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PubMed1975

Cytofluorometric studies on the action of podophyllotoxin and epipodophyllotoxins (VM-26, VP-16-213) on the cell cycle traverse of human lymphoblasts.

Flow microfluorometric analysis of human lymphoid cells exposed in vitro to cytostatic concentrations of podophyllotoxin (0.01-5 mug/ml for 24 h) shows that a major part of this population (40-60%) has the DNA content of cells in the G2-M part of the cell cycle, and that approximately 60% of these cells are arrested in mitosis. Although a similar pattern of DNA distribution is seen in cultures exposed to cytostatic concentrations of VM-26(0.01 mug/ml) and VP--16-213(0.1 mug/ml), no mitotic cells are seen in these cultures. Exposure to higher concentrations: of VM-26 (0.1 mug/ml) and VP-16-213 (1.0 mug/ml) inhibits cell cycle traverse, and after 24 hr of exposure a major part of the population is arrested with the DNA content of cell in the S part of the cell cycle. Exposure to higher drug concentrations leads to a reduction in the number of cells with the late S-G2DNA content. Whereas the cell cycle block induced by cytostatic concentrations of podophyllotoxin (0.01 mug/ml) is readily reversible by reincubation of cells in drug-free medium, cells blocked by VM-26 and VP-16-213 are unable to resume cell-cycle traverse under similar conditions.

Cell Count↗

PubMedDate not supplied

Topical self-treatment of penile warts with 0.5% podophyllotoxin in ethanol for four or five days.

Penile condylomata were eradicated from 26 (70%) of 37 and from 15 (63%) of 24 uncircumsized men with penile warts who performed one course of self-treatment with 0.5% podophyllotoxin in ethanol, which was applied twice daily for four and five days, respectively. In comparison with previous data on the efficacy for use of the same regimen for only three days, no major advantages were observed; instead, the frequency of local adverse effects was increased. However, because warts growing in a plaque-like fashion reacted favorably to the therapy, such lesions may be treated for four to five days if they are recalcitrant to the three-day regimen. The efficacy of application of 0.5% podophyllotoxin in ethanol only once daily was significantly lower than that resulting from application twice daily.

Administration, Topical↗

PubMed1991

Discrimination of mitotic cells using anti-p105 monoclonal antibody to analyze the mode of action of etoposide and podophyllotoxin in human gastric cancer cells.

Anti-p105 monoclonal antibody was used to discriminate between M-phase and G2-phase of gastric cancer cells. p105 is a proliferation-associated nuclear antigen and its expression increases with cell cycle progression, especially in the mitotic phase. As an example of cell cycle analysis, the modes of action of etoposide and podophyllotoxin were examined by multiparameter flow cytometry. We found that etoposide caused G2 block and retarded S phase transit and podophyllotoxin caused potential M phase block in gastric cancer cells. This cell cycle analysis by using anti-p105 monoclonal antibody should be useful for analysis of the actions of anti-tumor agents, especially for M phase analysis, because of its convenience and reliability.

Antibodies, Monoclonal↗

PubMed1992

Synthesis and evaluation of 2-diazo-3,3,3-trifluopropanoyl derivatives of colchicine and podophyllotoxin as photoaffinity labels: reactivity, photochemistry, and tubulin binding.

Derivatives of the tubulin polymerization inhibitors colchicine and podophyllotoxin bearing the photoreactive 2-diazo-3,3,3-trifluoropropanoyl (DTFP) group were synthesized for evaluation as potential photoaffinity labels of the tubulin binding site. All labels were assayed for their ability to inhibit tubulin polymerization, and N-DTFP-deacetylthiocolchicine was shown to competitively inhibit tubulin-colchicine binding with a Ki of 4-5 microM. The tubulin off-rate of this analog was similar to that of podophyllotoxin, rather than to the relatively irreversibly bound colchicine. Photochemical solvent insertion reactions of the labels were investigated. Radioactive samples of the two most active labels were prepared and used in initial protein-labeling experiments, during which the fractional occupancy of tubulin and extent of covalent incorporation were determined. A rearrangement of DTFP amides was encountered which is relevant to the utility of this moiety for use in synthesis of photoaffinity labels.

