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At least 19 recordsLinked to original sources

PubMed2003

Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts.

OBJECTIVES: To evaluate the efficacy and cost effectiveness of self applied podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream, compared to clinic applied 25% podophyllin in the treatment of genital warts over 4 weeks. METHODS: We conducted a randomised controlled trial in 358 immunocompetent men and women with genital warts of 3 months' duration or less. RESULTS: In the principal analysis both podophyllotoxin solution (OR 2.93, 95% CI 1.56 to 5.50) and podophyllotoxin cream (OR 1.97, 95% CI 1.04 to 3.70) were associated with significantly increased odds of remission of all warts compared to podophyllin. We performed two further analyses. When subjects defaulting from follow up were assumed to have been cured odds of remission of all warts were also significantly increased both for podophyllotoxin solution (OR 3.04, 95% CI 1.68 to 5.49) and for podophyllotoxin cream (OR 2.46, 95% CI 1.38 to 4.40). When subjects defaulting from follow up were assumed not to have been cured odds of remission of all warts were significantly increased for podophyllotoxin solution (OR 1.92, 95% CI 1.13 to 3.27), but not for podophyllotoxin cream (OR 1.17, 95% CI 0.69 to 2.00). Local side effects were seen in 24% of subjects, and recurrence of warts within 12 weeks of study entry in 43% of all initially cleared subjects, without statistically significant differences between the treatment groups. Direct, indirect, and total costs were similar across the three treatment groups. Podophyllotoxin solution was the most cost effective treatment, followed by podophyllotoxin cream, with podophyllin treatment being the least cost effective. CONCLUSIONS: Self treatment of anogenital warts with podophyllotoxin showed greater efficacy and cost effectiveness than clinic based treatment with podophyllin.

Adolescent↗

PubMed1995

A single-blind study of podophyllotoxin cream 0.5% and podophyllotoxin solution 0.5% in male patients with genital warts.

OBJECTIVE: To evaluate the efficacy-safety ratio of a new topical podophyllotoxin cream 0.5% compared with podophyllotoxin solution 0.5% (Condyline) in male patients with genital warts. METHODS: In an observer-blinded controlled study a total of 136 and 133 wart lesions were treated with podophyllotoxin cream 0.5% and podophyllotoxin solution 0.5%, respectively. The preparations were applied twice daily for 3 days, repeated with 4 days intervals for a minimum of two and a maximum of four treatment cycles. RESULTS: At the conclusion of the study (8 weeks after completion of therapy) a significant reduction in mean wart area was observed in both the cream group (87.7, SD 8.4 to 20.6, SD 2.7) and in the solution group (92.3, SD 7.5 to 21.5, SD 2.8) (p < 0.01). At the same time all treated warts had completely cleared in 63% of patients in both study groups. Mild to moderate side effects occurred to the same extent in both podophyllotoxin cream and podophyllotoxin solution recipients. CONCLUSION: We conclude that podophyllotoxin 0.5% administered in a cream formulation does not give additional clinical benefits when compared with podophyllotoxin solution 0.5% in male patients with external genital warts.

Administration, Topical↗

PubMed2004

[Preparation of liposome podophyllotoxin chitosan film and determination the podophyllotoxin content in the film by ultraviolet spectrophotometry].

OBJECTIVE: To optimize the formula of liposome podophyllotoxin chitosan film and accurately determine the podophyllotoxin content in the film. METHODS: Liposome podophyllotoxin chitosan films were prepared according to different formula derived from the results of orthogonal design by selecting chitosan, acetic acid and gelatin as the 3 factors for preparation, each factor including 3 levels with liposome podophyllotoxin as the blank factor. Comprehensive evaluation of the formulas was performed on the basis of the conglutination and solubility of the prepared film to select the optimal formula. The content of podophyllotoxin was determined by ultraviolet spectrophotometry at 292 nm. RESULTS: The conglutination and solubility were optimal of the film prepared from 2% chitosan, 1% acetic acid, 2% gelatin and 2.8% liposome podophyllotoxin chitosan, showing good linearity within podophyllotoxin concentration range of 5-25 microg/ml (r=0.999 89) with an average recovery rate of 99.7% (n=5) and RSD of 1.11%. CONCLUSION: The film prepared according to the orthogonal design results conforms to the requirements in terms of conglutination and solubility, and the method we adopted is fast and accurate, yielding qualified film with censored podophyllotoxin content that distributes homogeneously.

