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At least 19 recordsLinked to original sources

PubMed1991

Properties of bromodextran-trichosanthin: a comparison with trichosanthin, an anti-AIDS protein.

Trichosanthin was coupled with bromodextran and the reaction mixture chromatographed on Sephadex G-75 fine to yield two peaks. The first peak was judged to be bromodextran-trichosanthin by SDS-polyacrylamide gel electrophoresis. The yield was optimal when 4% trichosanthin and 8% bromodextran T20 were reacted for 210 hours. Bromodextran-trichosanthin exhibited an ultraviolet absorption spectrum similar to that of free trichosanthin and the complex reacted positively with the trichosanthin antiserum. It had lower abortifacient and protein synthesis inhibiting activities but it also possessed lower allergenicity, suggesting that it may be useful as a substitute of trichosanthin, especially when the problem of hypersensitivity caused by prolonged administration of trichosanthin is serious.

Abortifacient Agents↗

PubMed1990

Primary amino acid sequence of alpha-trichosanthin and molecular models for abrin A-chain and alpha-trichosanthin.

Ricin A-chain, abrin A-chain, and alpha-trichosanthin are members of a larger group of proteins called ribosome-inactivating proteins. These proteins all function to catalytically inactivate eukaryotic 60 S ribosomal subunits leading to rapid shutdown of protein synthesis. They are homologous in sequence and are probably evolutionarily related. We have determined the complete primary amino acid sequence of alpha-trichosanthin and have found it to be homologous, as expected, to that of abrin A-chain and ricin A-chain. A crystal structure for ricin, which includes ricin A-chain and ricin B-chain, has been determined from x-ray diffraction data. Based on the sequence homologies of these proteins, we fit the primary sequences of abrin A-chain and alpha-trichosanthin to the backbone structure for ricin A-chain and have generated energy-minimized molecular models for them. These models should prove useful in studying the structural-functional relationships of these proteins in particular and of the class in general.

Abrin↗

PubMed1991

Purified trichosanthin (GLQ223) exacerbation of indirect HIV-associated neurotoxicity in vitro.

A formulated preparation of trichosanthin (GLQ223, Pharmaceutical Development Group, Genelabs Inc., Redwood City, California, USA) has been shown to selectively inhibit HIV replication in vitro in lymphocytes and macrophages. In view of recent anecdotal reports of central nervous system (CNS) complications associated with trichosanthin use in some HIV-infected patients, we evaluated any potential drug effects leading to neurotoxicity using a human brain cell aggregate model. Brain cell aggregate cultures were incubated with dilutions of purified trichosanthin alone (trichosanthin), supernatants of HIV-infected macrophage cultures (S-HIV), supernatants of uninfected macrophage cultures (S-U), supernatants of purified trichosanthin-treated uninfected macrophage cultures (S-trichosanthin), or supernatants of purified trichosanthin-treated HIV-infected macrophage cultures (S-HIV-trichosanthin). Treatment with purified trichosanthin alone at up to 2 micrograms/ml, with S-U or with S-trichosanthin, produced no morphological signs of toxicity to brain cell aggregate cultures. S-trichosanthin treatment at 2 micrograms/ml did not result in a significant change in cyclic nucleoside phosphorylase (CNP) activity. Treatment of the brain aggregates with S-HIV and S-HIV-trichosanthin did, however, result in morphological alteration of the brain aggregates, with S-HIV-trichosanthin-treated brain aggregates showing the most severe damage. Although purified trichosanthin did not appear to be directly toxic to human brain aggregate cultures, trichosanthin treatment of infected macrophages may have increased the morphological alterations caused by supernatants of HIV-infected macrophages. These experimental observations may explain anecdotal reports of adverse CNS reactions in association with trichosanthin treatment of HIV-infected patients and emphasize the neurotoxic potential of any therapy targeted at HIV-infected macrophages.

Brain↗

PubMed1991

Increasing the plasma half-life of trichosanthin by coupling to dextran.

