with the disappearance of the above proteins, new basic proteins of higher molecular masses, related to the P1 and other proteins by peptide analysis, were observed in the drug-treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

A fluorescence stopped flow study of the competition and displacement kinetics of podophyllotoxin and the colchicine analog 2-methoxy-5-(2',3',4'-trimethoxyphenyl) tropone on tubulin.

The colchicine analog 2-methoxy-5-(2',3',4'-trimethoxyphenol) tropone (AC) was used as a fluorescent probe to study the binding kinetics of podophyllotoxin at high concentrations. The observed pseudo-first order rate constant showed a linear concentration dependence up to 1 mM. The bimolecular rate constant (195 M-1 s-1 at 15 degrees C) and the activation energy (57 kJ/mol) correspond perfectly with those previously determined in the submicromolar range (Cortese, F., Bhattacharyya, B., and Wolf, J. (1977) J. Biol. Chem. 252, 1134-1140). Displacement kinetics of bound AC by podophyllotoxin, allow the determination of the dissociation rate constants for AC. By studying the temperature dependence, and combining with the binding rate constants previously determined (Engelborghs, Y., and Fitzgerald, T.J. (1986) Ann. N.Y. Acad. Sci. 466, 709-717) a full characterization of the kinetic pathway is possible. This is shown to differ considerably from the pathway of colchicine binding.

Animals↗
PubMed1985

Timing of the initiation of rRNA gene expression and nucleolar formation in cleavage embryos arrested by cytochalasin B and podophyllotoxin and in cytoplasm-extracted embryos of Xenopus laevis.

The timing mechanism of rRNA gene expression was studied in Xenopus laevis embryos whose cleavage was arrested by treatment with cytochalasin B or podophyllotoxin, and in fertilized eggs from which about 40% of the cytoplasm was extracted by micromanipulation. rRNA synthesis was activated in the cleavage-arrested embryos and also in cytoplasm-extracted embryos at the time when the control embryos commenced synthesizing rRNA at the late blastula stage. Formation of the nucleolar structure occurred at the normal time in the nuclei of cleavage embryos arrested by podophyllotoxin. Therefore, neither twelve continuous cell divisions nor the nuclear division which normally precedes the MBT (mid-blastula transition) was the factor determining the timing of rDNA expression. Moreover, lowering of the cytoplasmic:nuclear ratio to a certain threshold level was not a prerequisite for rDNA activation. Some regulatory mechanism dependent on the time elapsed from fertilization is likely to be the important factor permitting rDNA expression.

Animals↗
PubMed1995

Synthesis of podophyllotoxin congeners as potential DNA topoisomerase II inhibitors.

We have synthesized a number of new podophyllotoxin congeners in which the A-ring is opened and the C-ring is aromatic. These are based on the chemically modified structures of the naturally occurring podophyllum lignan, diphyllin. These have been synthesized by employing the Michael Initiated Ring Closure methodology. These lignans exhibited considerable DNA topoisomerase II inhibition and were devoid of topoisomerase I inhibition; they did not exhibit very significant activities in the in vitro human tumour cell lines assay. The results obtained provide insights into the structure-activity relationships and the design of chemically modified podophyllotoxin congeners useful in cancer chemotherapy.

Animals↗
PubMed1978

Topical treatment of penile condylomata acuminata with podophyllin, podophyllotoxin and colchicine. A comparative study.

The effect of alcoholic solutions with 20% podophyllin from Podophyllum peltatum and Podophyllum emodi, 8% podophyllotoxin, and 8% colchicine, when applied to penile condylomata acuminata in 227 men, were statistically alike. Of the patients initially judged to be cured after 1-2 applications, 13% showed recurrence, thus bringing down the permanent cure frequency to only 43%. Local side effects were absent after only half the series of colchicine applications, whereas as much as about 3/4 of the treatment course with podophyllin and pure podophyllotoxin could be completed without provoking discomfort. Warts in the urinary meatus healed significantly less well than warts on the other genital mucous membranes. Eighty-nine per cent of patients who had previously been cured of concylomata became wart-free after 1-2 treatments, as opposed to only 40% of those who had never had this wart type previously. The use of the commercially available colchicine offers an opportunity to establish a standardized therapy; following application of an 8% solution, rinsing off should be performed after 6-8 hours.

Administration, Topical↗
PubMed1995

[Treatment of external ano-genital condylomata with 0.5% podophyllotoxin].

