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PubMed1985

CPH-86, a highly purified podophyllotoxin, efficiently suppresses in vivo and in vitro immune responses.

Podophyllotoxin, a component of the plant resin Podophyllin, has been used as a clinical drug for many years. Recently it has been highly purified under the denomination of CPH-86. We here demonstrate that extremely low doses of the compound efficiently inhibit antibody responses to SRBC and prolong allogeneic skin graft survival in mice. In vitro immune reactions, such as mitogen and alloantigen induced proliferation and development of cytotoxic T cells, are also suppressed in a dose dependent manner. This effect does not seem to be due to direct cellular toxicity or to a shift in the kinetic pattern of the responses.

Animals↗
PubMed1993

New compounds related to podophyllotoxin and congeners: synthesis, structure elucidation and biological testing.

4-Azido, 4-amino, 4-amido and 4-alkoxy compounds related to the lignans podophyllotoxin and 4'-demethylepipodophyllotoxin have been synthesized, and their structures elucidated. The Ritter reaction was shown to be useful in the preparation of the 4-amido compounds with the required stereochemistry. A preparative method for 4-chloro-4-deoxypicrophyllotoxin, for which all earlier synthetic attempts resulted in the two dehydrated compounds, alpha- and beta-apopicropodophyllotoxin, was developed. Supplementary preliminary studies of the biological activities of some of the compounds were performed. All compounds had pronounced inhibitory effect on the in vitro growth of human cervical cancer cells and TC-mouse cells with 4-amino-4-deoxypodophyllotoxin and 4-azido-4-deoxypodophyllotoxin showing the highest activity. Alkaline elution studies indicate that the toxicity of the 4'-demethoxy derivatives is due to protein-mediated DNA nicking. None of the compounds were found to have antiviral effect against herpes simplex type 2 (HSV-2), human immunodeficiency (HIV), and cytomegalovirus (CMV) in doses not toxic to the cells.

Animals↗
PubMedDate not supplied

Podophyllotoxin in serum: absorption subsequent to three-day repeated applications of a 0.5% ethanolic preparation on condylomata acuminata.

High-performance liquid chromatography was used for quantitative determination of podophyllotoxin in serum subsequent to repeated applications of a 0.5% ethanolic preparation on condylomata acuminata. The drug was not detectable in the serum of ten men treated with < or = 50 microliters. In serum of seven patients receiving 100-1,500 microliters on extraordinarily large en-plaque lesions, peak levels of 1-17 ng/ml were measured within 1-2 hr. The drug did not accumulate in serum. Dispersion of 100 microliters gave rise to peak levels of < or = 5.0 ng/ml and to subsequent levels of < or = 3.0 ng/ml for 4 hr. Larger doses gave rise to traceable amounts in serum for < or = 12 hr. Investigations with 52 patients indicated that volumes of > 100 microliters are rarely required for topical treatment of condylomata. It is concluded that application of volumes of < or = 250 microliters twice daily for three days would satisfy the most stringent safety precautions and avoid any danger of systemic toxicity. Potential hazards associated with use of the nonstandardized 20% podophyllin preparations are emphasized.

Absorption↗
PubMed1998

Effects of spin labeled derivatives of podophyllotoxin on cell cycle and macromolecular synthesis in human lymphoid leukemia Molt 4B cells.