Trichosanthin (TCS) is a plant protein which has a wide spectrum of pharmacological activities. It was demonstrated recently that this compound suppressed the replication of human immunodeficiency virus (HIV-1) in vitro. The mechanism of action is believed to be inhibition of protein synthesis. Trichosanthin is a low molecular weight protein which is expected to be easily filtered and eliminated through the kidney. To minimize renal loss, the molecular size of trichosanthin can be increased by coupling to dextran. The larger complex will not undergo glomerular filtration and therefore renal loss can be prevented. This study investigates the kidney's role in trichosanthin elimination and the beneficial effect afforded by coupling to dextran in prolonging plasma half-life. For this purpose, a radioimmunoassay has been developed to determine the concentration of TCS in plasma and urine. The sensitivity of this assay is in the nanogram range. Trichosanthin was coupled to dextran T40 by a dialdehyde method and successful coupling was confirmed by gel filtration chromatography. The complex retained specific binding to trichosanthin antibodies with decreased affinity which can be partially reversed after incubation with dextranase; an enzyme that digested dextran. The pharmacokinetics of intravenously administered trichosanthin (0.75 mg/kg) was compared between two groups of rats with normal and impaired renal function (bilateral renal arterial ligation). Rats with ligation showed a decrease in plasma clearance from 4780 +/- 570 to 220 +/- 20 microL/min and an increase in the mean residence time from 9 +/- 1 to 145 +/- 16 min. Despite the several-fold difference in these parameters, recovery of trichosanthin from normal rat urine was only 0.38 +/- 0.05%. This value can be increased by using higher injection doses. The data indicate that the kidney is an important organ for the elimination of trichosanthin. When the dextran-trichosanthin complex was injected into normal rats trichosanthin activity was not detected in the urine. All the pharmacokinetic parameters suggest that the dextran-trichosanthin complex stayed longer in the body and maintained a much higher plasma concentration than trichosanthin.

Animals↗

PubMed1991

Trichosanthin, a potent HIV-1 inhibitor, can cleave supercoiled DNA in vitro.

Trichosanthin, an abortifacient, immunosuppressive and anti-tumor protein purified from the traditional Chinese herb medicine Tian Hua Fen, is a potent inhibitor against HIV-1 replication. Under normal enzymatic digestion conditions, trichosanthin cleaves the supercoiled double-stranded DNA to produce nicked circular and linear DNA. Trichosanthin has no effect on linear double-stranded DNA. Neither does it convert relaxed circular duplex DNA into a supercoiled form in the presence of ATP. Thus trichosanthin is not a DNA gyrase. However, trichosanthin can cleave the relaxed circular DNA into a linear form, indicating that both the circular as well as the supercoiled forms are essential for trichosanthin recognition. In addition, trichosanthin contains one calcium metal ion per protein molecule, which presumably is related to its endonucleolytic activity.

Calcium↗

PubMed1992

The mechanism of action of trichosanthin on eukaryotic ribosomes--RNA N-glycosidase activity of the cytotoxin.

Trichosanthin is a ribosome-inactivating protein from root tubers of Trichosanthes kirilowii Maxim. In this paper, the mechanism of action of trichosanthin on eukaryotic ribosomes was studied. A fragment of about 450 nucleotides was released from 28S ribosomal RNA after treatment of rat liver ribosome with trichosanthin and its isolated ribosomal RNAs were treated with aniline. Analysis of nucleotide sequence of 5' terminus of this fragment revealed that the aniline-sensitive site of the phosphodiester bond was between positions A4324 and G4325 in the 28S rRNA. Adenine was recovered by ion-exchange column chromatography from the 50% ethanol soluble fraction of the reaction mixture in which rat liver ribosomes were treated with trichosanthin. Thin-layer chromatographic analysis indicated that 1 mol of adenine was released from 1 mol of ribosomes. When the ribosomes were incubated with trichosanthin in the presence of inorganic [32P]phosphate, little incorporation of radioactivity into 28S rRNA was observed, indicating that the release of adenine was not mediated by phosphorolysis. These results demonstrate that trichosanthin inactivates the ribosomes by cleaving the N-C glycosidic bond of adenylic acid at 4324 of 28S rRNA in a hydrolytic fashion.

