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At least 19 recordsLinked to original sources
PubMed1983

Podophyllotoxin-resistant mutants of Chinese hamster ovary cells: cross-resistance studies with various microtubule inhibitors and podophyllotoxin analogues.

The cross-resistances of several mutants of Chinese hamster ovary cells which have been obtained after one and two selection steps in the presence of the microtubule inhibitor podophyllotoxin (PodRI and PodRII mutants, respectively) towards various other inhibitors of microtubule assembly (e.g., colchicine, Colcemid, vinblastine, griseofulvin, maytansine, steganacin, nocodazole, and taxol) have been examined. Based upon their specific patterns of cross-resistance/sensitivity to various microtubule inhibitors, both the PodRI and PodRII classes of mutants appear to be of more than one kind. Studies on the binding of [3H]podophyllotoxin to cytoplasmic extracts indicate that one of the PodRII mutants which has been shown previously to be affected in a Mr 66,000 to 68,000 microtubule-associated protein shows reduced binding of the drug in comparison to the parental PodS and PodRI cells. The different PodRI and PodRII mutants exhibited proportionally increased cross-resistances to various podophyllotoxin analogues (e.g., deoxypodophyllotoxin, epipodophyllotoxin, beta-peltatin, 4'-demethylpodophyllotoxin, alpha-peltatin, podophyllotoxin-beta-D-glucoside, beta-peltatin-beta-D-glucoside, picropodophyllotoxin, and podophyllic acid) which possess microtubule-inhibitory activity. However, with the exception of one PodRI class of mutant, none of the mutants exhibited any cross-resistance to 4'-demethylepipodophyllotoxin thenylidine-beta-D-glucoside and 4'-demethylepipodophyllotoxin ethylidine-beta-D-glucoside, the 2 podophyllotoxin analogues which lack microtubule-inhibitory activity. The cross-resistance studies with these mutants, which, based upon the biochemical studies and their highly specific patterns of cross-resistance, are presumably affected in microtubules, provide some very novel insights into the mechanisms of action of various microtubule inhibitors. The results presented in this paper also show that the cross-resistance studies with the set of podophyllotoxin-resistant mutants provide a sensitive and highly specific screening procedure for identifying compounds which possess podophyllotoxin-like activity and for investigating the structure-activity relationship among them. The results of structure-activity relationship studies for the various podophyllotoxin analogues examined are discussed.

Animals↗
PubMed1994

Self-treatment using 0.25%-0.50% podophyllotoxin-ethanol solutions against penile condylomata acuminata: a placebo-controlled comparative study.

OBJECTIVE: To compare the efficacy of 0.50% and 0.25% podophyllotoxin preparations against previously untreated penile warts. DESIGN: The study was performed as a double-blind, placebo-controlled investigation on 57 males randomly allocated to one of three groups of 19 males in each, receiving either the placebo solution (70% ethanolic vehicle) or one of the two podophyllotoxin preparations for 1-2 self-treatment courses b.i.d. for three days, separated by a one-week drug-free interval. SETTING: The STD out-patient clinic of the Department of Dermatovenereology at Southern Hospital of Stockholm, Sweden. RESULT: The placebo solution merely exerted a marginal influence on the warts while a primary cure was documented in 72% (13/18) and 81% (13/16) of altogether 34 evaluable men who treated their warts with 0.25% and 0.50% podophyllotoxin, respectively. Follow-up investigation (range 5-23 weeks) was possible for 24 of 26 podophyllotoxin treated men who were primarily cured. Some degree of relapse occurred in nine of them (38%). Of these relapses, warts occurred on previously untreated sites only in three cases (33%), and in another four (44%) relapse was associated with regrowth on treated sites as well as on new sites. When analysing the debulking potential of podophyllotoxin, it appeared that 0.25% podophyllotoxin eradicated 184 of originally 217 warts (85%); the corresponding figure for 0.50% podophyllotoxin was as high as 130 of 135 lesions (96%). Side effects were generally mild-moderate and well tolerated. CONCLUSION: The results underscore the potential usefulness of low-dose podophyllotoxin preparations as first-line chemotherapy of condylomata acuminata for home-treatment. The efficacy from topical use of 0.25% podophyllotoxin detected in the study is certainly of a magnitude signifying that podophyllotoxin concentrations lower than 0.50% deserve further investigation if the drug may be incorporated into alternative vehicles such as creams or ointments.

