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PubMedDate not supplied

Optimization of culture parameters for production of podophyllotoxin in suspension culture of Podophyllum hexandrum.

The root explants of the germinated seedlings of Podophyllum hexandrum were grown in MS medium supplemented with indole acetic acid (IAA) (2 mg/L) and activated charcoal (0.5%), and healthy callus culture was obtained after incubation for 3 wk at 20 degrees C. The cultivation of plant cells in shake flask was associated with problems such as clumping of cells and browning of media, which were solved by the addition of pectinase and polyvinylpyrrolidone. The effect of major media components and carbon source was studied on the growth and podophyllotoxin production in suspension culture. It was found that glucose was a better carbon source than sucrose and that NH4+:NO3- ratio (total nitrogen concentration of 60 mM) and PO4(3-) did not have much effect on the growth and product formation. The relative effect of culture parameters (inoculum level, pH, IAA, glucose, NH4+:NO3- ratio, and PO4(3-)) on the overall growth and product response of the plant cell suspension culture was further investigated by Plackett-Burman design. This indicated that inoculum level, glucose, IAA, and pH had significant effects on growth and production of podophyllotoxin. To identify the exact optimum concentrations of these parameters on culture growth and podophyllotoxin production, central composite design experiments were formulated. The overall response equations with respect to growth and podophyllotoxin production as a function of these culture parameters were developed and used to determine the optimum concentrations of these parameters, which were pH 6.0, 1.25 mg/L of IAA, 72 g/L of glucose, and inoculum level of 8 g/L.

Biotechnology↗
PubMed2000

Antitumor properties of podophyllotoxin and related compounds.

The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Condyloma eradication: self-therapy with 0.15-0.5% podophyllotoxin versus 20-25% podophyllin preparations--an integrated safety assessment.

Topical application of podophyllin solution, long considered the therapy of first choice against condylomata acuminata, can no longer be recommended due to its low efficacy and gross toxicity. Self-treatment with 0.15-0.5% purified podophyllotoxin preparations, applied twice daily for 3 days, is now advocated as the alternative first-line therapy of choice, when significant improvement is conveniently, and cost-effectively, accomplished within a few weeks. This review provides a summary of the comparative efficacy and utility of podophyllin versus podophyllotoxin as well as a compilation of in vivo and in vitro safety evaluations. In light of overwhelming safety and efficacy data in favor of podophyllotoxin-derived products, it is concluded that podophyllin preparations have no place in the modern treatment portfolio for anogenital warts.

Administration, Topical↗
PubMed1981

Resistance to the microtubule inhibitor podophyllotoxin: selection and partial characterization of mutants in CHO cells.

Stable mutants two- to fourfold more resistant to the microtubule inhibitor podophyllotoxin (PodRI) have been selected in a single step in Chinese hamster ovary (CHO) cells. Mutants showing higher levels of resistance to the drug can be obtained in a second-step selection using the PodRI mutants (PodRII class). Prior treatment of cells with the mutagen ethylmethane sulfonate markedly enhanced the frequency of both PodRI and PodRII mutants in culture. The spontaneous rate of mutation of PodRI as determined by fluctuation analysis was found to be 1 - 2 x 10(-5) and 4 x 10(-7) mutations/cell/generation at 20 and 30 ng/ml podophyllotoxin, respectively. Somatic cell hybrids between PodRI x PodS and PodRII x PodS showed intermediate levels of resistance to the drug, indicating that the PodR phenotype behaves codominantly under these conditions. Cross-resistance studies with various PodRI and PodRII mutants show that they are not cross-resistant to other microtubule inhibitors, e.g., colchicine, colcemid, griseofulvin, vinblastin, that have been examined, or to a compound such as VP16-213, which is a podophyllotoxin derivative which lacks microtubule inhibitory activity. These results indicate that the lesion in PodR mutants is highly specific and probably does not involve a permeability alteration.

Animals↗
PubMed1989

Anticancer drugs. II. Synthesis and biological evaluation of spin labeled derivatives of podophyllotoxin.

