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 55 records · Page 3Linked to original sources
PubMed1994

Experimental podophyllotoxin (bajiaolian) poisoning: III. Biochemical bases for toxic effects.

The biochemical mechanism underlying the toxicity of podophyllotoxin is investigated. Previous studies from our laboratories suggested that hepatocytes were extremely sensitive to the toxicity of podophyllotoxin and a disruption of protein synthesis was suspected. Dose-response and time-course studies on the effects of podophyllotoxin on protein. RNA, and DNA syntheses on hepatocellular cultures were made. Inhibitions of protein, RNA, and DNA syntheses were demonstrated, and a direct correlated dose-response relationship on such effects was also evident. Inhibition of protein synthesis appeared to be a direct toxic effect of podophyllotoxin and occurred independently from that of RNA. The reduction of DNA synthesis was reflected by a reduction of H3-thymidine incorporation, which is believed to be the consequence of inhibition on the mitotic activity by podophyllotoxin.

Cells, Cultured↗
PubMed1982

Podophyllotoxin poisoning of microtubules at steady-state: effect of substoichiometric and superstoichiometric concentrations of drug.

Depolymerization kinetics of microtubules assembled to steady-state by podophyllotoxin treatment show a dose-dependent effect of this mitotic poison on the net rate of microtubule disassembly. Pulse-chase experiments with microtubules at steady-state indicate that the depolymerization effect induced by superstoichiometric concentrations of podophyllotoxin relative to tubulin is polar and time-dependent, i.e. the rate of tubulin loss decreases along with the time of treatment in the presence of the drug. Under these conditions the rate of microtubule disassembly is much faster than one could expect from a unique effect of drug-tubulin complex on the microtubule assembly end. Podophyllotoxin-tubulin complex is not able to induce active depolymerization of microtubules, while free podophyllotoxin is. These results are consistent with the hypothesis that this drug acts on the microtubule assembly-disassembly process by two different mechanisms: 1) as a free drug, it actively promotes polar depolymerization of microtubules, and 2) as a drug-tubulin complex, it retards the addition of subunits into the microtubule ends.

Animals↗
PubMed1998

Podophyllotoxin and nocodazole counter the effect of IKP104 on tubulin decay.

Tubulin, the subunit protein of microtubules, undergoes a time-dependent loss of functional properties known as decay. We have previously shown that the drug 2-(4-fluorophenyl)- -(2-chloro-3,5-dimethoxyphenyl)-3-methyl-6-phenyl-4(1H)-pyridinone (IKP104) accelerates decay, but that in the presence of colchicine, IKP104 becomes a stabilizer of tubulin. To see if this is due to conformational effects specific to colchicine or simply to occupancy at the colchicine site, we examined the effects of nocodazole and podophyllotoxin, two well-known competitive inhibitors of colchicine for binding to tubulin, on IKP104's acceleration of decay. We found that podophyllotoxin abolished IKP104's accelerating effect and, like colchicine, turned it into a stabilizer of tubulin. Nocodazole's effects were similar to those of podophyllotoxin and colchicine, in that it abolished IKP104-induced enhancement of decay; however, in the presence of nocodazole, IKP104 caused little or no stabilization of tubulin. Since colchicine, nocodazole, and podophyllotoxin have very different interactions with tubulin, but all inhibit the IKP104-induced enhancement of decay, our findings suggest that this inhibition arises from occupancy of the colchicine site rather than from a direct conformational effect of these two drugs.

Alkylation↗
PubMed2002

Effect of major nutrients on podophyllotoxin production in Podophyllum hexandrum suspension cultures.

The effect of major medium ingredients (sugar, nitrogen source and phosphate) in Podophyllum hexandrum suspension cultures was investigated in order to increase the production of podophyllotoxin, the raw material in the synthesis of anticancer drugs. Amongst B5, Eriksson, MS, Nitsch, Street and White's medium, MS medium resulted in high growth and podophyllotoxin accumulation. The optimum level of nitrogen was found to be 60 mM, with a combination of ammonium salts and nitrate in the ratio of 1:2. The highest level of podophyllotoxin was obtained at 60 g glucose/l and at 1.25 mM phosphate after 30 days. Statistical design was adopted to determine the optimum levels of the parameters for cell growth and podophyllotoxin production.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Synthesis and anticancer activities of fatty acid analogs of podophyllotoxin.