Adenosine Monophosphate↗

PubMed1987

Beta-trichosanthin: a new abortifacient protein from the Chinese drug, wangua, Trichosanthes cucumeroides.

beta-Trichosanthin was a new abortifacient protein purified from the Chinese drug, Wangua, root tubers of Trichosanthes cucumeroides (Cucurbitaceae). The purification procedure involved acetone fractionation, ammonium sulfate precipitation, ion-exchange chromatography on CM-Sepharose and preparative agarose electrophoresis. Homogeneity of beta-trichosanthin was demonstrated in immunoelectrophoresis, agarose electrophoresis and SDS-polyacrylamide gel electrophoresis. It had a molecular weight of 28,000 and no cysteine in its molecule. It differed from trichosanthin, a known abortifacient protein isolated from a related Chinese drug, Tianhuafen, root tubers of Trichosanthes kirilowii (Cucurbitaceae), in molecular weight, carbohydrate content, charge and amino acid composition. beta-Trichosanthin was, however, immunochemically identical to trichosanthin and was about twice as potent as trichosanthin in inducing mid-term abortion in mice.

Abortifacient Agents↗

PubMed1979

Induction of mid-term abortion by trichosanthin in laboratory animals.

Trichosanthin, a protein purified from the extract of the root tuber of Trichosanthis Kirilowii, Maxim, given once only induced midterm abortion in the mice and rabbits. The effective I.P. dose for the induction of abortion in 10- or 11-day pregnant mouse was 50 micrograms. In the rabbit a dose and state of pregnancy-dependent response to Trichosanthin-induced abortion was encountered. A dose as low as 0.5 mg Trichosanthin in 22-day pregnant rabbit was adequate but 2.0 mg was needed in 17-day pregnant rabbit. Attempts to terminate pregnancy in the rat and hamster using Trichosanthin was not successful even with higher doses. When compared with prostaglandin-F2 alpha, an established abortifacient, Trichosanthin appeared to be more effective and associated with less side effects in the induction of abortion in the rabbit. Trichosanthin was ineffective to terminate early pregnancy in the 4 species studied.

Abortifacient Agents↗

PubMed1979

Termination of pregnancy in rabbit and mouse by Trichosanthin.

The effects of a single intraperitoneal injection of Trichosanthin in 6-, 10-, 17- or 22-day pregnant rabbit (2 mg/rabbit) or in 11-day pregnant mouse (50 micrograms/mouse) were studied. Trichosanthin induced abortion in 100% of the 17- or 22-day pregnant rabbits within 48-72 hours and decreased circulating progesterone (delta 4P)concentrations with 24 hrs. On the other hand, the same dose failed to terminate pregnancy in 6- or 10-day pregnant rabbits and caused no significant changes in circulating delta 4P levels. Exogenous delta 4P or prolactin + human chorionic gonadotropin given twice daily failed to reverse the Trichosanthin-induced termination of pregnancy. However, this resulted in a delay of fetal expulsion. It is concluded that Trichosanthin-induced termination of pregnancy is not solely a result of luteolysis but is likely to be due to its toxic effects on placenta, embryo or both. A dose of 50 microgram Trichosanthin given to 11-day pregnant mice resulted in a termination of pregnancy within 96 hours and also a significant decrease in delta 4P levels in 24 hrs. The ratio of delta 4P to 20 alpha-dihydroprogesterone was also decreased steadily after Trichosanthin administration.

20-alpha-Dihydroprogesterone↗

PubMed1986

Selective killing of choriocarcinoma cells in vitro by trichosanthin, a plant protein purified from root tubers of the Chinese medicinal herb Trichosanthes kirilowii.

Trichosanthin is an abortifacient plant protein purified from the Chinese medicinal herb Tian-hua-fen, obtained from root tubers of Trichosanthes kirilowii (Cucurbitaceae). Recently, trichosanthin has also been used in the treatment of trophoblastic tumours, including hydatidiform mole, invasive mole and choriocarcinoma. We have examined the effects of trichosanthin on cultured cells and observed selective cytotoxic effects on choriocarcinoma cells. Mouse melanoma cells were also sensitive to its cytotoxic action. Cytotoxic effects on cultured cells were usually not prominent after 24 hr treatment. Continued incubation for 48 hr in control culture medium after treatment with trichosanthin enhances the cytotoxicity on cells. Our findings suggest that trichosanthin exerts specific cytotoxic activity towards trophoblastic cells.

Animals↗

PubMed1987

Conformation similarities of ricin A-chain and trichosanthin.

