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At least 163 records · Page 9Linked to original sources
PubMed1981

Podophyllotoxin resistance: a codominant selection system for quantitative mutagenesis studies in mammalian cells.

Mutants resistant to the microtubule inhibitor podophyllotoxin (PodR), a codominant marker, can be readily selected in various mammalian cell lines such as, CHO, HeLa, mouse L cells, Syrian hamster cells (BHK21) and a mouse teratocarcinoma cell line OC15. In CHO cells, the recovery of PodR mutants is not affected by cell density (up to 1 X 10(6) cells per 100-mm diameter dish), and after treatment with the mutagen ethyl methanesulfonate maximum mutagenic effect is achieved after a relatively short expression time (40-48 h). The frequency of PodR mutants in various cell lines increased in a dose-dependent manner in response to treatment with the mutagens ethyl methanesulfonate and N-methyl-N'-nitro-N-nitrosoguanidine. The PodR selection system thus provides a new genetic marker which should prove useful in studies of quantitative mutagenesis in mammalian cells.

Animals↗
PubMed1987

Purified podophyllotoxin (CPH-86) inhibits lymphocyte proliferation but augments macrophage proliferation.

Purified podophyllotoxin (CPH-86) is an inhibitor of microtubular aggregation used in the treatment of cancer, psoriasis and rheumatoid arthritis. To better understand its immunopharmacology we examined its effects on human lymphocytes and monocytes and guinea pig macrophages. CPH-86 inhibits mitogen-induced human lymphocyte proliferation and macrophage growth factor-stimulated macrophage proliferation with ID50s of approximately 10(-7) M. The effect of CPH-86 on lymphocytes in conjunction with mitogen is nonlethal, evident during the early but not the late phases of proliferation, and associated with early increases in cyclic AMP levels. In contrast to these obviously inhibitory effects, CPH-86 (10(-7) M) alone induces IL-1 by human monocytes and, with mitogen, it induces IL-2 production by human lymphocytes. It directly stimulates macrophage proliferation and potentiates the effects of low doses of macrophage growth factor to do so. The latter effects may be mediated by colony stimulating factor production. The effects of CPH-86 are not mediated by inhibition of prostaglandin synthesis. The stimulation of monokine and lymphokine production by CPH-86 may represent positive features of its action and may be immunotherapeutic.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Analysis of drug-tubulin interaction by trypsin cleavage: comparison for colchicine, podophyllotoxin, griseofulvin, vinblastine and taxol.

Trypsin preferentially cleaves the alpha subunit of depolymerized tubulin or vinblastine induced aggregates (in which longitudinal interactions between tubulin molecules could take place). No cleavage was found for tubulin polymerized into microtubules (containing lateral and longitudinal tubulin interactions), in the presence of taxol. In the presence of colchicine or podophyllotoxin the alpha subunit was partially protected from proteolytic digestion. Trypsin digestion pattern varied upon the addition of different concentrations of griseofulvin. At the higher concentration used, in which microtubules assembly was inhibited, both tubulin subunits were cleaved.

Alkaloids↗
PubMed1993

Determination of the new podophyllotoxin derivative NK 611 in plasma by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatographic method has been developed for the determination of the new podophyllotoxin derivative NK 611 in plasma samples. A solid-liquid extraction procedure with C18 extraction columns was used for extraction of plasma samples containing NK 611. The adsorbed NK 611 was eluted from the extraction columns with methanol-acetonitrile (50:50, v/v). The elution liquid was injected into a reversed-phase system consisting of a Chrompack C18 column. The mobile phase was acetonitrile-20 mM phosphate buffer, pH 7 (30:70, v/v). The UV detection mode allows sensitive determination of NK 611 in plasma within phase I trials. The limit of detection was 10 ng/ml, the limit of quantitation 35 ng/ml (for 1 ml of extracted plasma and 20-microliters injection volume). The calibration curve is linear within the concentration range 100-1000 ng/ml. The recovery of NK 611 from spiked plasma samples was approximately 80%.

Antineoplastic Agents↗
PubMed2006

Synthesis and cytotoxic evaluation of C-9 oxidized podophyllotoxin derivatives.

A series of podophyllotoxin and podophyllic aldehyde derivatives, lacking the lactone ring and oxidized at C-9 position, has been prepared. The functionalities considered at C-9 were carboxylic acids and several derivatives such as esters, amides, nitriles or anhydrides. The synthesized compounds were cytotoxic at the micromolar level, though less potent and selective than the parent compounds, revealing the influence of the C-9 electrophilic character on the potency and selectivity of these cyclolignans.

