Caso 5: Javier

Acronychia oblongifolia (Acronychia) (Rutaceae) Cytotoxic Location: In all types of rainforest.

Appearance (Figure 3.4) Stem: 12 m high.

Leaves: 4–12 cm long and emit a pleasant smell when crushed. Oil dots are visible and numerous, and the leaf blade is very glossy.

Flowers: they are produced on the bare stems and behind the foliage.

Parts used: bark, stem.

Active ingredients

● Flavonols: 5,3-dihydroxy-3,6,7,8,4-pentamethoxyflavone, 5-hydroxy-3,6,7,8,3,4-hexa-methoxyflavone, digicitrin, 3-O-demethyldigicitrin, 3,5,3-trihydroxy-6,7,8,4-tetramethoxyflavone and 3,5-dihydroxy-6,7,8,3,4-pentamethoxyflavone.

● Alkaloids: 1,2,3-trimethoxy-10-methyl-acridone, 1,3,4-trimethoxy-10-methyl-acridone, des-N-methyl acronycine, normelicopine and noracronycine.

Documented target cancers

● human nasopharyngeal carcinoma

● tubulin inhibitor.

Figure 3.4 Acronychia sp.

Further details

Related species

● Acronychia porteri contains various flavonols (see above) which showed activity against (KB) human nasopharyngeal carcinoma cells (IC₅₀0.04gml^1) and inhibited tubu-lin assembly into microtubules (IC₅₀12M) (Lichius et al., 1994).

● Acronychia pedunculata: The bark contains acrovestone and bauerenol, two crystalline substances (Wu et al., 1989; Zhu et al., 1989).

● Acronychia baueri (Rutaceae): the bark contains the alkaloids, 1,2,3-trimethoxy-10-methyl-acridone, 1,3,4-trimethoxy-10-1,2,3-trimethoxy-10-methyl-acridone, des-N-methyl acronycine, normeli-copine and noracronycine (Svoboda et al., 1966).

● Acronychia laurifolia BL: contains acronylin, a phenolic compound (Biswas et al., 1970).

● Acronychia haplophylla: This plant contains the alkaloids acrophylline and acrophyllidine (Lahey et al., 1968).

References

Biswas, G.K. and Chatterjee, A. (1970) Isolation and structure of acronylin: a new phenolic compound from Acronychia laurifolia BL. Chem. Ind. 16(20), 654–5.

Chowrashi, B.K., Mukherjea, B. and Sikder, S. (1976) Some central effects of Acronychia laurifolia Linn (letter). Indian J. Physiol. Pharmacol. 20(4), 250–1.

Funayama, S. and Cordell, G.A. (1984) Chemistry of acronycine IV. Minor constituents of acronine and the phytochemistry of the genus Acronychia. J. Nat. Prod. 47(2), 285–91.

Lahey, F.N. and McCamish, M. (1968) Acrophylline and acrophyllidine. Two new alkaloids from Acronychia haplophylla. Tetrahedron Lett., 12, 1525–7.

Lichius, J.J., Thoison, O., Montagnac, A., Pais, M., Gueritte-Voegelein, F., Sevenet, T., Cosson, J.P. and Hadi, A.H. (1994) Antimitotic and cytotoxic flavonols from Zieridium pseudobtusifolium and Acronychia porteri. J. Nat. Prod., 57(7), 1012–6.

Svoboda, G.H., Poore, G.A., Simpson, P.J. and Boder, G.B. (1966) Alkaloids of Acronychia Baueri Schott I.

Isolation of the alkaloids and a study of the antitumor and other biological properties of acronycine.

J. Pharm. Sci., 55(8), 758–68.

Wu, T.S., Wang, M.L., Jong, T.T., McPhail, A.T., McPhail, D.R. and Lee, K.H. (1989) X-ray crystal structure of acrovestone, a cytotoxic principle from Acronychia pedunculata. J. Nat. Prod., 52(6), 1284–9.

Zhou, F.X. and Min, Z.D. (1989) Studies on the chemical constituents of Acronychia pedunculata (L.) Mig.

Chung Kuo Chung Yao Tsa Chih. 14(2), 30–1, 62.

Agrimonia pilosa (Agrimony) (Rosaceae) Immunomodulator Cytotoxic Location: Of Chinese origin, it is found in most places – on hedge-banks, meadows, open woods and roadsides – though not in the far north.

Appearance

Stem: erect and cylindrical, hairy, 50–150 cm high, mostly unbranched.