The spin labeled derivatives of podophyllotoxin, 4-[4''-(2'',2'',6'',6''-tetramethyl-l''-piperidinyloxy)amino] -4'-demethylepipodophyllotoxin(GP-7,3) and N-podophyllic acid-N''-[4-(2,2,6,6-tetramethyl-l-piperidinyloxy)] thiosemicarbazide(GP-4,5) were synthesized and tested for their anticancer activity against the mouse solid tumors S180 and HepA in vivo, and the mouse lymphocytic leukemia L1210 and human stomach carcinoma SGC-7901 cells in vitro. At equitoxic concentrations, the anticancer activity of GP-7(3) was found to be similar to that of the clinically used VP-16(2). The toxicity of GP-7(3) (LD50231.2 mg/Kg) is 3.3 times lower than that of VP-16 (LD50 69.5 mg/Kg). GP-7(3) exhibits low subchronic toxicity. The total chemical yield of GP-7 (26%) is 4 times higher than that of VP-16 (6%) (based on podophyllotoxin). Therefore, GP-7(3) seems to be a promising new entry into the podophyllotoxin class of anticancer drugs.

Animals↗
PubMed1993

Podophyllotoxin, steganacin and combretastatin: natural products that bind at the colchicine site of tubulin.

A large number of antimicrotubule agents are known that bind to tubulin in vitro and disrupt microtubule assembly in vitro and in vivo. Many of these agents bind to the same site on the tubulin molecule, as does colchicine. Of these, the natural products podophyllotoxin, steganacin and combretastatin are the subjects of this review. For each of these, the chemistry and biochemistry are described. Particular attention is given to stereochemical considerations. Biosynthetic pathways for podophyllotoxin and congeners are surveyed. The binding to tubulin and the effects on microtubule assembly and disassembly are described and compared. In addition, structural features important to binding are examined using available analogs. Several features significant for tubulin interaction are common to these compounds and to colchicine. These are described and the implications for tubulin structure are discussed. The manifold results of applying these agents to biological systems are reviewed. These actions include effects that are clearly microtubule mediated and others in which the microtubule role is less obvious. Activity of some of these compounds due to inhibition of DNA topoisomerase is discussed. The range of species in which these compounds occur is examined and in the case of podophyllotoxin is found to be quite broad. In addition, the range of species that are sensitive to the effects of these compounds is discussed.

4-Butyrolactone↗
PubMed2003

Synthesis of 4beta-amido and 4beta-sulphonamido analogues of podophyllotoxin as potential antitumour agents.

The new 4beta-amido analogues of podophyllotoxin or 4'-O-demethylepipodophyllotoxin have been prepared either by the coupling of 4beta-amino podophyllotoxin or 4beta-amino-4'-O-demethyl epipodophyllotoxin with the corresponding acids in presence of DCC in dichloromethane or by treating the appropriate acid chloride or sulphonyl chloride in presence of Et(3)N. These 4beta-amido and 4beta-sulphonamido derivatives of podophyllotoxin have been evaluated for their cytotoxicity against six human cancer cell lines. Some of these analogues have shown promising anticancer activity.

Amides↗
PubMed2000

Podophyllotoxin.

Podophyllin, an ethanolic extract of Podophyllum peltatum L. or P. emodi Wall (syn. P. hexandnum Royle), is a good source of the aryltetralin-type lignan, podophyllotoxin. The latter compound, as well as its congeners and derivatives exhibit pronounced biological activity mainly as strong antiviral agents and as antineoplastic drugs. The podophyllotoxin derivatives etoposide, etopophos (etoposide phosphate), and teniposide are thus successfully utilized in the treatment of a variety of malignant conditions. Continued research on the Podophyllum lignans is currently focused on structure optimization to generate derivatives with superior pharmacological profiles and broader therapeutic scope, and the development of alternative and renewable sources of podophyllotoxin.

Podophyllotoxin↗
PubMed2002

Hemi-synthesis and biological activity of new analogues of podophyllotoxin.

Various 4-analogues of podophyllotoxin and epipodophyllotoxin were obtained via the formation of the corresponding 4-keto derivatives. Methyloximation of podophyllotoxone, followed by subsequent catalytic hydrogenation, gave stereoselective access to 4-alpha-amino-4-deoxypodophyllotoxin and from there, to the corresponding acetamido and formamido derivatives. Base-catalyzed isomerisation of 4-alpha-amino-4-deoxypodophyllotoxin led to the corresponding picropodophyllin isomer while the 4-beta-amino afforded a neopodophyllotoxin-like derivative. On the other hand, oxirane and hydroxymethyl-containing analogues were prepared from podophyllotoxin and 4-epi-4'-demethyl-podophyllotoxin, using a Takai olefination strategy. In the latter series, carboxaldehyde- and carboxylic acid-containing derivatives were also synthesized.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Enhanced production of podophyllotoxin by Podophyllum hexandrum using in situ cell retention bioreactor.

