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PubMed1980

Systemic effects of podophyllotoxin on phosphate metabolism in innervated and denervated, slow and fast muscles of the rat.

The systemic administration of podophyllotoxin gives qualitatively the same results as the administration of colchicine. It increases the specific activities and isotope uptakes of the inorganic phosphate and acid-soluble organic-bound phosphate fractions of slow and fast muscles. In the extensor digitorum longus muscles these increases are slowly reversible. In the two fast muscles -- gastrocnemius and extensor digitorum longus muscles -- significant interactions between podophyllotoxin treatment and 3 d-surgical denervation are observed. It is proposed that, like colchicine, podophyllotoxin induces denervation-like alterations in the Pi and POAS metabolism of skeletal muscle. In view of their structural dissimilarities it is further proposed that their action on muscle phosphate metabolism is mediated through a common property : i.e. binding to muscle free tubulin.

Animals↗

PubMed1992

Experimental podophyllotoxin (bajiaolian) poisoning: II. Effects on the liver, intestine, kidney, pancreas and testis.

Young male rats were orally intubated with podophyllotoxin: Group I, control animals, orally fed with vehicle only; Group II, fed with an initial dose of 5 mg.kg-1 b.w., followed by a daily dose of 1.67 mg.kg-1 b.w. for 7d. Group III, fed with an initial dose of 15 mg.kg-1 b.w., followed by a daily dose of 5 mg.kg-1 b.w. for 7d. All animals were sacrificed 72 h after the last dosing. Histopathological examination revealed dose-related fatty change of the liver, atrophy and degenerative changes of the intestinal epithelial linings and testicular seminiferous tubules. Depletion of the pancreatic acinar cell granules was also apparent in the Group III animals. No pathology, however, was observed in the kidneys. The present study demonstrated for the first time degenerative changes in the liver, intestine, testis, and pancreas of animals ingested podophyllotoxin. These pathological changes correlate well with the clinical signs/symptoms of abnormal liver function, abdominal pain and diarrhea, and reduced serum amylase in humans poisoned by podophyllum. Inhibition of protein synthesis and mitosis (disruption of microtubules) are believed to be the underlying mechanisms of these changes observed in the animals intoxicated by podophyllotoxin.

Animals↗

PubMed2006

Evaluation of cytotoxic potential of latex of Calotropis procera and podophyllotoxin in Allium cepa root model.

In the present study we have utilized the Allium cepa root tip meristem model to evaluate the cytotoxic and anti-mitotic activities of latex of Calotropis procera (DL) and podophyllotoxin. Standard cytotoxic drug cyclophosphamide and non-cytotoxic drugs cyprohcptadine and aspirin served as controls. Like cyclophosphamide, both DL and podophyllotoxin significantly inhibited the growth of roots and mitotic activity in a dose-dependent manner. However, podophyllotoxin was more potent in this regard and produced root decay. Cyproheptadine and aspirin, on the other hand, showed a marginal effect on the root growth and mitotic activity at much higher concentrations.

Calotropis↗

PubMed1990

[Therapy of penile viral condylomata with 0.5% podophyllotoxin].

Twenty male patients with penile warts (HPV induced papular and flat condylomata) attending the Venereal Disease Clinic at the Department of Dermatology, University di Pavia were treated with podophyllotoxin 0.5% in ethanol, self applied twice daily for 3 consecutive days, followed by 4 days without treatment. All the patients were cured after a maximum of 6 treatments; 10 patients (50%) were cured after 1 or 2 treatments. Three patients did not attend regularly at the control visits; 17 patients completed the study. Eight of the 17 patients (47.1%) showed recurrences of the warts; all of them were cured after successive podophyllotoxin treatments. Tolerance was good and only a few patients (30%) had mild adverse reactions. In conclusion podophyllotoxin 0.5% appeared to be safe and effective for the self treatment of genital warts.

Adolescent↗

PubMed1990

Current status of podophyllotoxin for the treatment of genital warts.

An evolutionary process that began 50 years ago with a crude plant resin (podophyllum) has currently developed to the point where a fine chemical podophyllotoxin can be safely and effectively applied by patients for the treatment of external genital warts. In this brief review, the fundamental chemistry, pharmacology, and toxicology of podophyllotoxin will be reviewed, along with the sequence of clinical studies that resulted in the development of patient applied podophyllotoxin.

Condylomata Acuminata↗

PubMed1989

[Experiences with podophyllotoxin in the treatment of condylomata acuminata].