AIM: To examine the effect of the spin labeled derivatives of podophyllotoxin, N-podophyllic acid-N"-[4-(2,2,6,6-tetramethyl-1-piperidinyloxy)] thiosemicarbazide (GP4) and 4-[4"-(2",2",6",6"-tetramethyl-1"-piperidinyloxy) amino]-4'-demethylepipodophyllotoxin (GP7) on the cell cycle and macromolecular synthesis of human lymphoid leukemia Molt 4B cells in vitro. METHODS: MTT assay, 3H incorporation, and flow cytometer were used. RESULTS: GP4, GP7, and etoposide 0.02-100 mmol.L-1 cultured for 48 h inhibited the proliferation of human lymphoid leukemia Molt 4B cells. IC50 values of GP4, GP7, and etoposide were 0.11, 4.7, and 1.6 mmol.L-1, respectively. DNA and protein syntheses were obviously suppressed by GP4, GP7, and etoposide 10 mmol.L-1 for 48 h. After Molt 4B cells were treated with GP4, GP7, and etoposide 10 mmol.L-1 for 6 and 12 h, the mitotic index was increased by GP4 and reduced by GP7 and etoposide. According to flow cytometric BrdU/DNA analysis, GP4 slightly retarded S phase and mainly arrested cell cycle progression in G2/M phase, whereas GP7 similar to etoposide induced cells accumulated at S phase and retarded the cells in G2 phase. CONCLUSION: GP4 and GP7 inhibit the proliferation of Molt 4B cells, but the mechanisms are different.

Antineoplastic Agents, Phytogenic↗
PubMed1998

[Synthesis of spin labeled analogue of podophyllotoxin glycoside].

A novel spin labeled analogue of podophyllotoxin glycoside 9 was synthesized by condensing 4'-demthyl-epipodophyllotoxin-beta-D-glucopyranose and 4-formyl-2, 2, 6, 6-tetrahydropuridine in presence of p-TsOH and triethyl orthoformate. It was shown to exhibit activity compatible to VP-16-213 in inhibiting L1210 cells.

Animals↗
PubMed2003

Preparation and comparative analysis of two podophyllotoxin liposomes.

OBJECTIVE: To prepare two different liposome gels containing podophyllotoxin (PPT) and compare their pharmaceutical properties. METHODS: PPT-Dipalmitoylphosphatidylcholine (DPPC) liposome and PPT-soya lecithin liposome were prepared by reverse phase evaporation technique, and optical and electron microscopy were performed respectively for examining the appearances of the 2 liposomes and the diameter of the particles. Gel filtration was employed to assess the embedding ratio of the liposomes. RESULTS: Under optical microscope, PPT-DPPC liposome was observed to be composed of spherical particles with diameter range of 2.05 to 0.825 microm (average 1.45 microm). The diameter range of the particles of PPT-soya lecithin liposome is 7.59 to 1.445 microm (average 3.78 microm). PPT-DPPC liposome appeared multivesicular under electron microscope, with the embedding ratio of 73.8%, and 79.1% for PPT-soya lecithin liposome (n=3). PPT-DPPC liposome had a embedding ratio of 65.2%, 58.8% and 56.4% after preserved 1, 3, 6 months respectively. As for PPT-soya lecithin liposome, the embedding ratios were 70.3%, 60.4%, and 51.3% respectively. CONCLUSION: The PPT in the liposomes prepared by reverse phase evaporation technique is evenly distributed throughout the gel. The preparation is relatively simple with high embedding ratio.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Experimental podophyllotoxin (bajiaolian) poisoning: I. Effects on the nervous system.

Bajiaolian, one of the species in the Mayapple family (Podophyllum pelatum), has been widely used as a traditional Chinese herbal medicine for the remedies of snake bites, general weakness, poisons, condyloma accuminata, lymphadenopathy, and certain tumors in China. In Western medicine, Podophyllum was first used medically as a laxative in the early 19th century. Since 1940, the resin of podophyllum has also been used topically for various skin lesions, such as warts and condyloma. Human poisonings have been reported. An animal model was established to investigate the neurotoxic effects of Bajiaolian. Podophyllotoxin, the major active ingredient in Podophyllum, was injected (ip) to young adult male rats at doses of 0, 5, 10, or 15 mg.kg-1 b.w.. The animals were sacrificed 72 h after injection. Neuronal changes were readily observable in animals treated with 10 or 15 mg.kg-1 of the toxin. Edematous changes of the anterior horn motoneurons were observed in the spinal cord. No neuronal necrosis was found. The type of neuronal swelling is believed to be only a transient change and would probably subside with time if no further assaults occur. More serious and perhaps longer term of changes were found in the dorsal ganglion neurons and the nerve fibers (axons) in the central and peripheral nervous system. Severe depletion of the Nissl substance (RNA/polyribosomes) was observed in the dorsal root ganglion neurons. Alterations in these sensory neurons would give rise to and correlate with the sensory disturbances experienced by the patients. Bodian staining also revealed a dose-related increase in the coarseness (thickness) of the nerve fibers (axons) in the cerebellum, cerebral cortex, brainstem, and spinal cord. This is the first scientific study showing the neurotoxicity of Bajiaolian, a commonly used Chinese herbal medicine. Toxicities on other organ systems by this drug certainly exist. Caution should be exercised in the dispensing and usage of this medicine.