The conformation of ricin A-chain from castor bean was studied by circular dichroism at pH 4.7, 7 and 9 and compared with that of trichosanthin from the Chinese herb Tianhuafen. The CD spectra of ricin A-chain and trichosanthin were nearly identical at each of the three pHs. Analysis of the data indicated that, like trichosanthin, ricin A-chain had about 29% alpha-helix and 42% beta-sheet but no beta-turn. However, there was a subtle difference in the CD spectra in 20 mM sodium dodecyl sulfate, the addition of which at pH 7 slightly increased the helicity and decreased the content of beta-sheet of ricin A-chain in contrast to a larger increase in helicity at the expense of beta-sheet for trichosanthin, thus indicating a different stability against the surfactant. Native ricin A-chain and trichosanthin had about the same amount of secondary structure, which supports the belief that a high degree of sequence homology of the two proteins [Zhang & Wang (1986) Nature 321, 477-478] may lead to a conformational similarity between them, even though the two proteins are not taxonomically related.

Abortifacient Agents, Nonsteroidal↗

PubMed1987

Purification and characterization of trichosanthin. Homology to the ricin A chain and implications as to mechanism of abortifacient activity.

Trichosanthin, a protein from the Chinese medicinal herb Trichosanthes kirilowii, was purified in two essentially quantitative steps involving CM-Sephadex chromatography and reverse-phase high performance liquid chromatography. The protein was found to have a molecular mass of 25-26 kDa, to contain no cysteine, and to contain no glycosidic linkages. Pure trichosanthin was found to have potent abortifacient activity in pregnant mice. In order to understand the molecular basis of this unique biological activity, we have examined the amino acid sequence of the protein. As purified, trichosanthin was found to contain two amino-terminal sequences which differed only in the absence or presence of a tyrosine at residue 1. Sequence analysis of trichosanthin has allowed for determination of the NH2-terminal 38-amino acid residues. Comparison of this sequence to those present in a data base revealed homology with the ricin A-chain. Consistent with this structural homology, we have found that trichosanthin is a potent inhibitor of protein synthesis in a reticulocyte lysate system.

Abortifacient Agents↗

PubMedDate not supplied

Studies on the mechanisms of abortion induction by Trichosanthin.

Radix trichosanthis, an abortifacient drug of mid-gestation, is extracted from the root tuber of Trichosanthes kirilowii Maxim, Cucurbitaceae. Its purified effective principle is a basic protein of molecular weight of approximately 18,000 and is named trichosanthin. By authorization it has been proved to be very effective in abortion induction of mid-gestation, particularly effective in curing ectopic pregnancy, hydatidiform mole, and invasive mole, and it has also some therapeutic action on choriocarcinoma. From the analysis of the experimental results on its initial site of action, the morphological and functional injury of trophoblast cells of placenta and of cultures in vitro and the effect on prostaglandin synthesis, the following conclusions are drawn concerning the mechanisms of abortion induction by trichosanthin: (1) Trichosanthin exerts its action directly on the placental trophoblasts and possesses a certain degree of specificity; (2) It selectively causes the necrotic denaturation of the syncytiotrophoblasts of placental villi, which makes fragments of the disintegrated cells clumped in the blood sinus, hence the coagulation of blood and the circulation hindrance, and tissue necrosis over large areas follows. The necrosis of placental villi is the primary response, and circulation hindrance secondary; (3) Structural injuries have been reflected on the impairment of functional activities; the concentrations of HCG and steroid hormones fall rapidly below the threshold values of threatened abortion. Serious structural and functional injuries bring about destructive disturbances on the normal endocrine relationship between the mother and the fetus and on metabolic exchanges. It is further postulated that through certain unknown mechanism the synthesis of prostaglandins increases, uterine contraction is initiated and abortion ensues. In summary, trichosanthin, a plant protein discovered from Chinese medicinal herbs, is a drug effective in abortion induction and against trophoblastic neoplasms. Preliminary elucidation of the mechanisms of abortion induction by trichosanthin has afforded a basis for the clinical application with better efficacy and its possible abortifacient use in early pregnancy and for the discovery of newer cancer chemotherapeutic agents.

Abortifacient Agents↗

PubMed1991

Toxicity and activity of purified trichosanthin.