Derivatives of podophyllotoxin were prepared by coupling 10 FA with the C4-alpha-hydroxy function of podophyllotoxin. The coupling reactions between FA and podophyllotoxin were carried out by dicyclohexylcarbodiimide in the presence of a catalytic amount of dimethylaminopyridine to produce quantitative yields of desired products. FA incorporated were the following: 10-hydroxydecanoic, 12-hydroxydodecanoic, 15-hydroxypentadecanoic, 16-hydroxyhexadecanoic, 12-hydroxyoctadec-Z-9-enoic, eicosa-Z-5,8,11,14-tetraenoic, eicosa-Z-8,11, 14-trienoic, eicosa-Z-11,14-dienoic, eicosa-Z-11-enoic, and eicosanoic acids. Spectroscopic studies confirmed the formation of the desired products. New molecules were investigated for their in vitro anticancer activity against a panel of human cancer cell lines including SK-MEL, KB, BT-549, SK-OV-3 (solid tumors), and HL-60 (human leukemia) cells. Most of the analogs were cytotoxic against cancerous cells, whereas no effect was observed against normal cells, unlike the parent compound podophyllotoxin, the use of which is limited due to its severe side effects.

Antineoplastic Agents↗
PubMed2005

Synthesis and in vitro cytotoxic activity of N-, F-, and S-ether derivatives of podophyllotoxin fatty acid adducts.

This paper represents the first synthesis, spectroscopic characterization, and antitumor evaluation of F-, N-, and S-containing C4alpha-FA derivatives of podophyllotoxin. In a synthetic strategy, a FA unit of 4-O-podophyllotoxinyl 12-hydroxyoctadec-Z-9-enoate 2, a derivative of podophyllotoxin, was functionalized at the C-12 position by incorporating the F atom and N-containing moieties. The FA olefin (Z, C-9/C-10) of 2 was hydrogenated to produce a derivative possessing a hydroxy function (C-12) on a saturated C18 FA chain. In another synthetic strategy, two S-ethers of podophyllotoxin (C4alpha) were synthesized from a terminal unsaturated FA analog, 4-O-podophyllotoxinyl undec-10-enoate. Syntheses were achieved through effective synthetic procedures; 1H NMR, 13C NMR, IR, and high-resolution mass data proved excellent tools to characterize these derivatives. In vitro antitumor activity was investigated against a panel of five human neoplastic cell lines, SK-MEL (malignant, melanoma), KB (epidermal carcinoma, oral), BT-549 (ductal carcinoma, breast), SK-OV-3 (ovary carcinoma), and HL-60 (human leukemia). Keeping in view the severe lack of tumor selectivity of podophyllotoxin over normal cells, we assayed new analogs against noncancerous mammalian VERO (African green monkey kidney fibroblast) cell lines to gauge their extent of toxicity. Several of these compounds showed excellent moderation of antitumor activity. In general, we found excellent growth inhibition against the human leukemia cell line (HL-60), particularly for the analogs containing S-ethers and carbamates. None of the compounds were toxic to normal cell lines.

Animals↗
PubMed1988

Methylenedioxy-benzopyran analogs of podophyllotoxin, a new synthetic class of antimitotic agents that inhibit tubulin polymerization.

A new class of compounds was synthesized and, based on structural analogy to podophyllotoxin, examined as potential microtubule inhibitors and evaluated for in vivo antineoplastic activity. These agents are derivatives of methylenedioxy-benzopyran bearing a phenyl substituent at position 8. The hydrogen atoms at positions 7 and 8 are in a trans configuration, in contrast to the cis configuration of analogous hydrogen atoms at positions 1 and 2 in podophyllotoxin. Compounds with a variety of substituents at positions 6 and 7 were examined, as well as compounds with varying methoxy substituent patterns on the phenyl ring attached at position 8. The most active compounds inhibited tubulin polymerization at concentrations approximately stoichiometric with tubulin, competitively inhibited the binding of colchicine to tubulin, and caused mitotic arrest at cytotoxic drug concentrations. No structure-activity correlations were obvious for the substituents at positions 6 and 7, but optimal activity was only observed when the phenyl substituent at position 8 was a trimethoxybenzene ring identical to the analogous ring in podophyllotoxin (i.e. methoxy groups at positions 3', 4' and 5'). Despite their structural and functional similarities to podophyllotoxin, however, the methylenedioxy-benzopyran derivatives subtly differ from the natural product in their interaction with tubulin, for they stimulated rather than inhibited tubulin-dependent GTP hydrolysis.

Animals↗
PubMed1988

Structure-bioactivation relationship of a series of podophyllotoxin derivatives.