The rhizomes of the rare plant Podophyllum hexandrum contain podophyllotoxin, which is a precursor of the anticancer drugs etoposide and teniposide. Batch cultivation of Podophyllum hexandrum was conducted using optimized medium in a 3 L bioreactor, which resulted in biomass and podophyllotoxin concentrations of 21.4 g/L and 13.8 mg/L in 24 and 26 days, respectively. The batch kinetics was used to identify the mathematical model. The model was extrapolated to identify the nutrient feeding rate (150 mL/d) and substrate concentration (105 g/L) in the incoming feed for nonlimiting and noninhibitory glucose concentration in the cell retention bioreactor. An improvement in cell growth to 53 g/L and intracellular podophyllotoxin accumulation of 48.8 mg/L was achieved in 60 days, when the bioreactor was operated in continuous cell retention cultivation mode.

Bioreactors↗
PubMed1975

Microtubules and axoplasmic transport. Inhibition of transport by podophyllotoxin: an interaction with microtubule protein.

Pharmacological evidence is presented for the involvement of microtubules in the process of fast axoplasmic transport. A quantitative measure of the inhibition of axoplasmic transport in an in vitro preparation of rat sciatic nerve is described. The alkaloids colchicine, podophyllotoxin, and vinblastine, which are known both to disrupt microtubules and to bind to the protein subunit of microtubules, are inhibitors of axoplasmic transport. Lumicolchine and picropodophyllin, unlike their respective isomers colchicine and podophyllotoxin, are poor inhibitors of axoplasmic transport. The dissociation constants for the binding of colchicine, lumicolchicine, podophyllotoxin, and picropodophyllin to purified microtubule protein from rat brain have been measured. Inhibition of axoplasmic transport by these drugs correlates favorably with their affinities of microtubule protein.

Animals↗
PubMed1995

Topical treatment of genital warts in men, an open study of podophyllotoxin cream compared with solution.

OBJECTIVE: To evaluate the clinical efficacy of a 0.15% and a 0.3% cream formulation of podophyllotoxin in comparison with the 0.5% solution in the treatment of condylomata acuminata and to compare the treatment modalities regarding side effects. DESIGN: The study was designed as an open randomised trial. Ninety male patients with signs of penile HPV infection, with either acuminate or papular lesions, were randomised into three parallel treatment groups. The study medication comprised 0.15% and 0.3% cream and 0.5% solution of podophyllotoxin. The patients treated themselves twice daily for three consecutive days and if total regression of the warts was not achieved after this first treatment cycle, further treatment cycles at 7-day intervals were to be repeated up to a maximum of four treatments. SETTING: The study was carried out in three outpatient clinics: two STD clinics, Department of Dermatology and Venereology, University Hospital (45 patients) and Institut Antoine Fournier, Paris (30 patients), and one military hospital, S1/FO 47/48, Sjukhusenheten, Enköping (15 patients). RESULTS: Statistical evaluation of the treatment effect was based on a "Response rate" calculation at each visit. The number of completely responding patients after the first, second, third and fourth cycle were 40 (44%), 61 (68%), 67 (74%) and 70 (78%), respectively. There was no statistically significant difference between the three treatments after four treatment cycles. However, the 0.15% cream had a significantly slower onset of efficacy as compared with the 0.3% cream and 0.5% solution. Adverse effects were less severe and less frequent with the 0.15% cream than with the other treatment modalities. Severe adverse effects were reported by 12 patients, of whom two were treated with 0.15% cream, five with 0.3% cream and five with 0.5% solution. Thirty-one patients were completely free from adverse effects. CONCLUSION: In this open randomised study with three parallel treatment groups, two cream formulations of 0.15% and 0.3% podophyllotoxin and a 0.5% solution of the same drug all showed an equally good response rate after four treatment cycles. Reported adverse effects were few and mild. The convenience of having different formulations to offer when prescribing treatment for condylomata must be considered.

Administration, Topical↗
PubMed1997

Podophyllin 0.5% or 2.0% v podophyllotoxin 0.5% for the self treatment of penile warts: a double blind randomised study.