Affinity Labels↗

PubMed1994

Topical 0.3% and 0.5% podophyllotoxin cream for self-treatment of condylomata acuminata in women. A placebo-controlled, double-blind study.

BACKGROUND: Genital warts are a well-recognized clinical entity and a disease of great antiquity that differ from skin warts both histologically and antigenically. It is a common sexually transmitted disease of high prevalence all over the world. Women are more likely to be unaware of such warts because it is harder for them to examine their genitalia. 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 cream emulsion (castor oil, BP as vehicle) to cure genital condylomata in women. METHODS: Preselected (n = 80) Asian females (mean age 23.6 years), harboring 544 warts (mean 6.8 in number), ranging from 1 to 9 mm in size (mean 2.1 mm) with biopsy-proven diagnosis of condylomata acuminata were randomly allocated to three groups (30 + 30 + 20). At home the patients applied the given trial medication themselves (using the finger) twice a day, for 3 consecutive days per week, and if not cured the same course was extended to 3 more weeks, in total 24 topical applications for 4 weeks. The patients were examined on a weekly basis, and a total regression of warts (biopsy-proven) was evaluated as complete cure. RESULTS: By the end of the study, the placebo group (20 patients, bearing 124 warts) did not show any regression or clinical efficacy, while 41/60 patients (68.3%) and 349/420 warts (83%) were cured in the 0.3% and 0.5% treatment groups (placebo vs. active groups p < 0.001). Patients using the 0.5% active medication had substantially more eliminated warts (205/349, 95.8%) than the 0.3% group (70%). Localized adverse symptoms were mild to moderate and were well tolerated by the patients with no dropout. Forty-three patients (53.8%) did not show any adverse reaction. The most frequent adverse symptoms were tenderness (23/80, 28.8%) and burning sensation (14/80, 17.5%). Among 41/80 (51.25%) cured patients 4 had a relapse after 16 weeks. CONCLUSION: Along with mild, tolerable side effects the study demonstrates that 0.5% podophyllotoxin cream is more efficacious than 0.3% (p < 0.01) and can be considered as a reliable home-based treatment.

Administration, Topical↗

PubMed1993

Topical treatment of penile condylomata acuminata with podophyllotoxin 0.3% solution, 0.3% cream and 0.15% cream. A comparative open study.

The purpose of this comparative open study was to determine the clinical efficacy of 0.3% podophyllotoxin both in 70% ethanolic solution and cream preparations on genital warts. Three parallel trial preparations, 0.3% solution, 0.3% and 0.15% cream, were randomly allocated to 60 circumcised Asian males (mean age 19.5 years), with the diagnosis of genital condyloma. Patients applied the trial preparation twice a day for 3 consecutive days. If total elimination was not achieved with one trial, it was extended to 3 similar cycles, in total of 4 weeks duration. Response was calculated with a response rate formula. After 3 weeks of treatment all the patients in the 0.3% solution group were evaluated as cured, with mild localized erythema and burning sensation. In the 0.3% cream preparation group, 75% of the patients were cured, and the remaining 25% were found to be cured after 4 treatments. In the 0.15% cream preparation group, 70% of the patients were evaluated as completely cured after 4 weeks. Non-objective, moderate to mild localized adverse symptoms were reported by both the active cream groups. Three of 54 patients (90%) with complete cure showed relapses after 16 weeks. It was concluded that 0.3% podophyllotoxin is more efficacious in ethanolic solution than in cream preparations.

Adolescent↗

PubMed1986

Response of solitary psoriatic plaques to experimental application of podophyllotoxin.