Root: long, woody and black.

Leaves: 7.7–20 cm long, pinnate with to other leaflets.

Flowers: small, yellow, on terminal spikes, emitting an apricot-like odor. Fruits bear hairy spines.

Fruit deeply grooved.

In bloom: June–September.

Tradition: One of the most famous “magic” herbs, it has been used against wounds of various causes and for the prevention and cure of liver disorders. The Chinese A. pilosa is known as xian he cao.

Part used: Root

Active ingredients: agrimoniin (tannin), unidentified components of methanolic extract.

Particular value: Its use presents a relatively low risk of side effects.

Precautions: Avoid use in case of constipation.

Indicative dosage and application: agrimoniin: intraperitoneal injection with 10 mg kg^1. Documented target cancers

● Agrimoniin is capable of inducing interleukin-1.

● The methanol extract from roots of the plant helps to prolong the life span of mammary carcinoma-bearing mice while inhibiting tumor growth.

● Is cytotoxic to tumor cells, normal cells are far less affected.

Further details

Related compounds

● An antimutagenic activity against benzo[a]pyrene (B[a]P) was marked in the presence of A. pilosa extracts (boiled for 2 h in a water bath) whereas that against 1,6-dinitropyrene (1,6-diNP) and 3,9-dinitrofluoranthene (3,9-diNF) varied from 20%

References

Horikawa, K., Mohri, T., Tanaka, Y. and Tokiwa, H. (1994) Moderate inhibition of mutagenicity and car-cinogenicity of benzo[a]pyrene, 1,6-dinitropyrene and 3,9-dinitrofluoranthene by Chinese medicinal herbs. Mutagenesis 9(6), 523–6.

Kimura, Y., Takido, M. and Yamanouchi, S. (1968) Studies on the standardization of crude drugs. XI.

Constituents of Agrimonia pilosa var. japonica Yakugaku Zasshi 88(10), 1355–7.

Koshiura, R., Miyamoto, K., Ikeya, Y. and Taguchi, H. (1985) Antitumor activity of methanol extract from roots of Agrimonia pilosa Ledeb. Jpn. J. Pharmacol. 38(1), 9–16.

Min, B.S., Kim, Y.H., Tomiyama, M., Nakamura, N., Miyashiro, H., Otake, T. and Hattori, M. (2001) Inhibitory effects of Korean plants on HIV-1 activities. Phytother. Res. 15(6), 481–6.

Murayama, T., Kishi, N., Koshiura, R., Takagi, K., Furukawa, T. and Miyamoto, K. (1992) Agrimoniin, an antitumor tannin of Agrimonia pilosa Ledeb., induces interleukin-1. Anticancer Res. 12(5), 1471–4.

Miyamoto, K., Kishi, N. and Koshiura, R. (1987) Antitumor effect of agrimoniin, a tannin of Agrimonia pilosa Ledeb., on transplantable rodent tumors. Jpn. J. Pharmacol. 43(2), 187–95.

Miyamoto, K., Kishi, N., Murayama, T., Furukawa, T. and Koshiura, R. (1988) Induction of cytotoxicity of peritoneal exudate cells by agrimoniin, a novel immunomodulatory tannin of Agrimonia pilosa Ledeb.

Cancer Immunol. Immunother. 27(1), 59–620.

to 86%. The observed differences in inhibition might be due to the inactivation of metabolic enzymes (Horikawa et al., 1994).

● A significant amount of interleukin-1 (IL-1) beta in the culture supernatant of the human peripheral blood mononuclear cells was stimulated with agrimoniin (Miyamoto, 1988). Agrimoniin induced IL-1 beta secretion dose- and time-dependently (Murayama, 1992). The adherent peritoneal exudate cells from mice intraperitoneally injected with agrimoniin (10 mg kg^1) also secreted IL-1 four days later. These results suggested that agrimoniin is a novel cytokine inducer.

Antitumor activity

● To evaluate the antitumor activity of A. pilosa, the effects of the methanol extract from roots of the plant (AP-M) on several transplantable rodent tumors were inves-tigated. AP-M inhibited the growth of S-180 solid type tumors (Miyamoto, 1987).