Aldehydes↗
PubMed2003

Synthesis, cytotoxicity and antiviral activity of podophyllotoxin analogues modified in the E-ring.

Several podophyllotoxin derivatives modified in the E-ring were prepared and evaluated for their cytotoxicity on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28) and for their antiherpetic activity against Herpes simplex virus type II. The trimethoxyphenyl moiety was oxidized to ortho-quinone and further condensed with diamines and enamines to form different heterocycles. Most of the compounds maintained their cytotoxicity at the muM level and some of them showed antiherpetic activity.

Animals↗
PubMed2005

Podophyllotoxin-loaded solid lipid nanoparticles for epidermal targeting.

The purpose of this study was to evaluate solid lipid nanoparticles as the topical carrier for epidermal targeting of podophyllotoxin (POD). The high pressure homogenization was employed to prepare drug-loaded solid lipid nanoparticles. The POD-loaded SLN stabilized by 0.5% poloxamer 188 and 1.5% soybean lecithin (P-SLN) and 2% polysorbate 80 (T-SLN) was characterized by photon correlation spectroscopy (PCS). P-SLN showed an average diameter of 73.4 nm and a zeta potential of -48.36 mV. The imaging of AFM indicated that the P-SLN had a spherical shape. DSC and X-ray diffraction analysis showed that POD was dispersed in SLN in an amorphous state. The in vitro permeation study showed that P-SLN increased the accumulative amount of POD in porcine skin 3.48 times over 0.15% tincture. But T-SLN with a diameter of 123.1 nm and a zeta potential of -17.4 mV did not show a high accumulative amount of POD when compared with P-SLN, though both P-SLN and T-SLN could avoid the systemic uptake of POD. Because of the fluorescence property of POD, fluorescence microscopy imaging was employed to visualize the penetration of POD into skin from SLN. The penetration of POD from P-SLN seemed to follow two pathways along the stratum corneum and hair follicle route. The imaging revealed that P-SLN had a strong localization of POD within epidermis. The penetration of P-SLN with low particle size into stratum corneum along the skin surface 'furrow' and the consequent controlled release of POD might lead to the epidermal targeting. P-SLN provides a good epidermal targeting effect and may be a promising carrier for topical delivery of POD.

Animals↗
PubMed2005

Apoptosis induced by one new podophyllotoxin glucoside in human carcinoma cells.

4-Demethyl-picropodophyllotoxin 7'-O-beta-D-glucopyranoside (4DPG), a new podophyllotoxin glucoside, was isolated from the rhizomes of Sinopodophyllum emodi (Wall.) Ying and showed cytotoxic effects in human carcinoma cells. Among the target cells (HeLa, A2 and SH-SY5Y), the cytotoxic effects of 4DPG showed dose- and time-dependency. Furthermore, the cervical carcinoma cell line, HeLa, was more sensitive to 4DPG. Flow cytometric analysis demonstrated the presence of apoptotic cells with low DNA content, a decrease of cell population at the G1 phase, and a concomitant increase of cell population at the G2/M phase. 4DPG also caused DNA fragmentation in HeLa cells. Treatment with 0.1 microM 4DPG increased p53 expression and Bax/Bcl-2 ratio in HeLa cells, as well as in A2 cells. These results suggested that 4DPG-induced apoptosis might be through a p53-dependent pathway.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Antitumor and antioxidant activity of spin labeled derivatives of podophyllotoxin (GP-1) and congeners.

The spin labeled derivative of podophyllotoxin, i.e. podophyllic acid-[4-(2,2,6,6,-tetramethyl-1-piperidyloxy)] hydrazone (GP-1,2) and its congeners (GP-1-OH,3, GP-1-H, 4) were synthesized. The inhibition activity to the transplanted tumor S180 and HepA and the LD50 values of these compounds in mice were tested. Their partition coefficients and pKa values were measured. The results showed that the anticancer activity of these compounds followed the order GP-1 >GP-1-OH> GP-1-H. It can be attributed to the influence of their partition coefficients and ionization constants to the compounds properties. Meanwhile, the antilipoperoxidative activities of GP-1, GP-1-OH and GP-1-H to MDA formation of liver homogenate of rat induced by Fe2+-ascorbic acid were measured. Electrochemical studies were carried out to measure the redox midpoint potentials. The relationship between the redox midpoint potentials and the antilipoperoxidative activity followed the same order as the antitumor activity. The EPR (Electron Paramagnetic Resonance) spectroscopy of the blood from carotid artery of anesthetized Wistar rat in vivo was measured. The results indicated that there is an equilibration between GP-1 and GP-1-OH, furthermore, GP-1-H can be oxidized partly to GP-1 and equilibrated with GP-1-OH in vivo. The EPR signal intensity of GP-1 is stronger than GP-1-OH and GP-1-H. It can be concluded that the oxidative state of nitroxide in compounds play a key role to the antioxidant activity.