A 16-week double-blind study of parallel groups was carried out in the treatment of 152 patients suffering from stable psoriasis vulgaris. Podophyllotoxin was applied once daily at three different concentrations in an ointment base, namely 0.1, 0.25 and 0.5%. One stable psoriatic lesion was selected and monitored during the study course. All three concentrations of podophyllotoxin induced a statistically highly significant improvement (p less than 0.001) of the selected lesions. There was statistically highly significant difference between the treated and control lesions already after 2 weeks of treatment (p greater than 0.001), and this difference increased further during the study course. Eleven patients experienced adverse reactions - severe skin rash - spontaneously reported by the patients.

Adult↗

PubMed1998

Inhibitory effects of podophyllotoxin derivatives on herpes simplex virus replication.

Podophyllotoxin and its derivatives were examined for inhibitory effects on the replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), including acyclovir-resistant virus and clinical isolates. Deoxypodophyllotoxin (RD4-6266) proved to be a highly potent and selective inhibitor of all HSV strains in MRC-5 cells. EC50 values of RD4-6283 (in which the methylenedioxy ring A is modified) for HSV-1 and -2 were inferior to those of deoxypodophyllotoxin. However, podorhizol (RD4-6277) and 5'-methoxy-podorhizol (RD4-6276), in which ring C is absent, did not inhibit HSV replication. Moreover, RD4-6266 also inhibited the production of infectious virus particles of HSV-1 KOS strain and HSV-2 G strain. In contrast, none of the podophyllotoxin derivatives were found to have an antiviral effect against influenza A virus, respiratory syncytial virus or human cytomegalovirus in doses not toxic to the cells.

Antiviral Agents↗

PubMedDate not supplied

Response to podophyllotoxin treatment of genital warts in relation to HIV-1 infection among patients in Dar es Salaam, Tanzania.

Forty-two Tanzanian patients with genital warts were treated with 0.5% podophyllotoxin solution (Wartec) for 3 days. Thirteen patients (30.9%) were cured and a further 7 patients (16.7%) had more than 50% of lesions cleared at 6 weeks, while 19 patients were resistant to treatment. Three patients had a recurrence of lesions after an initial response. Thirty-three patients were tested for serological evidence of infection with human immunodeficiency virus (HIV) and 15 (45.5%) patients were shown to be HIV-1 antibody positive. The response to treatment was analysed in relation to HIV antibody status. The cure rate was significantly higher in HIV seronegative patients (8/18 = 44.4%) compared to HIV seropositive patients (1/15 = 6.7%) (P = 0.018). We conclude that podophyllotoxin treatment provides a useful non-hospital based treatment for genital warts, but HIV infection appears to contribute to the failure of treatment for genital warts.

Adolescent↗

PubMed1992

Podophyllotoxin intoxication: toxic effect of Bajiaolian in herbal therapeutics.

Bajiaolian (Dysosma pleianthum), one species in the Mayapple family, has been widely used as a general remedy and for the treatment of snake bite, weakness, condyloma accuminata, lymphadenopathy and tumours in China for thousands of years. However, the textbooks of traditional Chinese medicine mention little about the toxicity of Bajiaolian. Within 1 year, the authors saw five people who manifested nausea, vomiting, diarrhoea, abdominal pain, thrombocytopenia, leucopenia, abnormal liver function tests, sensory ataxia, altered consciousness and persistant peripheral tingling or numbness after drinking infusions made with Bajiaolian. The herb was recommended by either traditional Chinese medical doctors or herbal pharmacies for postpartum recovery and treatment of a neck mass, hepatoma, lumbago and dysmenorrhoea. Podophyllotoxin is one of the main ingredients of the Bajiaolian root. The clinical manifestations observed in our patients were consistent with podophyllum intoxication. Podophyllotoxin intoxication usually results from the accidental ingestion or topical application of podophyllum resin. However, these cases of Bajiaolian intoxication were iatrogenic and results from 'therapeutic doses' of Bajiaolian cited in the textbooks of traditional Chinese medicine.

Adult↗

PubMed2000

Podophyllotoxin aza-analogue, a novel DNA topoisomerase II inhibitor.