On the other hand, the prolongation of life span induced by AP-M on S-180 ascites type tumor-bearing mice was markedly minimized or abolished by the pretreatment with cyclophosphamide. AP-M showed considerably strong cytotoxicity on MM-2 cells in vitro, but the effect was diminished to one-tenth by the addition of serum to the culture. Against the host animals, the peripheral white blood cells in mice were significantly increased from 2 to 5 days after the i.p. injection of AP-M. On day 4 after the injection of AP-M, the peritoneal exudate cells, which possessed the cyto-toxic activity on MM-2 cells in vitro, were also increased to about 5-fold relative to those in the non-treated control. The spleen of the mice was enlarged, and the spleen cells possessed the capacity to uptake 3H-thymidine. However, AP-M did not show direct migration activity like other mitogens against spleen cells from non-treated mice (Miyamoto, 1987). These results indicate that the roots of A. pilosa contain some antitumor constituents, and possible mechanisms of the antitumor activity may include host-mediated actions and direct cytotoxicity.

Pei, Y.H., Li, X., Zhu, T.R. and Wu, L.J. (1990) Studies on the structure of a new flavanonol glucoside of the root-sprouts of Agrimonia pilosa Ledeb Yao Xue Xue Bao 5(4), 267–70.

Angelica archangelica L. (Angelica) (Umbelifereae) Cytotoxic Location: Of Syria origin, native in cold and moist places in Scotland, and in countries further north (Lapland, Iceland). It can be easily found, as it is largely cultivated in some places.

Appearance (Figure 3.5)

Stem: stout, fluted, 1.3–2 m high and hollow.

Root: long, spindle-shaped, thick and fleshy with large heavy specimens.

Leaves: bright green, composed of numerous small leaflets, divided into three principal groups each of which is subdivided into three lesser groups. Edges are finely toothed or serrated.

Flowers: small and numerous, yellowish or greenish, grouped into large, globular umbels.

In bloom: July.

Tradition: It was well known for its protection against contagion, for purifying the blood and for curing every conceivable malady, such as poisons, agues and all infectious maladies.

Part used: root, leaves, seeds.

Active ingredients

● Pyranocoumarins: decursin, archangelici, and 8(S),9(R)-9-angeloyloxy-8,9-dihydrooroselol.

● Chalcones: 4-hydroxyderricin, xanthoangelol and ashitaba-chalcone.

● Polysaccharide: uronic acid.

Precautions: Should not be given to patients who have tendency towards diabetes, because it increases sugar in the urine.

Documented target cancers: Skin cancer (mouse), Ehrlich tumors (mouse), and the stimulation of the uptake of tritiated thymidine into murine and human spleen cells.

Figure 3.5 Angelica archangelica.

References

Ahn, K.S., Sim, W.S. and Kim, I.H., (1996) Decursin: a cytotoxic agent and protein kinase C activator from the root of Angelica gigas. Planta Med. 62(1), 7–9.

Choy, Y.M., Leung, K.N., Cho, C.S., Wong, C.K. and Pang, P.K. (1994) Immunopharmacological studies of low molecular weight polysaccharide from Angelica sinensis. Am. J. Chin. Med. 22(2), 137–45.

Haranaka, K., Satomi, N., Sakurai, A., Haranaka, R., Okada, N. and Kobayashi, M. (1985) Antitumor activities and tumor necrosis factor producibility of traditional Chinese medicines and crude drugs.

Cancer Immunol. Immunother. 20(1), 1–5.

Further details

Related compounds

● Pyranocoumarins decursin is cytotoxic against various human cancer cell lines, possibly due to protein kinase C activation. Relatively low cytotoxicity against normal fibroblasts.

● Polysaccharide: cytotoxic, immunostimulating.

Related species

● Angelica gigas: roots contain the cytotoxic pyranocoumarin decursin (also found in A. decursiva) Fr. et Sav. (Ahn et al., 1996).

● Angelica sinensis: the rhizome contains a low molecular weight (3 kd) polysaccharide composed partly of uronic acid. It shows strong antitumor activity on Ehrlich Ascites tumor-bearing mice. It also exhibits immunostimulating activities, both in vitro and in vivo (Choy et al., 1994).

● Angelica keiskei: roots contain two angular furanocoumarins, archangelicin and 8(S),9(R)-9-angeloyloxy-8,9-dihydrooroselol as well as three chalcones, 4-hydroxyderricin, xanthoangelol and ashitaba-chalcone which can suppress 12-O-tetrade-canoylphorbol-13-acetate (TPA)-stimulated ³²P_i-incorporation into phospholipids of cultured cells. In addition, 4-hydroxyderricin and xanthoangelol have antitumor-promoting activity in mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) plus TPA, possibly due to the modulation of calmodulin involved systems (Okuyama et al., 1991).