With the aim of elucidating the structural requirements for O-demethylation of the antitumor agent VP-16-213 by cytochrome P-450, the binding of a series of podophyllotoxin derivatives to rat liver microsomal cytochrome P-450 was studied. The examined podophyllotoxin derivatives were: VP-16-213, VM-26, podophyllotoxin, 4'-demethylepipodophyllotoxin (the aglycone of VP-16-213 and VM-26) and 3,5-dimethoxy-4-hydroxytoluene (a model compound for the E-ring of VP-16-213). The binding to phenobarbital (Pb)-induced microsomes was more extensive than that to 3-methylcholanthrene (3-MC)-induced microsomes. Experiments on the binding to cytochrome P-450 in Pb-induced microsomes led to the following findings: (a) the presence of the polycyclic skeleton is necessary for binding; (b) the presence of the sugar moiety gives a further extension of binding, and changes in the sugar moiety affect binding; (c) binding increases on elevation of hydrophobicity; (d) the E-ring itself does not bind. For binding to cytochrome P-450 in 3-MC-induced microsomes conclusions (a) and (d) appeared to hold true. For the O-demethylation of the podophyllotoxin derivatives containing the dimethoxyphenol ring by Pb- and 3-MC-induced microsomes, the following order was observed: VM-26 greater than VP-16-213 greater than aglycone much greater than E-ring. A similar sequence was observed for the cytotoxicity against Chinese hamster ovary cells.

Animals↗
PubMed2004

Comparison of different extraction methods for the determination of podophyllotoxin and 6-methoxypodophyllotoxin in Linum species.

Three extraction methods for analysis of podophyllotoxin and its derivatives from Linum species were compared. No statistical difference on the percentage of recovery were found between the methods. The "glycosidase-method" showed the best result with respect to the accuracy studies; the "acetone-method" has an advantage compared to the other methods due to its capability to calculate the aglycone, lignan glycoside and total lignan. The content of podophyllotoxin and 6-methoxypodophyllotoxin in Linum mucronatum subsp. mucronatum Bertol, Linum arboreum L., and the endemic Turkey species of Linum flavum subsp. scabrinerve Davis were determined. This is the first report on the analysis of podophyllotoxin and 6-methoxy podophyllotoxin of natural collected Linum flavum subsp. scabrinerve and Linum arboreum.

Chromatography, High Pressure Liquid↗
PubMed1999

Drug delivery of anticancer agents: water soluble 4-poly (ethylene glycol) derivatives of the lignan, podophyllotoxin.

This paper reports on the synthesis and in vivo oncolytic activity of a series of water-soluble acyl derivatives of polyethylene glycol (PEG) conjugated podophyllotoxin. Some analogs of the polymer conjugate showed significantly better activity in a murine leukemia model than native podophyllotoxin suspended in an intralipid emulsion. Additionally, when tested intravenously against a solid lung tumor (A549) model, some conjugated analogs were equivalent to the podophyllotoxin/intralipid emulsion, while those compounds demonstrating slower rates of plasma hydrolysis (in vitro) appeared to cause greater toxicity. There appeared to be an overall correlation between the in vivo antitumor activity of the conjugate and its rate of hydrolysis in vitro, with those showing faster release possessing greater antitumor activity. In conclusion, the solubilization and predictable release of podophyllotoxin from a PEG carrier was achieved and resulted in some derivatives demonstrating, at a minimum, equivalency with podophyllotoxin when administered on an equal molar basis. Further studies may be warranted to assess the PEG-conjugates pharmacokinetics and therapeutic indices in leukemic models.

Animals↗
PubMed1981

Interaction of tubulin with drugs and alkylating agents. 2. Effects of colchicine, podophyllotoxin, and vinblastine on the alkylation of tubulin.

The antimitotic drugs colchicine, podophyllotoxin, and vinblastine are known to be potent inhibitors of microtubule polymerization, but little is known about how they affect the chemical properties of the tubulin molecule. In the preceding paper [Ludueña, R. F., & Roach, M. C. (1981) Bio-chemistry (preceding paper in this issue)], we have shown that the alkylating agent iodo[14C]acetamide reacts specifically with the sulfhydryl groups of tubulin and that its bifunctional analogue, N,N'-ethylenebis(iodoacetamide) (EBI), reacts with native tubulin to convert beta-tubulin into a form, designated beta*, which appears to represent an intrachain cross-linked form of beta. In this paper, we have incubated tubulin with the drugs prior to alkylation and measured their effects on the alkylation reactions. We have found that at 100 microM concentrations, podophyllotoxin, colchicine, and vinblastine inhibited the reaction of tubulin with iodo[14C]acetamide by 19-32%, 33-47%, and 62-72%, respectively; each drug was half-maximally effective at 3-5 microM, indicating that the suppressive effects of the drugs were mediated by their high-affinity binding sites. Similarly, beta* formation induced by EBI was suppressed by 92-94% in the presence of either colchicine or podophyllotoxin In contrast, vinblastine enhanced beta* formation by 40%. Alkylation with longer chain analogues of EBI revealed no evidence that the reactive sulfhydryls were being pushed apart by the drugs. These results indicate that each of the drugs has potent effects on the accessibility of the sulfhydryl groups of tubulin and that the effects of vinblastine are very different from those of either colchicine or podophyllotoxin.