Animals↗
PubMed2004

[Preparation and characterization of podophyllotoxin-dipalmitoylphosphatidylcholine proliposome].

OBJECTIVE: To prepare podophyllotoxin-dipalmitoylphosphatidylcholine (PPT-DPPC) proliposomes (PPT-DPPC-PL) for improvement of the stability of PPT-DPPC liposome. METHODS: Freeze-drying method was used to prepare PPT-DPPC-PL, and the particle morphology, size range, encapsulation efficiency and stability of PPT-DPPC liposome were investigated. RESULTS: After hydration of PPT-DPPC-PL, PPT-DPPC liposome appeared multivesicular under electron microscope and the particles were distributed homogeneously with an average particle size of 1.45+/-0.38 microm. The encapsulation efficiency of PPT was 72.3%, and after storage at 4 to 40 degrees Celsius; for 1 to 6 months, the proliposome remained stable. CONCLUSION: The prepared PPT-DPPC-PL particles by freeze-drying method are evenly distributed. The preparation method is relatively simple with higher embedding ratio and better stability.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

[Spectral study of podophyllotoxin and its derivatives].

In this paper, we have studied all kinds of static absorption spectra and transient absorption spectra of podophyllotoxin and its derivatives. We have located the site of absorption spectra and their forming mechanism with spectrofluorometry, Ultraviolet, pulse radiolysis and laser photolysis, and suggested the connection of their structrue with their anti-tumour and toxicity.

Antineoplastic Agents↗
PubMed2005

Cytotoxic activity of a podophyllotoxin-like lignan from Linum tauricum Willd.

The present study describes the preliminary evaluation of the cytotoxic activity of a podophyllotoxin-like compound 4'-demethyl-6-methoxypodophyllotoxin (4'-DM-6-Mptox), isolated as one of the main lignans of Linum tauricum Willd. ssp. tauricum. The cytotoxic effects 4'-DM-6-Mptox were assessed by the MTT-dye reduction assay against the human leukemic cell lines HL-60, BV-173 and LAMA-84. DNA-fragmentation analysis and NF-kB inhibition assay were performed in order to elucidate some of the mechanistic aspects of the cytotoxic action of the investigated compound. 4'-DM-6-Mptox was found to exert prominent cytotoxicity, with IC50 values being several-fold lower than those of the referent antineoplastic agent etoposide. The DNA-fragmentation analysis revealed that 4'-DM-6-Mptox treatment triggered apoptosis in BV-173 and HL-60 cells. In our hands 4'-DM-6-Mptox was found to induce concentration-dependent NF-kB inhibition in HeLa cells as assessed by the IL-6 luciferase gene reporter assay, which though not quite prominent, at least partly contributes to the cytotoxic potential of the tested lignan. On the basis of the results obtained it could be concluded that 4'-DM-6-Mptox necessitates further pharmacological and toxicological evaluation as a possible chemotherapeutic agent. Furthermore due to its relatively high concentrations in the described plant source the possibility for its use as a precursor for the semisynthetic production of lignan-based drugs, could be considered.

Antineoplastic Agents, Phytogenic↗
PubMed2006

L-carnitine inhibits apoptotic DNA fragmentation induced by a new spin-labeled derivative of podophyllotoxin via caspase-3 in Raji cells.