Adolescent↗
PubMed1977

Podophyllotoxin as a probe for the colchicine binding site of tubulin.

The binding of [3H]podophyllotoxin to tubulin, measured by a DEAE-cellulose filter paper method, occurs with an affinity constant of 1.8 X 10(6) M-1 (37 degrees at pH 6.7). Like colchicine, approximately 0.8 mol of podophyllotixin are bound per mol of tubulin dimer, and the reaction is entropy-driven (43 cal deg-1 mol-1). At 37 degrees the association rate constant for podophyllotoxin binding is 3.8 X 10(6) M-1 h-1, approximtaely 10 times higher than for colchicine; this is reflected in the activation energies for binding which are 14.7 kcal/mol for podophyllotoxin and 20.3 kcal/mol for colchicine. The dissociation rate constant for the tubulin-podophyllotoxin complex is 1.9 h-1, and the affinity constant calculated from the ratio of the rates is close to that obtained by equilibrium measurements. Podophyllotxin and colchicine are mutually competitive inhibitors. This can be ascribed to the fact that both compounds have a trimethoxyphenyl ring and analogues of either compound with bulky substituents in their trimethoxyphenyl moiety are unable to inhibit the the binding of either of the two ligands. Tropolone, which inhibits colchicine binding competitively, has no effect on the podophyllotoxin/tubulin reaction. Conversely, podophyllotoxin does not influence tropolone binding. Moreover, the tropolone binding site of tubulin does not show the temperature and pH lability of the colchicine and podophyllotoxin domains, hence this lability can be ascribed to the trimethoxyphenyl binding region of tubulin. Since podophyllotoxin analogues with a modified B ring do not bind, it is concluded that both podophyllotoxin and colchicine each have at least two points of attachment to tubulin and that they share one of them, the binding region of the trimethoxyphenyl moiety.

Animals↗
PubMed1989

The effect of podophyllotoxin on microtubule dynamics.

We have investigated the effects of podophyllotoxin on the dynamic properties of microtubules assembled from pure tubulin dimer. Excess podophyllotoxin causes the complete disassembly of microtubules, through formation of a tubulin-GTP-podophyllotoxin ternary complex with a dissociation rate constant of 160 s-1 at 37 degrees C, similar to that found upon extensive isothermal dilution in this buffer system. Addition of substoichiometric concentrations of podophyllotoxin causes partial disassembly of microtubules through production of an equivalent amount of the ternary complex. Microtubule length measurements and incorporation of [3H]GTP-tubulin dimer show that podophyllotoxin can suppress the dynamic instability of tubulin dimer microtubules and that it acts substoichiometrically in so doing. We interpret the action of substoichiometric podophyllotoxin on microtubule ends in terms of effects on interconversion of growing and shrinking microtubules in a dynamic system in which tubulin-GTP-podophyllotoxin is kinetically analogous to tubulin-GTP in addition and to tubulin-GDP in dissociation. The ability to suppress dynamic instability may be one way in which drugs such as podophyllotoxin, acting at relatively low concentrations, are able to arrest cell growth and development in a selective way, without necessarily affecting the integrity of the major part of the cytoskeletal microtubule network.

Kinetics↗
PubMed1986

Inhibition of respiration in mitochondria and in digitonin-treated rat hepatocytes by podophyllotoxin.

The effects of the microtubular inhibitor, podophyllotoxin, on mitochondrial respiration were determined using isolated, digitonin-permeabilized hepatocytes and isolated mitochondria. In hepatocytes, podophyllotoxin (1.5 mM) inhibited coupled and uncoupled respiration of both FAD and NAD-linked substrates. In mitochondria, podophyllotoxin inhibited State III respiration, prevented the return to State IV respiration, and inhibited uncoupled respiration. There was no inhibition of ascorbate/TMPD oxidation in either the hepatocytes or the mitochondria. Podophyllotoxin had no effect upon oligomycin inhibition of coupled respiration. Oligomycin had no effect on the podophyllotoxin-inhibition of uncoupled respiration in either hepatocytes or mitochondria. The results indicate that podophyllotoxin alters electron flow at a site early in the electron transport chain.