Alkylating Agents↗
PubMed2004

Cytotoxicity of in vitro produced podophyllotoxin from Podophyllum hexandrum on human cancer cell line.

Podophyllotoxin was produced by cell culture of Podophyllum hexandrum under in vitro culture conditions. A maximum of 4.26 mg/L of podophyllotoxin was produced when P. hexandrum was cultivated in 3 L stirred tank bioreactor. The compound extracted from the cell culture was applied to the human breast cancer cell line (MCF-7) and 1 nM podophyllotoxin was able to inhibit the growth of the cancer cells by 50%. The most profound inhibitory effect of podophyllotoxin was observed when it was applied in the beginning of cell growth.

Breast Neoplasms↗
PubMed2001

Podophyllotoxin lignans enhance IL-1beta but suppress TNF-alpha mRNA expression in LPS-treated monocytes.

There exists a growing body of research which indicates that antimitotics such as taxol and colchicine influence cytokine gene expression. In the present study we examined the effect of podophyllotoxin and six analogs on nuclear factor kappa B (NF-kappa B) activation, and on interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) mRNA expression in human THP-1 monocytes. All compounds were inactive between 0.001microM and 10microM when tested alone. However, podophyllotoxin (0.1 microM) enhanced LPS-induced NF-kappa B activation and IL-1beta mRNA expression between 2 and 3-fold. In contrast, LPS-induced TNF-alpha mRNA expression was decreased between 3 and 6-fold. Comparable results were also observed with the three analogs acetylpodophyllotoxin, 4'-demethylpodophyllotoxin and alpha-peltatin. The remaining three analogs (podophyllotoxin-4-O-glucoside, beta-peltatin-beta-D-glucopyransoide and 1,2,3,4-dehydrodesoxypodophyllotoxin) were inactive. Clearly certain structural features such as the presence of a glycosidic group or ring aromatization results in loss of biological activity. Interestingly, the analogs that were inactive in our assays have also been previously shown to lack affinity for tubulin binding. These results suggest that during the initial hours of exposure to podophyllotoxin or specific analogs these compounds do not act as independent stimulants of human monocyte activation, but can selectively enhance or suppress LPS-induced cytokine gene expression.

Cells, Cultured↗
PubMedDate not supplied

Self-treatment using a 0.5% podophyllotoxin cream of external genital condylomata acuminata in women. A placebo-controlled, double-blind study.

In a double-blind, placebo-controlled study, self-treatment with a 0.5% podophyllotoxin cream was evaluated among 60 women afflicted solely with outer vulvoanal warts; 12 women received treatment with placebo cream and 48 women with active substance, administered twice daily in 3-day cycles once weekly for up to 3 weeks. Patients who were not completely cured after three cycles were classified as treatment failures. Four patients treated with podophyllotoxin cream were excluded: two were considered drop-outs, another patient was concurrently afflicted with intraanal warts, and a fourth patient refused further therapy with the cream due to the severity of local side effects occurring from the first course of therapy. Of the remaining 44 patients treated with active substance, the primary cure rates were 43%, 66%, and 91% after 1, 2, and 3 treatment cycles, respectively. Within a 3-month follow-up period, 6 (14%) patients who were originally considered cured exhibited some degree of either "recurrence" or "reoccurrence". Thus, a complete and permanent cure from podophyllotoxin cream occurred in 38 out of 44 patients (77%). Placebo lacked therapeutic influence. A slight-to-moderate tenderness, pain, burning, or all of the above in the treated areas was noted by more than 60% of the women who were treated with the podophyllotoxin cream.

Administration, Topical↗
PubMed1996

Studies to show that with podophyllotoxin the early replicative stages of herpes simplex virus type 1 depend upon functional cytoplasmic microtubules.