L-carnitine (beta-hydroxy-trimethylaminobutyric acid) plays an essential metabolic role that consists of transferring the long chain fatty acids through the mitochondrial barrier, thus allowing their energy-yielding oxidation. GP7 (4-[4''-(2'', 2'', 6'', 6''-tetramethyl-l''-piperidinyloxy) amino] -4'-demethyl-epipodophyllotoxin) is a new spin-labeled derivative of podophyllotoxin semi-synthesized by our university. In this study, we examined the activity of L-carnitine in GP7-induced apoptosis in Burkitt's lymphoma cell line, Raji. GP7 induced time- and dose-dependent apoptotic DNA fragmentation accompanied by caspase-3 activation in Raji cells, and the kinetics of caspase-3 activation induced by GP7 was well correlated with that of apoptotic DNA fragmentation. L-carnitine treatment prevented GP7-induced caspase-3 activation, suppressed caspase-3 cleavage and abrogated GP7-induced apoptotic DNA fragmentation in Raji cells. Our findings suggest that L-carnitine is a potent anti-apoptotic agent to human lymphoma cells and may exert its anti-apoptotic effect via inhibition of caspase-3 activity in GP7-treated Raji cells.

Apoptosis↗
PubMed1991

Metal- and photo-induced cleavage of DNA by podophyllotoxin, etoposide, and their related compounds.

Podophyllotoxin (PD) and its derivative etoposide (VP-16), a clinically useful anticancer drug, exhibit different mechanisms of action. PD binds specifically to tubulin to prevent its polymerization, whereas VP-16 lacks this action. The DNA strand breakage caused by VP-16 is thought to be due to its interaction with topoisomerase II or to free radical formation by oxidation of its 4'-phenolic hydroxyl group to a semiquinone free radical. We have demonstrated that PD, VP-16, 4'-demethylepipodophyllotoxin (DEPD), and syringic acid (SA) exhibit no DNA-cleaving activity but, in the presence of metal ions such as Cu2+ and Fe3+, DEPD and SA form metal complexes, which in turn show high activity for DNA strand scission at pH 7.8 under air. Furthermore, it was found that DNA cleavage was greatly promoted by irradiation with UV light. The PD-Fe3+ system at pH 7.8 showed very low DNA-cleaving activity, but irradiation with UV light in the system induced almost complete DNA breakage. DNA cleavages were significantly inhibited in the presence of hydroxyl radical scavengers, such as sodium benzoate and dimethylurea, in the Cu(2+)-SA and Fe(3+)-PD systems, with or without UV irradiation. These reactions were investigated by optical and ESR spectra, coupled with ESR spin-trapping techniques, by which the formation of hydroxy radicals was clearly detected in all systems. These findings have led us to a new proposal of the metal- and photo-induced mechanism for understanding the antitumor action of PD, VP-16, and their related compounds.

DNA↗
PubMed1987

Spin-labeled antitumor derivatives of podophyllotoxin.

Three spin-labeled antitumor derivatives of podophyllotoxin, containing an iminoxyl radical, have been synthesized. Preliminary pharmacological tests showed that these derivatives have significant antitumor activity in several experimental tumor systems with a marked decrease in toxicity compared with the parent compound. The relative intensities of ESR signals of these spin-labeled compounds were linearly proportional to their concentrations, the levels of the agent in blood and organs of mice or rabbits can be measured via ESR spectrometry.

Animals↗
PubMedDate not supplied

Inhibition of ConA-induced proliferative response in human lymphocytes by podophyllotoxin and a detergent, Tween80.

Podophyllotoxin (CPH86), at concentrations of 5 ng/ml or more, inhibited [3H]-thymidine uptake of ConA-induced proliferation of human peripheral mononuclear blood cells. Tween80, the detergent included in the anti-inflammatory drug Proresid, containing podophyllum lignan derivatives, also inhibited lymphocyte proliferation in a dose-dependent manner. Combination of the two drugs did not, or did only weakly, potentiate the inhibitory effect of each drug.

Concanavalin A↗
PubMed1987

Mitochondrial binding of a protein affected in mutants resistant to the microtubule inhibitor podophyllotoxin.