There are several possible protocols for the treatment of ano-genital condylomata. In this study, the efficacy of podophyllotoxin (0.5%) was assessed. The authors observed a recovery rate at 1 month of 81% in cases of condylomata of the balano-preputial and vulvar mucous membranes, a rate of 67% in condylomata of the keratinized tissues and 63% in those of the anal margin. Response to treatment is also dependent on the morphology of the lesion; regression was observed in 78% of cases of condylomata acuminata and in 57% of cases of endophytic condylomata. The side effects were local and consisted of erosion in 20% of cases. The efficacy of treatment was, amongst other things, analysed according to the recurrence of the infection at one month, which occurred in 16% of cases affecting mucous membranes. In the therapeutic arsenal for the treatment of condylomata, podophyllotoxin 0.5% is a first line treatment for condylomata acuminata of the genital mucous membranes.

Adult↗
PubMedDate not supplied

Antiproliferative effects on human peripheral blood mononuclear cells and inhibition of in vitro immunoglobulin synthesis by Podophyllotoxin (CPH86) and by semisynthetic lignan glycosides (CPH82).

A mixture of natural and semisynthetic (modified) glycosides from Podophyllum emodi (Proresid) has been used for many years in the treatment of rheumatoid arthritis, but its use is hampered by gastrointestinal side effects. Highly purified podophyllotoxin (CPH86) and a preparation containing two semisynthetic podophyllotoxin glycosides (CPH82) are currently being tested in clinical trials. In this study these drugs were shown to inhibit in vitro [3H]-thymidine uptake of human peripheral blood mononuclear cells stimulated by the mitogens concanavalin A, phytohemagglutinin and pokeweed mitogen. Complete inhibition was observed with CPH86 in concentrations > or = 20 ng/ml and with CPH82 in concentrations > or = 1 microgram/ml. In vitro production of IgG, IgM and IgA by PWM-stimulated cells cultured for 7 days was unaffected by 10 ng/ml CPH86 and 100 ng/ml CPH82, but was strongly inhibited by concentrations of CPH86 at > or = 20 ng/ml and CPH82 at > or = 1 microgram/ml. In conclusion, both CPH86 and CPH82 inhibit mitogen induced lymphocyte proliferation and immunoglobulin synthesis and the results may be of help in determining optimal dose levels if related to treatment effects.

Cell Division↗
PubMed1993

Antitumor activity of a new low immunosuppressive derivative of podophyllotoxin (GP-11) and its mechanisms.

The spin-labeled derivative of podophyllotoxin, N'-podophyllic acid-N-[3-(2,2,5,5-tetramethyl pyrrolinenyloxy)] semicarbazide (GP-11), was synthesized and tested for its antitumor activity against mouse transplantable tumors, Sarcoma-180, Hepatoma-A, P388 leukemia and Ehrlich ascites carcinoma. At an equitoxic dose, the antitumor activity of GP-11 was similar to that of etoposide (VP-16). However, the immunosuppressive effects of GP-11 were weaker than that of VP-16. In vitro, GP-11 and VP-16 inhibited the proliferation of human lymphoid leukemia Molt 4B cells and suppressed DNA and protein syntheses, but the effect of GP-11 and VP-16 on cell cycle progression was different. The mitotic index was increased by GP-11 and reduced by VP-16. On the basis of flow cytometric bromodeoxyuridine (BrdU)/DNA analysis, GP-11 and VP-16 resulted in the accumulation of cells in the S and G2/M phases. G2/M arrest by GP-11 on cell cycle progression was stronger than that of VP-16, while S arrest was weaker than that of VP-16. After the removal of drugs, the arrest by GP-11 and VP-16 still existed and was irreversible. These results may provide insights into the structure-activity relationships and the design of novel derivatives of podophyllotoxin useful in cancer chemotherapy.

Animals↗
PubMed1998

Requirements for P-glycoprotein recognition based on structure-activity relationships in the podophyllotoxin series.

Podophyllotoxin and epipodophyllotoxin react with tubulin at the same binding site as colchicine, but in contrast to colchicine, do not appear to exert their cytotoxicities by mechanisms dependent on P-glycoprotein (Pgp) expression. To investigate structural requirements for Pgp recognition a series of podophyllotoxin and epipodophyllotoxin derivatives have been synthesized. Their interactions with the multidrug resistance-related protein Pgp have been studied by evaluating their relative cytotoxicities versus P388-sensitive murine leukemic cells and a classic multidrug-resistant (MDR) Pgp-overexpressing subline (P388/ADR), and their relative tubulin polymerization inhibitory activities against microtubular proteins have been determined. Based on tridimensional structure-activity relationships within this series of compounds, structural requirements for Pgp recognition have been identified. Moreover, proposals are made for extending these criteria to other chemical classes of anticancer drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Antineoplastic and antiviral activities of podophyllotoxin related lignans.