The pendant E-ring moiety of the podophyllotoxin aza-analogue 1 that is a potent inhibitor of microtubule assembly was modified in order to acquire inhibitory activity of DNA topoisomerase II. The monophenolic analogue 2 did not exhibit human topoisomerase II inhibition, while the ortho-quinone 3 that was obtained by oxidation of 2 inhibited its catalytic activity (decatenation) in a dose-dependent manner and stimulated double strand DNA breaks in supercoiled circular plasmid DNA, resulting in the production of linear DNA. These results showed that the topoisomerase II inhibition of the ortho-quinone 3 is due to stabilization of the topoisomerase II-DNA covalent binary complex. On the other hand, the ortho-quinone 3 did not inhibit the relaxation process of supercoiled DNA by topoisomerase I at concentrations up to 400 microM, nor was intercalation observed in unwinding measurements of 3. Therefore, the ortho-quinone 3 was shown to be a novel nonintercalative topoisomerase II specific inhibitor that stabilizes the cleavable complex. The present results suggest that the 4'-free hydroxyl group on the E-ring and the sugar moiety on the C-ring are not a prerequisite for topoisomerase II inhibition by podophyllotoxin derivatives.

DNA↗

PubMed2005

Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents.

Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.

Animals↗

PubMed1985

Effects on bone marrow cells of oral treatment with podophyllotoxin derivatives in rheumatoid arthritis.

SPG 827, a mixture of podophyllotoxin derivatives, has been thought to alleviate the symptoms of rheumatoid arthritis (RA) by arresting cell division in metaphase (i.e. resulting in an increase of the mitotic index) of rapidly proliferating cells of the immune apparatus. In contrast, the present study produced evidence that peroral SPG treatment of RA patients reduced the mitotic index of bone marrow cells, mainly in erythropoiesis. At the same time, slight megaloblastic changes appeared in the erythroblasts. These observations suggest that SPG treatment induced an interphase block in the G2 phase of the cell cycle, analogous to the cell action of the newer podophyllotoxin derivatives teniposide and etoposide. It may be that part of the clinical effect of SPG in rheumatoid arthritis is due to the described interphase-blocking activity.

Administration, Oral↗

PubMed1978

Correlation of tubulin-binding and antitumor activities of podophyllotoxin analogs.

The tubulin-binding affinities of podophyllotoxin and 12 related compounds have been compared with the effectiveness of these drugs in three assays of antitumor activity: (1) The mastocytoma assay of inhibited tumor cell growth in vitro; (2) the 37 sarcoma assay of tumor remission in vivo; and (3) the Stentor regeneration inhibition assay which detects a requirement for microtubule polymerization. The results indicate that there is a positive Spearman rank correlation coefficient between the inhibition constant for the binding of colchicine to tubulin in the presence of these compounds and the effectiveness of the compounds in the three assays of tumor growth inhibition. It is suggested that tubulin-binding assays may be a useful step in the screening of podophyllotoxin-like compounds suspected of disrupting mitosis by binding to microtubule protein.

Animals↗

PubMed2001

[Determination of podophyllotoxin lignans in Dysosma and its allied plants].

The existence of podophyllotoxin lignans in Dysosma versipellis and its allied plants was analyzed by twice developing TLC, and the content by chromotropic-colorimetric assay. The results showed that podophyllotoxin lignans exist in the rhizoma, radix, stem and leaf of Dysosma versipellis and its allied plants. The total lignans content is 2%-7%, and there is a big variation between different species. The total lignans content of Dysosma versipellis is related to the habitat.

Berberidaceae↗

PubMed2001

Linker length in podophyllotoxin-acridine conjugates determines potency in vivo and in vitro as well as specificity against MDR cell lines.