Specific antibodies to a protein P1 Mr approximately equal to 63,000) from Chinese hamster ovary cells, which is affected in mutants resistant to the microtubule inhibitor, podophyllotoxin, and behaves like a microtubule-related protein by certain criteria [14], have been raised. The antibody reacts specifically with the P1 protein in one- and two-dimensional immunoblots, and a cross-reacting protein of similar molecular mass and electrophoretic mobility is also found in cells from various vertebrate and invertebrate species. The observed similarity in the peptide maps of the cross-reacting protein from human, mouse, Chinese hamster and chicken cells indicates that the structure of this protein should be highly conserved. However, no P1-antibody cross-reacting protein was observed in plants (corn, mung), fungus (Neurospora crassa), yeast (Saccharomyces cerevisiae) and bacteria (Escherichia coli and Salmonella typhimurium). Immunofluorescence studies with the P1-antibody show that, in interphase cells of various cross-reacting species, it bound specifically to mitochondria which were associated and distributed on and along the length of microtubules. Similar association and codistribution of mitochondria and microtubules were not observed in mitotic cells. Some implications of the mitochondrial localization of the protein P1 and the observed association between microtubules and mitochondria are discussed.

Actin Cytoskeleton↗
PubMed1987

Podophyllotoxin analogues: synthesis and computer modelling investigation of structure-activity relationships.

The conformations of four 2-substituted-4-deoxy-analogues of podophyllotoxin have been studied using data obtained from X-ray structure determinations and molecular modelling studies. In these, root mean square differences between these structures and those of the cytotoxic agents 6'-bromopodophyllotoxin and colchicine were determined. Attempts have been made to correlate structure with the available biological activity data.

Antineoplastic Agents↗
PubMedDate not supplied

Complement activating rheumatoid factors in rheumatoid arthritis studied by haemolysis in gel: relation to antibody class and response to treatment with podophyllotoxin derivatives.

Complement (C) activating rheumatoid factors (RF) were measured in 16 patients with rheumatoid arthritis (RA) by a simple haemolysis in gel (HIG) assay. IgM-RF, but not IgG-RF or IgA-RF, measured by an enzyme linked immuno-sorbent assay, were closely correlated with C activating RF (r = 0.86). In neither assay did the concentrations of RF appear to be directly related to C1 activation as expressed by serum concentrations of C1r-C1s-C1 inactivator complexes or of C4. In the sera, C1q binding substances, measured by C1q binding assay, were markedly correlated with C activating RF (r = 0.88), whereas C1q binding substances detected by the C1q deviation test were not. Treatment with podophyllotoxin derivatives for 6 months clearly reduced patients' RF concentrations. The decrease of IgG-RF, IgA-RF and IgM-RF was significantly more pronounced than that of the IgG, IgA and IgM concentrations, respectively.

Adult↗
PubMed1982

Glycosylated podophyllotoxin congeners: loss of microtubule inhibition and permission of invasion in vitro.

Podophyllotoxin (PPT) and its glycosylated congeners, 4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-beta-D-glucopyranoside] (VP-16-213) and 4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-thenylidene-beta-D-glucopyranoside] (VM-26), were studied for their effects on the following activities of MO4 mouse fibrosarcoma cells in vitro: growth as an aggregate in culture on a gyrotory shaker, directional migration from an aggregate explanted on glass, organization of the cytoplasmic microtubule complex as inferred from immunostaining with an antiserum against tubulin, and invasion into fragments of 9-day-old embryonic chick cardiac muscle. At concentrations that inhibited growth (greater than or equal to 0.03 microgram/ml), PPT arrested directional migration, abolished the cytoplasmic microtubule complex, and interfered with invasion. VM-26 (0.1-1.0 microgram/ml) and VP-16-213 (1-30 micrograms/ml) interfered with growth but permitted directional migration, organization of the cytoplasmic microtubule complex, and invasion. These observations imply that microtubule inhibitors are anti-invasive because they interfere with the assembly of the cytoplasmic microtubule complex and not because they inhibit growth.

Animals↗