28 cyclolignans, most of them derived from podophyllotoxin, have been evaluated for their antineoplastic and antiviral activities. They were subjected to screening against P-388 murine leukemia, A-549 human lung carcinoma, and HT-29 colon carcinoma, while antiviral assays were performed on herpes simplex virus type I infecting fibroblasts of monkey kidney (HSV/CV-1) and on vesicular stomatitis virus infecting fibroblasts of hamster kidney (VSV/BHK). A number of substances were active in both groups of assays at concentrations below 1 microM; deoxypodophyllotoxin (1) being the most potent compound in all cases.

Animals↗
PubMed1999

Crystallization of a macromolecular ring assembly of tubulin liganded with the anti-mitotic drug podophyllotoxin.

The interaction of the anti-cancer drug podophyllotoxin with a high-molecular-weight assembly of tubulin has been employed to produce three-dimensional crystals from avian erythrocyte tubulin as well as from pig brain tubulin. Avian erythrocyte tubulin crystals belong to the space group C2 with unit cell dimensions a = 740 A, b = 330 A, c = 460 A, beta = 128 degrees. The basis of these crystals is ring oligomers with a molecular mass of approximately 6 x 10(6) Da. So far, the crystals diffract to 8-A resolution and a first complete data set to 12-A resolution has been collected under cryogenic conditions. The crystals grew from conventionally purified tubulin consisting of multiple isoforms and different posttranslational modifications. Thus, the use of highly homogeneous tubulin preparations should improve the diffraction quality of these crystals.

Animals↗
PubMed1982

The podophyllotoxin derivatives VP16-213 and VM26.

VP16-213 and VM26 are compounds with definite anticancer activity in specific tumor types. Despite 10 years of clinical development the full impact of these compounds in current cancer therapy requires further study. There is no conclusive evidence that one compound is superior to the other in any specific tumor type. The composite activities suggest possible differences in certain cancers such as small cell anaplastic lung cancer, lymphoma, leukemia, bladder and ovarian cancer, but sufficiently adequate studies to determine this have not been reported for any tumor. Understanding the basic pharmacology of these compounds should also be considered of high priority since it is obvious that there is much to learn in this area and further clarification should allow improved clinical utilization. It is hoped that the presentations and discussions of the First International Symposium will generate a new wave of interest in future podophyllotoxin research and development.

Animals↗
PubMed1979

Podophyllotoxin derivative VP 16-213.

VP 16-213, a derivative of podophyllotoxin, is currently entering phase-III studies. Its mode of action is incompletely understood, but differs markedly from that of its parent compound. The greatest lethal damage is experienced by cells in the late S and G2 phases. In the L 1210 system the drug shows marked schedule dependency: prolonged administration may be more effective than single bolus administration. As a single agent, VP 16-213 is the most active compound yet tested against small-cell bronchial carcinoma. It may also prove to be a useful agent in patients with other types of lung tumour, testicular teratomas, and some types of leukaemia. No long-term or cumulative toxicity has been reported. Most side effects are predictable and reproducible.

Animals↗
PubMed1996

Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK 611. A study by the AIO groups PHASE-I and APOH.

NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity. A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m2 [maximum tolerated dose (MTD) 120 mg/m2] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parentheses): mean residence time (MRT) 16.5 (5.4-42.3)h, terminal half-life 14.0 (8.2-30.5)h, volume of distribution at steady state (V(ss)) 11.4 (7.9-18.1) l/m2 and plasma clearance (Cl(p)) 15.1 (3.6-36.4) ml min-1 m-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 micrograms ml-1 h. The mean AUC (+/- SD) increased with the dose from 78.7 +/- 3.7 micrograms ml-1 h at 60 mg/m2 up to 202.8 +/- 157.2 micrograms ml-1 h at 120 mg/m2. The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and 25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx.. 99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUC(free). The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be investigated in further studies.

Adult↗
PubMed1996

Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative.