Animals↗

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↗

PubMed2001

High yield of podophyllotoxin from leaves of Podophyllum peltatum by in situ conversion of podophyllotoxin 4- O-beta-D-glucopyranoside.

Rehydration of powdered tissues of Podophyllum peltatum L. prior to extraction with an organic solvent allows endogenous beta-glucosidases to hydrolyze lignan 4-O-beta-D-glucosides in situ and increase the yield of podophyllotoxin. Aqueous extraction of rhizomes and leaves of P. peltatum yielded 4- to 10-fold greater quantities of podophyllotoxin than the traditional ethanolic extraction. Most significantly, leaves were shown to contain over 52 mg of podophyllotoxin per g of dry weight (5.2%), exceeding levels previously reported from any source. These results point to the use of leaves harvested from cultivated P. peltatum as an attractive alternative to the destructive collection of natural populations.

Glucosides↗

PubMedDate not supplied

An open, comparative, study of the efficacy of 0.5% podophyllotoxin lotion and 25% podophyllotoxin solution in the treatment of condylomata acuminata in males and females.

The efficacy and safety of topical treatment for external condylomata acuminata with either self-applied 0.5% podophyllotoxin (PT) or hospital-applied 25% podophyllin (PODO) solution was compared in 138 males and 67 females in an open multicentre study. After one week of treatment, wart clearance was observed in 53% of males and 37% of females in the PT group as compared with 19% of males and 19% of females in the PODO group (P < 0.001 in males; P = 0.13 in females). At 5 weeks after commencing treatment, clearance of warts had been achieved in 86% males and 72% females in the PT group as compared with 78% of males and 62% females in the PODO group (P = 0.08 in males; P = 0.14 in females). Treatment had cleared 81% of 180 treated sites in all PT recipients as compared with 61% of 95 treated sites in all PODO recipients (P < 0.001). The increased speed of action of PT was associated with an increased incidence of symptoms and signs of inflammation at treatment sites in both males and females (P < 0.001). These were generally mild, did not interfere with continuing treatment, and were more frequent in those patients whose warts were eradicated most rapidly. Home-based treatment with 0.5% podophyllotoxin lotion in appropriately instructed patients of either sex is superior in efficacy to outpatient applied 25% podophyllin and has the potential to reduce the number of hospital attendances required in genital wart eradication.

Administration, Topical↗

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↗

PubMed2006

Meta-analysis of 5% imiquimod and 0.5% podophyllotoxin in the treatment of condylomata acuminata.

BACKGROUND: Genital warts are a common sexually transmitted disease caused by human papillomaviruses. Podophyllotoxin 0.5%, approved for patient self-administration, has been used most extensively in the treatment of genital warts. Imiquimod, a novel immune response modifier capable of inducing interferon-alpha and a variety of cytokines, has been examined as a potential treatment for genital warts. But 0.5% podophyllotoxin and 5% imiquimod have not been compared in any extensive and formal studies, although they are the common topical agents for genital warts. OBJECTIVE: To evaluate the efficacy and safety of topical 5% imiquimod and 0.5% podophyllotoxin in the treatment of genital warts. METHODS: We searched Medline (1966 to June 2005), Embase (1974 to June 2005) and the Cochrane Controlled Trials Register (issue 3, 2005). Randomized controlled trials of 5% imiquimod or 0.5% podophyllotoxin in the treatment of genital warts were collected. Two reviewers extracted the data and independently assessed the quality of the included medical literature. Then, meta-analysis was conducted. RESULTS: Twelve studies including 3 placebo-controlled trials of imiquimod and 9 placebo-controlled trials of podophyllotoxin were included. The clinical cure rates of imiquimod and podophyllotoxin were 50.34 and 56.41%, respectively, without statistically significant differences between the two (p > 0.05). A combined analysis of the 3 studies on imiquimod showed a statistically significant difference to the placebo group [pooled odds ratio (OR) 11.65, 95% confidence interval (CI) 6.05-22.44], as did a combined analysis of the 9 studies on podophyllotoxin (pooled OR 16.70, 95% CI 7.06-39.48). The most common adverse events of imiquimod were erythema, erosion, excoriation, itching and burning; those of podophyllotoxin were burning, pain, erosion, itching and inflammation. CONCLUSION: Imiquimod and podophyllotoxin possess similar curative effects on condylomata acuminata but podophyllotoxin has more serious adverse effects.