The antiviral activity of podophyllotoxin against herpes simplex type 1 virus (HSV-1) grown in Vero cells was studied by a simple microtitration assay. Antiviral effects were induced at similar concentrations as direct cellular toxicity, as characterised by a time-dependent loss of cell monolayer. Podophyllotoxin-mediated toxicity arises from cytoplasmic microtubular, and hence cytoskeletal, decay. Some degree of selectivity was seen for inhibition of virus replication over direct cellular toxicity. Podophyllotoxin acted against an early viral process, as an antiviral effect was still seen if drug was removed 2 h after infection. Similar effects were seen with colchicine, a classical tubulin-binding compound, but not with bromovinyldeoxyuridine. Podophyllotoxin was capable of inducing a cytoprotective effect in Vero cells, as pre-treatment of cells abrogated virus growth for up to 90 min after removal of drug. This is coincident with the repolymerisation of cellular microtubules and re-formation of the cytoskeleton. We conclude that HSV-1 relies upon a functional cellular cytoskeleton for efficient completion of an early replicative event. Such a process may be the transport of viral material to the nucleus or inhibition of the formation of intranuclear viral 'replication factories', bodies containing cytoskeletal fragments constructed after viral infection.

Animals↗
PubMed1988

Podophyllotoxin 0.5% v podophyllin 20% to treat penile warts.

The increasing incidence of genital warts has led to more public awareness of this infection and its possible sequelae. Currently available treatment remains unsatisfactory, and there is pressure to develop effective and convenient alternatives. Podophyllotoxin is standardised and stable, whereas podophyllin has a variable composition. In an open comparison of self applied podophyllotoxin 0.5% versus podophyllin 20% applied by a doctor to treat external penile warts, podophyllotoxin was more effective and gave quicker resolution than podophyllin. Side effects were similar for both preparations, and few patients experienced complications severe enough to stop treatment. Podophyllotoxin can therefore be used safely and effectively for home treatment monitored at an outpatient clinic and provides a useful alternative to treatment with podophyllin at overburdened genitourinary medicine clinics.

Adult↗
PubMed1994

Topical 0.3% and 0.5% podophyllotoxin cream for self-treatment of molluscum contagiosum in males. A placebo-controlled, double-blind study.

BACKGROUND: Molluscum contagiosum is generally a self-limiting benign skin disease that affects mostly children and young adults. OBJECTIVE: The purpose of this multicenter, double-blind, placebo-controlled study was to compare the clinical efficacy and tolerance of 0.3% and 0.5% podophyllotoxin in a hydrophilic cream base to cure molluscum contagiosum in Asian males. METHODS: Preselected patients (n = 150), age range 10-26 years (mean: 15.4), harboring 1,125 lesions (mean: 7.5), with size ranging from 2 to 8 mm in diameter (mean spot size 3.2 mm) and biopsy-proven diagnosis of molluscum contagiosum, were randomly allocated to three parallel groups. Twenty-four (16%) patients had atopic dermatitis. Patients self-administered placebo, 0.3% or 0.5% podophyllotoxin cream, twice daily for 3 consecutive days, and if total elimination was not achieved with one trial (6 topical applications), the same treatment was extended to 3 more weeks (24 topical applications in 4 weeks). The duration of the study was 12 weeks with 6 months (on monthly basis) follow-up. By the end of the treatment 80 patients (52, 92 and 16% patients in the 0.3%, 0.5% and the placebo groups, respectively) were evaluated as completely cured. During the treatment 92 patients (61.3%) did not complain of any allergic or localized adverse symptoms. Tolerable moderate to mild frequent side effects were pruritus (20.6%) and erythema (18%), with no dropouts. No recurrence was seen after 9 months of follow-up. Response to the trial medications appeared to be directly proportional to the concentration of podophyllotoxin (p < 0.001). Self-medication was well accepted by all the patients. It was concluded that the 0.5% podophyllotoxin cream preparation was more efficacious than the 0.3% incorporation (p < 0.001) and can be considered a safe, home-based first line of therapy to cure molluscum contagiosum.

Adolescent↗
PubMedDate not supplied

The cost effectiveness of treatment of genital warts with podophyllotoxin.

The cost effectiveness of 25% podophyllin resin and 0.5% podophyllotoxin solution in the treatment of genital warts in Genitourinary Medicine Clinic attenders was studied. Although the average treatment cost for a course of podophyllotoxin was more than that for podophyllin resin (20.75 pounds v. 14.95 pounds respectively) the overall cure rate with podophyllotoxin was 66% as opposed to 34.6% with podophyllin. When the costing of secondary treatment options was considered the cost per patient cured of warts with podophyllin resin was 27.15 pounds compared with 25.73 pounds for podophyllotoxin solution (not significant).

Adult↗