NK611 is a novel water-soluble podophyllotoxin derivative that has comparable antitumour activity but higher potency and better bioavailability in animals as compared with etoposide. The primary objectives of this study were to determine, after both oral and intravenous administration in the same patient, the bioavailability and the pharmacokinetic profile of NK611. Secondary objectives involved evaluation of the toxicity and the antitumor activity. Patients were randomly assigned to receive oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg/m2 on day 1, when pharmacokinetic studies were performed. A daily oral dose of 20 mg/m2 was then given from day 4 through day 7 for respective total doses of 85, 90, and 100 mg/m2. NK611 and its metabolites were determined in plasma and urine by two different high-performance liquid chromatography (HPLC) methods with UV detection. A total of 21 adult patients entered the study and received the complete first cycle and at least the 1st day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the plasma decay curve of NK611 followed a two-exponential model, and after oral administration it declined monoexponentially in most cases. At all dose levels, bioavailability values were around 100%. At concentrations between 10 and 20 mg/m2 after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma clearance, and volume of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to the dose. The urinary excretion of NK611 corresponded to 10-15% of the dose after administration by both routes, whereas that of N-demethyl NK611 and its picroform was highly variable. The features of neutropenia were comparable with those noted for etoposide involving a high degree of interpatient variability and recovery within 1 month after treatment. A daily dose of 20 mg/m2 for 5 consecutive days every 4 weeks is the recommended regimen for phase II studies in patients who have never been treated or have undergone previous chemotherapy only once.

Administration, Oral↗
PubMed2005

Influence of methyl jasmonate on podophyllotoxin and 6-methoxypodophyllotoxin accumulation in Linum album cell suspension cultures.

The accumulation of podophyllotoxin (PTOX) and 6-methoxypodophyllotoxin (6MPTOX) was enhanced about twofold in the suspension culture of Linum album line 2-5 aH following the addition of methyl jasmonate (MeJas) to the cultivation medium, reaching 7.69+/-1.45 mg/g dry weight and 1.11+/-0.09 mg/g dry weight, respectively. There was no increase in 6MPTOX accumulation following the addition of MeJas to suspension cells of L. album line X4SF, whereas PTOX accumulation was enhanced about tenfold to 0.49+/-0.10 mg/g dry weight. Phenylalanine ammonia-lyase activity increased immediately after the addition of MeJas to a cell suspension culture of line X4SF, reaching a maximum between 4 h and 1 day after elicitation, while cinnamyl alcohol dehydrogenase activity and the lignin content of the cells were not affected.

Acetates↗
PubMed2002

Biosynthesis of podophyllotoxin in Linum album cell cultures.

Cell cultures of Linum album Kotschy ex Boiss. (Linaceae) showing high accumulation of the lignan podophyllotoxin (PTOX) were established. Enzymological studies revealed highest activities of phenylalanine ammonia-lyase, cinnamyl alcohol dehydrogenase, 4-hydroxycinnamate:CoA ligase and cinnamoyl-CoA:NADP oxidoreductase immediately prior to PTOX accumulation. To investigate PTOX biosynthesis, feeding experiments were performed with [2-(13)C]3',4'-dimethoxycinnamic acid, [2-(13)C]3',4'-methylenedioxycinnamic acid (MDCA), [2-(13)C]3',4',5'-trimethoxycinnamic acid, [2-(13)C]sinapic acid, [2-(13)C]- and [2,3-(13)C(2)]ferulic acid. Analysis of the metabolites by HPLC coupled to tandem mass spectrometry revealed incorporation of label from ferulic acid into PTOX and deoxypodophyllotoxin (DOP). In addition, MDCA was also unambiguously incorporated intact into PTOX. These observations suggest that in L. album both ferulic acid and methylenedioxy-substituted cinnamic acid can be incorporated into lignans. Furthermore, it appears that, in this species, the hydroxylation of DOP is a rate-limiting point in the pathway leading to PTOX. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/wo.1007/s00425-002-0834-1.

Alcohol Oxidoreductases↗
PubMed1994

Site-specific DNA cleavage by Cu(II) complexes of podophyllotoxin derivatives.

Site-specific DNA cleavage in the presence of Cu(II) complexes of podophyllotoxin derivatives was investigated with a modified Sanger sequencing method. Cu(II) complexes of 4'-demethylepipodophyllotoxin (DEPD) and syringic acid (SA) cleaved M13mp18 single-strand DNA site-specifically at both cytosine (C) and guanine (G) positions in the GC rich regions and C position, respectively, at pH 7.8. The apparent binding constants of calf thymus DNA-Cu(II) complexes estimated by the differential UV-absorption spectra revealed that both Cu(II)-VP-16 and -DEPD complexes bind to DNA more strongly than does the Cu(II)-SA complex.

Base Sequence↗