We treated 26 patients with condylomata acuminata with a 0.5% solution of podophyllotoxin (Condyline). Twelve of these patients were unsuccessfully pretreated with a common podophyllin 20% solution - some of them up to three months. In 22 patients (84.5%) we observed complete healing of lesions within 30 (6 bis 175) days with podophyllotoxin. Prompt response, minor side-effects, and the possibility for the patients to carry out the treatment themselves are the advantages of this podophyllotoxin preparation.

Administration, Topical↗

PubMed1984

Analysis of the inhibitory effects of VP-16-213 (etoposide) and podophyllotoxin on thymidine transport and metabolism in Ehrlich ascites tumor cells in vitro.

These studies explore the effects of an epipodophyllotoxin on the membrane transport and metabolism of thymidine in Ehrlich ascites tumor cells. Uptake of 3H after exposure of cells to [3H]-thymidine is characterized by a rapid initial velocity that approximates membrane transport followed by a slower rate of uptake that parallels the accumulation of phosphorylated derivatives of thymidine, primarily thymidine triphosphate, within the cell. The high rate of thymidine transport relative to thymidine metabolism to the triphosphate within the cell decreases as the extracellular nucleoside concentration is reduced due to a much greater decrease in membrane transport than the subsequent metabolic step. Hence, as extracellular thymidine is decreased, transport becomes increasingly rate limiting to metabolism within the cell. VP-16-213 (etoposide) or podophyllotoxin inhibits the initial uptake rate for thymidine and, as a consequence, inhibits the intracellular formation of thymidine triphosphate. When extracellular thymidine is high, inhibitory effects on transport are transient, and the net rate of thymidine triphosphate accumulation within drug-treated cells rapidly approaches a velocity comparable to that of control cells, indicating no direct VP-16-213 or podophyllotoxin effect on nucleoside and nucleotide phosphorylation. When extracellular thymidine is reduced so that transport is rate limiting to metabolism, the duration of the inhibitory effects of VP-16-213 on thymidine triphosphate formation is prolonged. A secondary effect of VP-16-213 becomes manifest beyond 10 min of incubation with [3H]thymidine with the virtual complete cessation of thymidine incorporation into the acid precipitate without any change in the thymidine triphosphate level. This late effect is not observed with podophyllotoxin and indicates a direct effect of VP-16-213 on DNA synthesis that is distinct from the earlier inhibitory effect on thymidine phosphorylation, which is secondary to membrane transport.

Animals↗

PubMed1978

Structure-activity study of the inhibition of microtubule assembly in vitro by podophyllotoxin and its congeners.

This study investigates the inhibition of microtubule assembly in vitro by podophyllotoxin and its derivatives, which include in part the antitumor compounds 4'-demethylepipodophyllotoxin ethylidene beta-D-glucoside (VP-16-213) and 4'-demethylepipodophyllotoxin thenylidene beta-D-glucoside (VM-26); the cyclic ethers, cyclic sulfides, and cyclic sulfones of podophyllotoxin and deoxypodophyllotoxin; epipodophyllotoxin; picropodophyllotoxin; and several 4'-demethyl compounds. The inhibitory activity of these derivatives is sensitive to the configuration and size of substituents at position 4 in ring C and to steric features of substituents at position 12 in ring D. Decreasing activity correlates with the increasing size of the substituent at position 12, as indexed by their van der Waals radii. These results suggest that rings C and D of these drugs are involved in their interaction with the podophyllotoxin-binding site in tubulin.

Animals↗

PubMed1982

Interactions of the tau-tubulin-vinblastine complex with colchicine, podophyllotoxin, and N,N'-ethylenebis(iodoacetamide).

Microtubule assembly is inhibited by anti-mitotic drugs such as colchicine or podophyllotoxin and also by sulfhydryl-oxidizing reagents, but it is not known which tubulin-tubulin interactions are disrupted by these agents. We have studied the interactions of a complex of tubulin, vinblastine, and tau protein with these agents. This complex has the form of a spiral filament and may consist of tubulin dimers joined end to end as in a protofilament; presumably, therefore, the lateral interaction sites should be accessible in this structure but not in the intact microtubule. Unlike the microtubule, the complex binds to colchicine and podophyllotoxin with high affinity. Again, unlike intact microtubules, the complex reacts with N,N'-ethylene-bis(iodoacetamide) to generate an intra-chain cross-link in beta-tubulin. Tubulin molecules containing this cross-link are unable to polymerize, suggesting that formation of this cross-link involves sulfhydryl groups that are critical for assembly. These results are consistent with a model whereby colchicine-, podophyllotoxin-, and sulfhydryl-oxidizing agents inhibit microtubule assembly by preventing lateral interactions between tubulin molecules in adjacent protofilaments.