Animals↗
PubMed1997

Synthesis and antitumor activity of spin labeled derivatives of podophyllotoxin.

Three new nitroxyl labeled derivatives of podophyllotoxin 4-6 have been synthesized and evaluated for their antitumor activity in vitro. Compounds 4-6 showed significant inhibitory activity against human nasopharyngeal carcinoma KB,lung cancer A549 and stomach carcinoma SGC-7901 cells, as well as mouse leukemia L1210 and P388 cells. Compounds 4 and 5 exhibited comparable or superior activity to clinically used etoposide (VP-16,2) in their inhibition of these cell lines.

Animals↗
PubMed1997

New spin labeled analogues of podophyllotoxin as potential antitumor agents.

Four new nitroxyl labeled derivatives of podophyllotoxin, 4-(2, 2, 6, 6-tetramethyl-1-oxyl-4-piperidyl)oxy-epipodophyllotoxin (4), 4-(2, 2, 6, 6-tetramethyl-1-oxyl-4-piperidyl)oxy-4'-demethylepipodophyllotoxin (5), 4-(2, 2, 5, 5-tetramethyl-1-oxyl-3-pyrrolinyl)formyloxy-epipodophyllotox in (6) and 4-(2, 2, 5, 5-tetramethyl-1-oxyl-3-pyrrolinyl)formyloxy-4'-demethylep ipodophyllotoxin (7), have been synthesized and evaluated for their antitumor activity in vitro. Compounds 5 and 7 showed superior activity to clinically used etoposide (VP-16,2) in their inhibition of leukemia P388, lung cancer A549 and stomach carcinoma SGC-7901 cells. 4'-Demethyl-epipodophyllotoxins 5 and 7 was found to be more active than eipodophyllotoxins 4 and 6 lacking a free phenolic hydroxyl group at C-4'.

Animals↗
PubMed2003

Synthesis and cytotoxicity of podophyllotoxin analogues modified in the A ring.

Several podophyllotoxin derivatives lacking the methylenedioxy group or with different functionalization of the A-ring of the cyclolignan skeleton have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28). Most of them maintained their cytotoxicity at the microM level.

Animals↗
PubMed1998

Discovery of podophyllotoxins.

This review deals with the historical discovery of particularly important lignan derivatives used in cancer chemotherapy. From isolation of the naturally occurring podophyllotoxin, an inhibitor of microtubule assembly, to hemisynthesis of the clinically important anticancer drugs etoposide and teniposide, it will be demonstrated how the activities and the ability of this class of compounds to inhibit topoisomerase II were discovered by different research teams. By virtue of these discoveries, new hemisynthetic derivatives, with different mechanisms of action, are bringing improvements in the ability to treat cancer.

Animals↗
PubMed2000

4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: simple aza-podophyllotoxin analogues possessing potent cytotoxicity.

4-Aza-2,3-dehydro-4-deoxypodophyllotoxin analogues 3a-n were synthesized through quinolines 2a-n. Comparison of their cytotoxicity against P-388 leukemia cells revealed that the steric effects of the ring B substituents on the activity are greater than the electronic effects, while the presence of a methoxy group on the ring E is not essential to exhibit potent cytotoxicity. Analogues 3a and 3b proved to be more than twice as cytotoxic as natural podophyllotoxin (1).

Antineoplastic Agents, Phytogenic↗
PubMed1986

Antitumor agents. 78. Inhibition of human DNA topoisomerase II by podophyllotoxin and alpha-peltatin analogues.

It has been reported that the action of etoposide (VP-16) (14) as an antitumor agent is mediated through its interaction with DNA topoisomerase II which results in DNA breakage inside the cell. In order to understand the mechanism of action as well as structure-activity relationships of 14, several novel, synthetic and some naturally occurring analogues related to podophyllotoxin were examined for inhibition of the DNA topoisomerase II activity. Compound 2 exhibited enhanced activity and compound 5 slightly diminished activity relative to 14. A 4 beta-substituted ether at the C ring and O-demethylation at the E ring appear to enhance activity.

Antineoplastic Agents, Phytogenic↗
PubMed1977

Nonenolizable podophyllotoxin derivatives.

To block epimerization and the resulting biological deactivation podophyllotoxin compounds, the lactone carbonyl group has been changed to methylene. Syntheses of several of these delactonized derivatives are described, all with modifications in the original lactone ring and some without the 4-hydroxyl group. Several biological assays show that most of the nonenolizable derivatives retain activity.

Animals↗