OBJECTIVE: To compare the effectiveness and cost of self treatment of penile warts with a commercial preparation of podophyllotoxin 0.5% (PDX 0.5%) with podophyllin 0.5% and podophyllin 2.0% sourced from Podophyllum emodii. DESIGN: A prospective double blind randomised study. SUBJECTS: 315 patients with penile warts attending two departments of genitourinary medicine. MAIN OUTCOME MEASURES: Absence of warts, cessation of treatment due to severe side effects at 5 weeks. RESULTS: Of the 315 patients, 244 conformed to the protocol. Analysis was on an intention to treat basis. At 5 weeks no significant differences were found in the extent of healing of warts or in side effects for the three treatment groups. The costs of drug treatment (excluding staff time) are at least pounds 10.00 less for podophyllin than podophyllotoxin. A fourfold variation in the active constituents of the podophyllin preparations did not produce appreciably different clinical responses. In a subanalysis no evidence of deterioration in effectiveness of podophyllin over time was demonstrated. CONCLUSIONS: Penile warts in selected cases can be safely treated with 0.5-2.0% podophyllin self applied by the patient at a fraction of the cost of commercially available podophyllotoxin. The shelf life of the podophyllin extracts is at least 3 months. These findings may be especially relevant in countries where resources for health care are limited.

Condylomata Acuminata↗
PubMed1995

Human leukocyte interferon-alpha versus podophyllotoxin in cream for the treatment of genital warts in males. A placebo-controlled, double-blind, comparative study.

BACKGROUND: The incidence of overt genital warts, a common sexually transmitted disease of high prevalence, has been on the rise for the last few years. The infection is caused by several types of human papillomaviruses (HPVs), some of which have been accepted as a factor in the pathogenesis of genital squamous-cell carcinomas. OBJECTIVE: The aim of this double-blind, placebo-controlled study was to compare and evidence differences in clinical efficacy and tolerance between human leukocyte interferon-alpha (2 x 10(6) IU/g) and podophyllotoxin (0.5%), incorporated in a hydrophilic cream base to cure genital warts in Asian males. METHODS: Sixty patients, circumcised, who ranged in age from 18 to 40 years (mean 25.0), diagnosed with the evidence of penoscopy and HPV DNA (Southern dot blot) as harboring 396 lesions (mean 6.6), were randomized to three parallel groups. Each subject was allocated a precoded tube (40 g) containing one of two trial preparations or matching placebo for 3 days' (consecutive) usage, thrice daily. The study lasted 16 weeks with 4 weeks of active treatment. The patients were examined on a weekly basis, and a clinically and HPV-DNA-confirmed total regression of lesions was recorded as cured. Patients cured during the treatment were spared further therapy and were requested to visit us as scheduled for poststudy follow-up. RESULTS: Findings indicated that patients treated with leukocyte interferon-alpha cream had shown comparatively better results than the podophyllotoxin-treated group (90 vs. 55%, p < 0.0285) or the placebo group (15%). Mild and transient localized erythema (8.3%), burning sensation (6.6%) and transitory increase in body temperature (> 38 degrees C; 6.6%) were the most frequent adverse symptoms with no dropout. The study was followed up for 1 year, and out of 32/60 (53.3%) cured patients 3 had a relapse after 10 months. CONCLUSION: Leukocyte interferon-alpha (2 x 10(6) IU/g) has shown comparatively better results than 0.5% podophyllotoxin and placebo in a hydrophilic cream base, thus leukocyte interferon-alpha in cream may provide an alternative and effective regimen to treat genital warts in males.

Administration, Topical↗
PubMed1992

Effects of vinblastine, podophyllotoxin and nocodazole on mitotic spindles. Implications for the role of microtubule dynamics in mitosis.

Inhibition of mitosis by many drugs that bind to tubulin has been attributed to depolymerization of microtubules. However, we found previously that low concentrations of vinblastine and vincristine blocked mitosis in HeLa cells with little or no depolymerization of spindle microtubules, and spindles appeared morphologically normal or nearly normal. In the present study, we characterized the effects of vinblastine, podophyllotoxin and nocodazole over broad concentration ranges on mitotic spindle organization in HeLa cells. These three drugs are known to affect the dynamics of microtubule polymerization in vitro and to depolymerize microtubules in cells. We wanted to probe further whether mitotic inhibition by these drugs is brought about by a more subtle effect on the microtubules than net microtubule depolymerization. We compared the effects of vinblastine, podophyllotoxin and nocodazole on the organization of spindle microtubules, chromosomes and centrosomes, and on the total mass of microtubules. Spindle organization was examined by immunofluorescence microscopy, and microtubule polymer mass was assayed on isolated cytoskeletons by a quantitative enzyme-linked immunoadsorbence assay for tubulin. As the drug concentration was increased, the organization of mitotic spindles changed in the same way with all three drugs. The changes were associated with mitotic arrest, but were not necessarily accompanied by net microtubule depolymerization. With podophyllotoxin, mitotic arrest was accompanied by microtubule depolymerization. In contrast, with vinblastine and nocodazole, mitotic arrest occurred in the presence of a full complement of spindle microtubules. All three drugs induced a nearly identical rearrangement of spindle microtubules, an increasingly aberrant organization of metaphase chromosomes, and fragmentation of centrosomes. The data suggest that these anti-mitotic drugs block mitosis primarily by inhibiting the dynamics of spindle microtubules rather than by simply depolymerizing the microtubules.