Trichosanthin was purified from fresh Chinese root tubers of Trichosanthes kirilowii and evaluated for anti-HIV activity. Trichosanthin inhibited syncytium formation between infected H9 cells and uninfected Sup-T1 cells from 0.5 to 4 micrograms/ml. Trichosanthin also inhibited HIV replication in H9 and CEM-SS cells at 1 microgram/ml, but was toxic for MT-4 cells (HTLV-I-positive), at doses greater than 0.25 microgram/ml. This new purification procedure confirms the anti-HIV activity of trichosanthin on some cell lines in different biological assays.

Amino Acids↗

PubMed1989

Ectopic pregnancy treated with trichosanthin. Clinical analysis of 71 patients.

Pathological studies on the aborted materials after the administration of trichosanthin at the end of mid-term gestation have revealed that there is an extensive coagulative necrosis of the trophoblastic tissue of the placental villi. In 1971, we first used trichosanthin successfully to treat ectopic pregnancy instead of salpingectomy. Trichosanthin was given to the patients with ectopic pregnancy who were clinically stable and had no signs of acute distress or large quantity of intraperitoneal hemorrhage. From 1971 to 1986, a total of 71 patients were treated with trichosanthin with a success rate of 85.9% and a subsequent fertility rate of 82.6%.

Abortifacient Agents↗

PubMed1986

The immunomodulatory and antitumor activities of trichosanthin-an abortifacient protein isolated from tian-hua-fen (Trichosanthes kirilowii).

Trichosanthin, a basic protein purified from the root tuber of Trichosanthes kirilowii, has been used effectively in China to induce midterm abortion in humans. In this paper, we show that trichosanthin at non-cytotoxic concentrations markedly inhibited the mitogen-induced lymphoproliferative response and the generation of a primary alloreactive CTL response in vitro. Similarly, the production of IL-2 by Con A activated splenocytes and the in vitro effector functions of macrophages were also significantly suppressed. In contrast, the cytolytic activity of CTL and NK cells was unimpaired. Moreover, the in vivo activation of NK cells was not significantly altered by a single injection of a non-toxic microgram amount of trichosanthin into mice. However, other immune reactivities such as the induction of a DTH response and the humoral antibody formation to SRBC were markedly depressed. Our data suggest that trichosanthin is a potent immunosuppressive protein that could affect humoral immunity and a variety of cell-mediated processes. In addition, our preliminary results show that this abortifacient protein could also inhibit the growth of a murine malignant tumour (MBL-2), both in vivo and in vitro.

Abortifacient Agents↗

PubMed1986

Conformation of abortifacient proteins: trichosanthin, alpha-momorcharin and beta-momorcharin.

The conformations of three abortifacient proteins, trichosanthin from the Chinese herb Tianhuafen and alpha- and beta-momorcharin from the Chinese herb Kuguazi, were studied by circular dichroism. Their spectra in the ultraviolet region (188-250 nm) were similar to each other and also pH-independent (between pH 5 and 9). All three proteins contained about 30% helix, as compared with 39% for trichosanthin by X-ray diffraction study, and 40-60% beta-sheets, but had no beta-turns, suggesting a structural homology among the proteins. The addition of 20 mM sodium dodecyl sulfate nearly doubled the helicity of beta-momorcharin at the expense of beta-sheets but had a small effect on the conformation of alpha-momorcharin, whereas the corresponding change in conformation for trichosanthin was in between the two momorcharins. This implies a marked difference in stability of the three proteins against the surfactant.

Abortifacient Agents↗

PubMed1990

Toxicities of trichosanthin and alpha-momorcharin, abortifacient proteins from Chinese medicinal plants, on cultured tumor cell lines.

Trichosanthin and alpha-momorcharin are abortifacient proteins extracted from Chinese medicinal herbs. Study of their in vitro cytotoxicities showed that the two proteins selectively injured choriocarcinoma and melanoma cells. Hepatoma cells represented the most resistant cell line among the various cell lines investigated. Cytotoxicity profiles of trichosanthin and alpha-momorcharin differed from those of anti-cancer drugs which interfere with DNA metabolism such as cisplatin, methotrexate and 5-fluorouracil. Radioactive precursor incorporation studies suggested that the two abortifacient proteins inhibited cellular protein synthesis. The marked decrease in secretion of human chorionic gonadotrophin and progesterone by choriocarcinoma cells after treatment with the proteins could be attributed mainly to loss of cells.

Abortifacient Agents, Nonsteroidal↗