Animals↗

PubMed1994

[A primary clinical trial of genital warts treated with domestic highly purified podophyllotoxin].

Genital warts (condyloma accunimata) are a kind of sexually transmitted disease (STD) caused by human papillomavirus (HPV). In this article, we report 75 cases of genital warts treated with highly purified podophyllotoxin. All volunteers were selected in our clinic and diagnosed according to typical skin lesions and positive 0.5% acetic acid test. Of the 74 cases 48 were male and 26 were female, with a mean age of 28.4 years (21-54). The average duration of disease was 4.4 months (2 weeks-3 years). All lesions were treated with 0.5% podophyllotoxin-ethanal solution topically 2 times per day for 3 successive days. The treatment was repeated if any warts persisted, but not more than 3 therapies in total were applied. The results showed that 41/48 (85.4%) of male and 23/26 (88.5%) of female patients were cured, the overall cure rate was 86.5% and the effectiveness rate (more than 50% lesions disappeared) was 96.15%. During another 3 months of follow-up, 9 male and 4 female patients (17.6% in total) experienced relapsed warts; these were cured with another treatment. Side effects including slight local irritation and erythema or superficial erosions were common, but 3 male and 2 female patients complained of sever pain and local swelling. All side effects were tolerable. It is concluded that our domestically produced highly purified podophyllotoxin is an effective, comparatively safe drug for the treatment of genital warts. It is also very simple to apply, and can be used for self-treatment.

Adult↗

PubMedDate not supplied

A comparison of the mechanisms of action of VP-16-213 and podophyllotoxin.

A comparison of the mechanism of action of VP 16-213 and podophyllotoxin has revealed that although both drugs inhibit nucleoside uptake in HeLa cells, they exhibit other biological properties which are quite distinct. Podophyllotoxin inhibits microtubule assembly in vitro while VP-16-213 has no effect in this system. VP-16-213 induces single-stranded breaks in DNA in HeLa cells, an effect which may explain the cytoxicity of VP-16-213. In contrast to VP-16-213-treated cells, cells treated with podophyllotoxin maintain DNA integrity and show no evidence of single-stranded breaks.

Biological Transport↗

PubMed1983

Antitumor agents LXII: synthesis and biological evaluation of podophyllotoxin esters and related derivatives.

Synthetic esters of the C-4 hydroxyl group of podophyllotoxin (I) were prepared. In addition, esters were synthesized using the diol system of tetrahydropyranyl podophyllol (XV), produced by reducing the lactone ring of tetrahydropyranyl podophyllotoxin with lithium aluminum hydride. Six compounds, the acrylate (IV), 3,3-dimethyl acrylate (V), phenoxyacetate (IX), and ethyl adipate (XI) of I as well as podophyllol (XIV) and tetrahydropyranyl podophyllol dimesylate (XVIII), showed significant activity when tested using the P-388 lymphocytic leukemia screen at 3 mg/kg/day. None of the esters showed higher activity than that shown by the parent molecule I when tested at the same dosage level.

Animals↗

PubMed1986

Thermal chemistry of podophyllotoxin in ethanol and a comparison of the cytostatic activity of the thermolysis products.

Podophyllotoxin (1) in buffered ethanolic solution is degraded by two pathways. One leads to (a) picropodophyllin (2), which undergoes dehydration to give alpha-apopicropodophyllin (5), which rearranges to give beta-apopicropodophyllin (6), (b) the ethyl ether of picropodophyllotoxin, 8, and (c) the ethyl ether of epipicropodophyllotoxin, 7. The other pathway leads directly to epipodophyllotoxin (10) and the corresponding ethyl ether, 9, and possibly, via a transient 3,4-dehydropodophyllotoxin (5'), to beta-apopicropodophyllin (6). The 1H NMR spectra of these compounds are described, their in vitro cytostatic activity compared, and their syntheses, including that of podophyllotoxin ethyl ether, reported.

Antineoplastic Agents↗

PubMedDate not supplied

Podophyllotoxin-induced modifications of the nuclear envelope.

In spermatids of Culex tigripes (Culicidae) the manchette is composed of numerous expansion-bearing microtubules which surround the nucleus. Under the action of podophyllotoxin, in zones where manchette microtubules are absent, the nuclear envelope bulges and forms abnormal extranuclear vesicles. We hypothesize that this newly recognized capacity of podophyllotoxin is due to its action on microtubule-membrane relationships.