Animals↗
PubMed1982

VP16-213 and podophyllotoxin. A study on the relationship between chemical structure and biological activity.

VP16-213, a semi-synthetic derivative of podophyllotoxin, is an effective antitumor agent in the treatment of a variety of leukemias and solid tumors. A comparison of the mechanism of action of VP16-213 and podophyllotoxin has revealed that although both drugs inhibit the uptake of nucleosides into HeLa cells, they exhibit other biological properties which are quite distinct. Podophyllotoxin is a potent inhibitor of microtubule assembly in vitro, while VP16-213 has no effect in this system. VP16-213 induces single stranded breaks in HeLa cells DNA, an effect which may be related to its antitumor activity. In contrast to VP16-213 treated cells, podophyllotoxin-treated cells maintain DNA integrity. Structure-activity relationship studies have identified some of chemical sites of VP16-213 and podophyllotoxin responsible for each of their biological properties. These studies illustrate that chemical modification of podophyllotoxin can generate derivatives which possess new and unique biological properties.

Animals↗
PubMed1991

Expression of c-myc proto-oncogene during podophyllotoxin induced IW32 erythroleukemia cell differentiation.

The effect of hemin or podophyllotoxin on the differentiation of the erythropoietin (epo)-producing IW32 erythroleukemia cells was investigated. Podophyllotoxin induced IW32 cells to differentiate, and hemin potentiated the differentiation. Hemin had no effect on cell proliferation whereas podophyllotoxin inhibited cell growth. c-myc mRNA levels decreased biphasically by hemin or podophyllotoxin, while the combined treatment of hemin plus podophyllotoxin did not result in the initial decrease in c-myc mRNA level. Our data suggested that down-regulation of c-myc expression was not a prerequisite of IW32 cell differentiation induced by hemin and podophyllotoxin combined.

Animals↗
PubMed1976

Effects of podophyllotoxin and VP-16-213 on microtubule assembly in vitro and nucleoside transport in HeLa cells.

VP-16-213, a semisynthetic derivative of podophyllotoxin, is an active antitumor agent. In this paper, the effects of VP-16-213 and podophyllotoxin on microtubule assembly in vitro and nucleoside transport in HeLa cells are compared. At 100 muM, VP-16-213 does not inhibit microtubule assembly in vitro, while 5 muM podophyllotoxin completely prevents the formation of microtubules. The presence of the glucoside moiety in VP-16-213 is responsible for the inactivity of VP-16-213 in this system because 4'-demethylepipodo-phyllotoxin, the nonglucoside congener of VP-16-213, inhibits microtubule assembly. In HeLa cells, VP-16-213 and podophyllotoxin share a common biological property; both agents inhibit the uptake of thymidine and uridine into cells by inhibiting the facilitated diffusional component of nucleoside transport. The conncentrations of drug necessary to inhibit thymidine and uridine uptake into HeLa cells by 50% are 10 and 5 muM, respectively, for podophyllotoxin, and 25 and 20 muM for VP-16-213. The action of podophyllotoxin on nucleoside transport appears unrelated to its effect on microtubule assembly, since VP-16-213, which does not inhibit microtubule assembly, inhibits nucleoside transport.

Adenosine↗
PubMed1981

Incorporation of radioactive tubulin into microtubules at steady state. Experimental and theoretical analysis of the effect of podophyllotoxin.