Cell Cycle↗
PubMed1992

Antitumor agents. I. DNA topoisomerase II inhibitory activity and the structural relationship of podophyllotoxin derivatives as antitumor agents.

Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and antitumor activity in vivo (L 1210). An intact 6,7-methylenedioxy group of DPT is necessary to inhibit tubulin polymerization and topoisomerase II. 4'-Phenolic hydroxyl group of DPT is essential to inhibit DNA topoisomerase II and the inhibitory effect on DNA topoisomerase II contributes to a high cytotoxicity. The introduction of an aminoalkoxy group at 1-position of DPT enhances the inhibitory activity against DNA topoisomerase II and cytotoxic effect, causing the inhibitory activity against tubulin polymerization to disappear. The results of antitumor test in mice bearing L 1210 on podophyllotoxin derivatives suggest the following: 1) the strong cytotoxic effect itself is not a good indication of antitumor activity in vivo as long as it is associated with inhibition of tubulin polymerization. DNA topoisomerase II inhibitory effect contributes to an antitumor activity in vivo; 2) detailed measurements of cytotoxicity and inhibition on DNA topoisomerase II and tubulin polymerization in vitro are necessary to evaluate podophyllotoxin derivatives.

Animals↗
PubMed2002

Synthesis and insecticidal activity of novel 4beta-halogenated benzoylamino podophyllotoxins against Pieris rapae Linnaeus.

Twelve new 4beta-halogenated benzoylamino compounds (7.1-7.12) of podophyllotoxin have been synthesized, and their structures were confirmed by IR, 1H-NMR, MS spectra as well as CHN elemental analysis. These compounds showed delayed insecticidal activity against 5th instar larvae of Pieris rapae Linnaeus in vivo, when tested by a leaf-dipping method at a concentration of 250ppm. By preliminary qualitative structure-activity relationship analysis, we found the following results: 1) Compounds 7.2, 7.5-7.9 were more potent than the nature parent product in the mortality after 15 d against P. rapae in vivo. Especially compounds 7.5 and 7.6 bearing meta- and para-chlorobenzene substituents respectively, were the most potent of these compounds; 2) Substitution on the benzene ring moiety of 4beta-benzoylamino podophyllotoxin (PPT) with Cl, Br, I at the para or at the meta position yielded compounds which were as potent or more potent than those containing the corresponding substituting group at the ortho position. 3) Substitution on the benzene ring moiety of 4beta-benzoylamino podophyllotoxin with I either at the ortho, meta or para position yielded less potent compounds (7.10-7.12) when compared with PPT.

Animals↗
PubMed1996

Topical treatment of venereal warts: a comparative open study of podophyllotoxin cream versus solution.

Podophyllotoxin solution (0.5%) is licensed for use in the treatment of condylomata acuminata (genital warts) in men in a number of European countries. In some countries, approval also extends to treatment of genital warts in women. This controlled randomized prospective study evaluated the efficacy and safety of a cream formulation of podophyllotoxin at 2 concentrations (0.15% and 0.3%), using 0.5% podophyllotoxin solution as a reference treatment. Two separate studies were initiated, to assess the 3 treatment groups in (a) male patients, and (b) female patients. Statistical evaluation was based on a "response rate' calculated at each clinic visit. The mean "response rates' in the male patient study at 4 weeks were 75.1%, 79.0% and 85.6% in the 0.15% cream, 0.3% cream and 0.5% solution groups, respectively. The corresponding "response rates' for the female patient study were 86.2%, 92.6%, and 93.1%, respectively. The relapse rates for both male and female patients were 6.0% in the 0.15% cream group, 8.6% in the 0.3% cream group and 8.6% in the 0.5% solution group. The results show that there were no statistically significant differences between the 3 treatments with regard to both efficacy and safety. This was true for both the male and female patient groups.

Administration, Topical↗