We have synthesized two podophyllotoxin-acridine conjugates-pACR6 and pACR8. In these compounds an 9-acridinyl moiety is beta linked to the C4 carbon of the four ring system in 4'-demethylepipodophyllotoxin (epiDPT) via eighter an N-6-aminohexanylamide linker (pACR6) or via an N-8-aminooctanylamide linker containing two more carbon atoms (pACR8). The acridine-linker moiety occupies the position where different glucoside moieties, dispensable for activity, are normally linked to epiDPT in the well known epipodophyllotoxins VP-16 and VM-26. As with VP-16 and VM-26, pACR6 and pACR8 show evidence of being topoisomerase II poisons as they stimulate topoisomerase II mediated DNA cleavage in vitro and induce DNA damage in vivo. This in vivo DNA damage, as well as pACR6/pACR8 mediated cytotoxicity, is antagonized by the catalytic topoisomerase II inhibitors ICRF-187 and aclarubicin, demonstrating that topoisomerase II is a functional biological target for these drugs. Despite their structural similarities, pACR6 was more potent than pACR8 in stimulating topoisomerase II mediated DNA cleavage in vitro as well as DNA damage in vivo and pACR6 was accordingly more cytotoxic towards various human and murine cell lines than pACR8. Further, marked cross-resistance to pACR6 was seen among a panel of multidrug-resistant (MDR) cell lines over-expressing the MDR1 (multidrug resistance protein 1) ABC drug transporter, while these cell lines remained sensitive towards pACR8. pACR8 was also capable of circumventing drug resistance among at-MDR (altered topoisomerase II MDR) cell lines not over-expressing drug transporters, while pACR6 was not. Two resistant cell lines, OC-NYH/pACR6 and OC-NYH/pACR8, were developed by exposure of small cell lung cancer (SCLC) OC-NYH cells to gradually increasing concentrations of pACR6 and pACR8, respectively. Here, OC-NYH/pACR6 cells were found to over-express MDR1 and, accordingly, displayed active transport of 3H-labeled vincristine, while OC-NYH/pACR8 cells did not, further suggesting that pACR6, but not pACR8, is a substrate for MDR1. Our results show that the spatial orientation of podophyllotoxin and acridine moieties in hybrid molecules determine target interaction as well as substrate specificity in active drug transport.

Aclarubicin↗

PubMed2005

[Preparation of stearic acid solid lipid nanoparticles containing podophyllotoxin].

OBJECTIVE: To improve the therapeutic efficacy and reduce the adverse effect of podophyllotoxin (PPT) by wrapping it in stearic acid solid lipid nanoparticles. METHODS: Stearic acid solid lipid nanoparticles containing podophyllotoxin was prepared using modified microemulsion technique, whose morphology was examined by transmission electron microscope. High-performance of liquid chromatography was employed to determine the entrapment efficiency of PPT in the nanoparticles. RESULT: The entrapment efficiency of PPT in the nanoparticles was 85.6% and the mean diameter of the particles was 56.5+/-25.8 nm. CONCLUSION: The stearic acid solid lipid nanoparticles has high entrapment efficiency for PPT and is homogeneous in size, which can be a promising targeted preparation for epidermal delivery.

Condylomata Acuminata↗

PubMed1989

Podophyllotoxin analogs: effects on DNA topoisomerase II, tubulin polymerization, human tumor KB cells, and their VP-16-resistant variants.

Several derivatives of podophyllotoxin with modifications at the C-4 position of ring C, in addition to demethylation at the C-4' position of ring E, were examined for inhibitory activity against DNA topoisomerase II and tubulin polymerization, generation of protein-linked DNA breaks, and cytotoxicity against KB cells and VP-16-resistant KB variants. Substitution of podophyllotoxin with a group in the beta configuration at the C-4 position of ring C resulted in compounds with greater inhibitory activity against DNA topoisomerase II and lower inhibitory activity against tubulin polymerization than those with an alpha configuration. These active analogs exhibited the same mechanism of DNA topoisomerase II inhibition as the epipodophyllotoxin derivative VP-16, which causes protein-linked DNA breaks in vitro as well as in cells. Two analogs selectively inhibited DNA topoisomerases II to a greater extent than tubulin polymerization. These analogs were cytotoxic towards KB cells in addition to VP-16-resistant KB cell lines, which indicated limited cross-resistance with VP-16 in VP-16-resistant KB variants.

DNA Damage↗