Aminoquinolines↗

PubMed2006

[Studies on antitumor effects of podophyllotoxin nanoliposome].

OBJECTIVE: To compare the antitumor effects of the podophyllotoxin nanoliposome and the suspensions of podophyllotoxin in bearing-tumor mice. METHOD: The experimental mice were inoculated by suspension liquid of tumor cell in axillary region near the forelimb, 0.2 mL each. The mice had been randomly divided into 8 groups 24 h latter. The podophyllotoxin nanoliposome, suspension liquid of the podophyllotoxin, CX or NS was given to each group respectively. Except CX was given by celiac injection once, the other groups were injected every 4 days for three times. The mice were killed by hauling necks on the twelfth day after treatment, the tumor was weighed and the inhibitory rate was calculated. RESULT: When the dosage of podophyllotoxin nanoliposome and the suspensions of podophyllotoxin reached 5.0 mg x kg(-1), the rate of inhibiting tumor were 52.37% and 38.25% to the H22 liver cancer of mice respectively. CONCLUSION: Podophyllotoxin nanoliposome and the suspensions of podophyllotoxin have the effect in anti-liver cancer. And podophyllotoxin nanoliposome have stronger inhibitory rate compared with suspension liquid of the podophyllotoxin in same dose.

Animals↗

PubMed2006

Oxalone and lactone moieties of podophyllotoxin exhibit properties of both the B and C rings of colchicine in its binding with tubulin.

Thermodynamics of podophyllotoxin binding to tubulin and its multiple points of attachment with tubulin has been studied in detail using isothermal titration calorimetry. The calorimetric enthalpy of the association of podophyllotoxin with tubulin is negative and occurs with a negative heat capacity change (DeltaC(p) = -2.47 kJ mol(-)(1) K(-)(1)). The binding is unique with a simultaneous participation of both hydrophobic and hydrogen-bonding forces with unfavorable negative entropic contribution at higher temperature, favored with an enthalpy-entropy compensation. Interestingly, the binding of 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone (AC, a colchicine analogue without the B ring) with tubulin is enthalpy-favored. However, the podophyllotoxin-tubulin association depending upon the temperature of the reaction has a favorable entropic and enthalpic component, which resembles both B- and C-ring properties of colchicine. On the basis of the crystal structure of the podophyllotoxin-tubulin complex, distance calculations have indicated a possible interaction between threonine 179 of alpha-tubulin and the hydroxy group on the D ring of podophyllotoxin. To confirm the involvement of the oxalone moiety as well as the lactone ring of podophyllotoxin in tubulin binding, analogues of podophyllotoxin are synthesized with methoxy substitution at the 4' position of ring D along with its isomer and another analogue epimerized at ring E. From these results, involvement of oxalone as well as the lactone ring of the drug in a specific orientation inclusive of ring A is indicated for podophyllotoxin-tubulin binding. Therefore, podophyllotoxin, like colchicine, behaves as a bifunctional ligand having properties of both the B and C rings of colchicine by making more than one point of attachment with the protein tubulin.

Animals↗

PubMed2004

Radioprotective effect of podophyllotoxin in Saccharomyces cerevisiae.

Recent reports showed that whole extract of Podophyllum hexandrum was radioprotective in mice. Podophyllotoxin is one of the major constituents of the whole extract of Podophyllum. In this study we report on the radioprotective action of podophyllotoxin in Saccharomyces cerevisiae yeast. Proliferating yeast cells pretreated with podophyllotoxin (2.5-5.0 microg/mL) for > or =3 hours showed a higher surviving fraction after (60)Co-gamma-irradiation (200-600 Gy) than did the irradiated cells not pretreated with podophyllotoxin. The maximum increase (2.0 times) in surviving fraction was observed in cells treated with 2.5 microg/mL podophyllotoxin, 5 hours before (60)Co-gamma-irradiation (400 Gy). Podophyllotoxin was not mutagenic or recombinogenic at radioprotective doses (2.5 microg/mL). A post-irradiation decrease in revertants and gene convertants was observed in cells treated with podophyllotoxin (2.5 microg/mL podophyllotoxin, -5 hours, 400 Gy). This study indicates that podophyllotoxin is radioprotective in yeast, and its radioprotective effects in higher eukaryotes would be worth investigating.