Animals↗

PubMed1995

Management of genital warts in women with human leukocyte interferon-alpha vs. podophyllotoxin in cream: a placebo-controlled, double-blind, comparative study.

The purpose of this double-blind, placebo-controlled, comparative study was to evaluate the specific clinical efficacy and tolerance of human leukocyte interferon-alpha (2 x 10(6) IU/g) and podophyllotoxin 0.5% incorporated in a hydrophilic cream to cure genital warts. Preselected Asian women (n = 60) aged 18-40 years (mean 22.9), with a clinical and biopsy-confirmed diagnosis of genital warts, harboring 322 lesions (mean 5.36) were randomly assigned to three parallel groups to receive one of the two test drugs or placebo. Each patient received a precoded tube (40 g) containing either human leukocyte interferon-alpha, podophyllotoxin, or identically appearing placebo cream for 3 days' usage. In addition to written instructions, each subject was shown how to apply a minimal amount of trial medication on their lesions thrice daily for 3 consecutive days per week (maximum nine topical applications per week). Patients were examined on a weekly basis, and a cure was considered to be a biopsy-confirmed, total elimination of a lesion. Moreover, patients cured during the study period were spared further therapy, and were requested to return in 16 weeks to monitor for the occurrence of a relapse. The remaining patients' empty tubes were collected, and similarly precoded replacement tubes were given to continue the treatment; a total of 214 tubes were used. The study was scheduled for 16 weeks with 4 weeks of active treatment. Individuals were excluded from the study due to pregnancy, breast feeding, or the receiving of any type of antiviral therapy during the 4 weeks preceding enrollment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1982

Current development of podophyllotoxins.

The unique biological properties and therapeutic efficacy of the podophyllotoxin derivatives, Vumon (VM26, teniposide) and Vepesid (VP16-213, etoposide), are stimulating the interest of both laboratory and clinical researchers. Investigations on new pharmaceutical formulations, pharmacokinetics and metabolism are providing more appropriate information in drug administration; experimental chemotherapy indicates that, among others, cytosine arabinoside and cisplatin are highly synergistic with podophyllotoxins; single agent and combination treatment clinical trials are defining the respective role of Vumon and Vepesid in cancer chemotherapy.

Chemistry, Pharmaceutical↗

PubMed1979

Comparison of a water-soluble and a water-insoluble podophyllotoxin derivative in murine neoplasms.

Comparison of a water-soluble (27-487) with a water-insoluble (VP-16-213) podophyllotoxin derivative in seven murine neoplasms revealed slight therapeutic superiortiy of VP-16-213 but also slightly greater toxicity when compared with 27-487. A strikingly good response of the Taper liver tumor to both compounds was observed, providing further incentive to the use of podophyllotoxin derivatives in human hepatomas.

Animals↗

PubMed2004

Biotechnological aspects of the production of the anticancer drug podophyllotoxin.

The natural lignan podophyllotoxin, a dimerized product of two phenylpropanoid moieties which occurs in a few plant species, is a pharmacologically important compound for its anticancer activities. It is used as a precursor for the chemical synthesis of the anticancer drugs etoposide, teniposide and etopophose. The availability of this lignan is becoming increasingly limited because of the scarce occurrence of its natural sources and also because synthetic approaches for its production are still commercially unacceptable. Biotechnological production using cell culture may be considered as an alternative source. Selection of the best performing cell line, its maintenance and stabilization are necessary prerequisites for its production in bioreactors and subsequent scale-up of the cultivation process to the industrial level. Scale-up of growth and product yield depends on a multitude of factors, such as growth medium, physicochemical conditions, seed inoculum, type of reactor and processing conditions. The composition of the growth medium, elicitors and precursors, etc. can markedly influence the production. Optimum levels of parameters that facilitate high growth and product response in cell suspensions of Podophyllum hexandrum have already been determined by statistical design. P. hexandrum cells have successfully been cultivated in a 3-l stirred-tank bioreactor under low shear conditions in batch and fed-batch modes of operation. The batch kinetic data were used to identify the mathematical model which was then used to develop nutrient-feeding strategies for fed-batch cultivation to prolong the productive log phase of cultivation. An improvement in the production of podophyllotoxin to 48.8 mg l(-1) in a cell culture of P. hexandrum was achieved, with a corresponding volumetric productivity of 0.80 mg l(-1) day(-1), when the reactor was operated in continuous cell-retention mode. Efforts are being made to further enhance its production levels by the development of hairy root culture or by varying the channeling of precursors towards the desired biosynthetic pathway by molecular approaches.

Antineoplastic Agents, Phytogenic↗