Addition of a substoichiometric amount of podophyllotoxin to microtubules which are at steady state decreases the rate of incorporation of radioactive subunits into the microtubules. The magnitude of this effect depends on the fraction of the total number of each of the microtubule ends which is capped by tubulin-podophyllotoxin subunits; these fractions depend on the concentration of podophyllotoxin used. A quantitative relationship is presented which correlates the extent of tubulin-podophyllotoxin capping of the microtubule ends with alterations in the rate for steady state subunit incorporation. An analysis based upon this relationship reveals that tubulin-podophyllotoxin caps both ends of the microtubule. Previously proposed mechanisms which involve tubulin-podophyllotoxin capping at only one end of the microtubule are analyzed.

Animals↗
PubMedDate not supplied

Self-treatment of female external genital warts with 0.5% podophyllotoxin cream (Condyline) vs weekly applications of 20% podophyllin solution.

Sixty women with genital warts were randomly allocated to treatment with either weekly application of 20% podophyllin solution or self-treatment with 0.5% podophyllotoxin cream twice daily for three days in weekly intervals. After a maximum of 4 treatment cycles a final assessment was carried out after 3 months. Primary clearance after termination of treatment was 82% for podophyllotoxin and 59% for podophyllin solution. After excluding relapses at the 3-month follow-up, final clearance for podophyllotoxin (71%) was significantly better (P < 0.05) than that for podophyllin solution (48%). The total frequency of warts eradicated was 94% with podophyllotoxin and 74% with podophyllin solution (P < 0.001). Local adverse effects were generally mild or moderate. Podophyllotoxin cream provides a mode of easy application for women with external genital warts and had in this study a significantly better effect than podophyllin solution.

Administration, Cutaneous↗
PubMed1991

[Preliminary report of podophyllotoxin in the treatment of genital warts in China].

Sixty-five patients with various types of genital warts were treated with 0.5% podophyllotoxin ethanol solution provided by Conpharm AB Sweden including 49 male and 16 female patients. The patients were treated topically bid, for 3 days as one treatment. If the desired effect was not achieved following one treatment, it was repeated in weekly intervals for no more than 3 treatments. Cumulative cure rates of 73.85%, 80% and 81.54% were obtained with podophyllotoxin treatment after the 1st, 2nd and 3rd treatments respectively. The genital warts cured by podophyllotoxin relapsed after one month at a rate of 14.9%. None of the patients treated with podophyllotoxin showed any systemic side effects, but mild local superficial erosions and slight pain appeared in most of the patients on the 3rd day of therapy. It is our opinion that external use of 0.5% podophyllotoxin for treating genital warts should be the method of choice for its high cure rate, time saving, safety and convenience.

Administration, Topical↗
PubMed1984

4'-Demethylepipodophyllotoxin-beta-D-glucoside: a new podophyllotoxin derivative with VM-26-like and VP-16-213-like activities.

Mutants of Chinese hamster ovary (CHO) cells independently selected for resistance to the anticancer drug 4'-demethylepipodophyllotoxin thenylidene-beta-D-glucoside (VM-26) and the microtubule inhibitor podophyllotoxin exhibit mutually an exclusive cross-resistance pattern toward various podophyllotoxin derivatives that possess either VM-26-like or podophyllotoxin-like activities, respectively. The cross-resistance studies with these mutants have led to the identification of a new podophyllotoxin derivative, 4'-demethylepipodophyllotoxin-beta-D-glucoside (compound No. 13), which possesses VM-26-like and 4'-demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP-16-213)-like activity. This inference is strongly supported by our observation that, like VM-26 and VP-16-213, compound No. 13 showed no antimitotic activity (as seen by the effect on the mitotic index) but was highly active in inducing DNA strand breaks, sister chromatid exchanges, and mutations at the hypoxanthine-guanine phosphoribosyl transferase and adenosine kinase loci in CHO cells. On the basis of structure-activity data of various podophyllotoxin derivatives, three structural features have been identified that appear essential for VM-26-like activity. These are: 1) the presence of an hydroxyl group at the 4'-carbon, 2) an epi-configuration at the C-4 position, and 3) the presence of a glycoside moiety on the hydroxyl group at the C-4 position. In addition, the nature of the glycoside substituents at the C-4 position greatly affects the relative VM-26-like activity of various compounds.

Animals↗
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↗
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↗
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↗
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↗