Dose-Response Relationship, Radiation↗

PubMed2002

[Changes in serum concentration of podophyllotoxin after its topical application with liposome on rat skin].

OBJECTIVE: To investigate the changes of serum concentration of podophyllotoxin after topical application of liposome podophyllotoxin suspension on rat skin. METHODS: SD rats were used in this study, which were divided into test group (n=48) to receive application of liposome podophyllotoxin (0.5 % ) suspension and control group (n=48) treated with 0.5 % podophyllotoxin alcohol solution. Blood samples were obtained from the heart at 1, 2, 4, 6, 8, 10, 12 and 24 h respectively after drug application, and the serum concentration of podophyllotoxin was determined by spectrofluorometry. RESULTS: The area under the curve of plasma drug concentration of the control group was 2.3-fold greater than that of the test group. Eight hours after drug application, the serum concentration of podophyllotoxin reached the peak in the test group, while in the control group, only two hours was needed to reach the peak. The peak serum level of podophyllotoxin in the test group were significantly lower than that of the control group (166.395 +/- 14.634 ng/ml vs 378.603 +/- 26.105 ng/ml, P<0.001). CONCLUSION: The systemic absorption of podophyllotoxin in rats after its topical application in liposome suspension is significantly lower than that after application of 0.5 % podophyllotoxin alcohol solution, therefore the systemic toxicity may be reduced.

Administration, Cutaneous↗

PubMed1949

The effect of podophyllotoxin on tissue metabolism and enzyme systems.

Podophyllotoxin, 10(-3) (M), inhibits the respiration in vitro of rat lymph nodes, thymus, kidney, tumor, spleen, liver, brain, testis, and chicken embryo. Lymph node and spleen respiration are most sensitive, and the degree of inhibition increases with time. The injection of podophyllotoxin into tumor-bearing mice (20 mg. per kg.) causes a dramatic reduction in the respiration of tumor slices. Within 6 hours, the respiration approaches zero. Inhibition is evident 2 hours after injection of the drug. Spleen respiration is reduced 50 per cent within 6 hours. Kidney and liver respirations remain within normal limits. Marked reductions in the respiration of spleen, lymph nodes, and thymus glands of normal rats are produced by the injection of 15 mg. per kg. Thymus gland is the most sensitive of these three tissues, and its respiration is reduced 66 per cent 24 hours after injection of the drug. The injection of 0.8 microgram podophyllotoxin into the yolk sac of chicken eggs bearing 5 day embryos has no effect on the respiration of the embryo within 8 hours, although this is a sufficiently toxic dose to kill 80 per cent of the embryos (within 24 hours). Kidney respiration in the presence of acetate, glucose, alanine, and glutamate is inhibited to approximately the same degree as in the absence of added substrate. Succinate and pyruvate oxidation by rat kidney slices appear to be less sensitive. Oxidation of acetate and butyrate by rabbit kidney homogenate is more sensitive to podophyllotoxin than oxidation by rabbit kidney homogenate without added substrate. Glucose oxidation by this preparation is not inhibited by 10(-3)M podophyllotoxin. The anaerobic glycolysis of chicken embryo, rat brain, and rat testis is stimulated by 10(-5) and 10(-6)M podophyllotoxin, and is inhibited by 10(-3)M. The following enzymes are not inhibited by 10(-3)M podophyllotoxin: succinoxidase from pigeon breast muscle, choline, xanthine and tyrosine oxidase from rat liver homogenate, and leucine oxidase from Proteus vulgaris; alkaline and acid phosphatase from dog serum; adenosine triphosphatase from rat liver; choline esterase from rat brain homogenate; ribonucleodepolymerase from spleen mince and thymonucleodepolymerase from dog serum. High concentrations of podophyllotoxin do not influence the viscosity and degree of polymerization of thymonucleic acid.

Animals↗

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↗

PubMed1998

Podophyllotoxins: current status and recent developments.

Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum emodi and has long been known to possess medicinal properties. Etoposide (VP-16), a podophyllotoxin derivative, is currently in clinical use in the treatment of many cancers, particularly small cell lung carcinoma and testicular cancer. This compound arrests cell growth by inhibiting DNA topo-isomerase II, which causes double strand breaks in DNA. VP-16 does not inhibit tubulin polymerization, however, its parent compound, podophyllotoxin, which has no inhibitory activity against DNA topoisomerase II, is a potent inhibitor of microtubule assembly. In addition to these two mechanisms of action, an unknown third mechanism of action has also been proposed for some of the recent modifications of podophyllotoxins. Owing to its severe toxic side effects a number of modifications have been done on podophyllotoxin structure. Some of the congeners exhibited potent antitumor actiivity, of which etoposide and teniposide are in clinical use, NK 611 is in phase II clinical trials and many compounds are in the same line. Recent developments on podophyllotoxins have led structure-activity correlations which have assisted in the design and synthesis of new podophyllotoxin derivatives of potential antitumor activity. Modification of the A-ring gave compounds having significant activity but less than that of etoposide, whereas modification of the B-ring resulted in the loss of activity. One of the modifications in the D-ring produced GP-11 which is almost equipotent with etoposide. E-ring oxygenation did not affect the DNA cleavage which led to the postulation of the third mechanism of action. It has also been observed that free rotation of E-ring is necessary for the antitumor activity. The C4-substituted aglycones have a significant place in these recent developments. Epipodophyllotoxin conjugates with DNA cleaving agents such as distamycin increased the number of sites of cleavage. The substitution of a glycosidic moiety with arylamines produced enhanced activity. Modification in the sugar ring resulted in the development of the agent, NK 611 which is in clinical trial at present. This article review, the progress of podophyllotoxins from its early applications in folk medicine to the most recent modifications and the mechanism(s) of action, pharmacology and the structure-activity relationships.

Animals↗

PubMed2002

Drugs that inhibit tubulin polymerization: the particular case of podophyllotoxin and analogues.

Tubulin being a major cellular target for antitumor drugs, tubulin-interacting compounds have attracted great attention as antimitotic agents. Two main classes of antimitotic drugs are known and one of them includes podophyllotoxin, a natural product. The clinical use of podophyllotoxin in the treatment of cancer has been limited by severe toxic side effects. In an attempt to find less toxic analogues, many podophyllotoxin derivatives have been prepared. Identification of two types of mechanisms of action has led to the development of two groups of podophyllotoxin analogues: tubulin polymerisation inhibitors and topoisomerase II inhibitors. The present article focuses on the first group of podophyllotoxin analogues i.e. those that retain "podophyllotoxin-like" activity. The review starts with a short summary of the structural characteristics of tubulin and its interactions with drugs that affect the microtubule dynamics and then deals with the particular case of podophyllotoxin. Particular attention is given to the nature and the location of the binding sites compared to those of colchicine. The main purpose of the present review being the search for structure-activity relationships, the structural significant features required for antitubulin activity are described and discussed in details.

Animals↗

PubMed2002

Experimental study of podophyllotoxin dipalmitoylphosphatidylcholine liposome for topical skin application.

OBJECTIVE: To observe the drug release of podophyllotoxin liposome and the drug retention in the skin. METHODS: Two liposome suspensions containing respectively podophyllotoxin dipalmitoylphosphatidylcholine (DPPC) and soya bean lecithin were prepared ultrasonically. Podophyllotoxin anhydride and the liposome suspensions were applied onto the skin of young pigs to observe the drug retention in the skin at different time points in the following 2 days, with exclusive liposome or anhydride serving as control. RESULTS: One hour after application of podophyllotoxin anhydride, a peak of the drug concentration in the skin occurred followed by immediate declination, a process not observed after the application of bean lecithin liposome due to gradual drug release that produced drug concentration constantly much higher than that of podophyllotoxin anhydride. A peak concentration was also observed 4 h after application of podophyllotoxin DPPC liposome, which then declined slowly to and stabilized at a higher level than that of bean lecithin liposome of anhydride within 48 h. CONCLUSION: DPPC liposome-embedded podophyllotoxin better targets the drug to the skin after application, and is a suitable preparation for topical skin application.

1,2-Dipalmitoylphosphatidylcholine↗