● Angelica acutiloba is one of the main components of the oriental Kampo-prescription, Shi-un-kou (in which other two constituents are Lithospermum erythrorhizon and Macrotomia euchroma). The drug exhibits inhibitory activity on Epstein–Barr virus acti-vation and skin tumor formation in mice. Roots contain an immunostimulating poly-saccharide (AIP) consisting of uronic acid, hexose and peptide (Kumazawa et al., 1982).

● Angelica radix is another oriental herb whose administration in mice is associated with an increased production of the TNF, possibly through stimulation of the retic-uloendothelial system (RES) (Haranaka et al., 1985).

Konoshima, T., Kozuka, M., Tokuda, H. and Tanabe, M. (1989) Anti-tumor promoting activities and inhibitory effects on Epstein–Barr virus activation of Shi-un-kou and its constituents Yakugaku Zasshi.

109(11), 843–6.

Kumazawa, Y., Mizunoe, K. and Otsuka, Y. (1982) Immunostimulating polysaccharide separated from hot water extract of Angelica acutiloba Kitagawa (Yamato tohki). Immunology 47(1), 75–83.

Okuyama, T., Takata, M., Takayasu, J., Hasegawa, T., Tokuda, H., Nishino, A., Nishino, H. and Iwashima, A.

(1991) Anti-tumor-promotion by principles obtained from Angelica keiskei. Planta Med. 57(3), 242–6.

Annona cherimola (Annona) (Annonaceae) Cytotoxic

Location: Central America (Ecuador, Colombia and Bolivia) Appearance (Figure 3.6)

Stem: 5–10 m high, erect, low brunched.

Leaves: briefly deciduous, alternate, 2-ranked, with minutely hairy petioles 0.8–1.5 cm long, ovate to elliptic or ovate-lanceolate.

Flowers: fragrant, solitary or in groups of 2 or 3, on short hairy stalks along the branches, 3 outer greenish petals and 3 smaller, inner pinkish petals.

In bloom: Spring, summer, autumn, winter.

Part used: fruit.

Active ingredients: Annonaceous acetogenins (lactones), alkaloids.

Figure 3.6 Annona sp.

Documented target cancers

● Prostate adenocarinoma

● pancreatic carcinoma cell line (human)

● sarcoma.

Further details

Related species

● Annona muricata: leaves contain two Annonaceous acetogenins, muricoreacin and murihexocin C., showing significant cytotoxicities among human tumor cell lines with selectivities to the prostate adenocarinoma (PC-3) and pancreatic carcinoma (PACA-2) cell lines (Kim et al., 1998).

● Annona senegalensis is used against sarcomas (Durodola et al., 1975a,b).

● Annona purpurea contains alkaloids (Sonnet et al., 1971).

● Annona reticulata: seeds contain the cytotoxic gamma-lactone acetogenin, cis-/trans-isomurisolenin, along with annoreticuin, annoreticuin-9-one, bullatacin, squamocin, cis-/trans-bullatacinone and cis-/trans-murisolinone (Chang, 1998).

Related compounds

● The bark of A. squamosa yielded three new mono-tetrahydrofuran (THF) ring acetogenins, each bearing two flanking hydroxyls and a carbonyl group at the C-9 position. These compounds were isolated using the brine shrimp lethality assay as a guide for the bioactivity-directed fractionation. (2,4-cis and trans)-Mosinone A is a mixture of ketolactone compounds bearing a threo/trans/threo ring relationship and a double bond two methylene units away from the flanking hydroxyl. The other two new acetogenins differ in their stereochemistries around the THF ring; mosin B has a threo/trans/erythro configuration across the ring, and mosin C possesses a threo/cis/threo relative stereochemistry. Also found was annoreticuin-9-one, a known acetogenin that bears a threo/trans/threo ring configuration and a C-9 carbonyl and is new to this species. The structures were elucidated based on spectroscopic and chemical meth-ods. Compounds 1–4 all showed selective cytotoxic activity against the human pan-creatic tumor cell line, PACA-2, with potency 10–100 times that of Adriamycin (Hopp et al., 1997).

● Activity-guided fractionation of the stem bark of A. senegalensis gave four bioactive ent-kaurenoids. Compound 2 showed selective and significant cytotoxicity for MCF-7 (breast cancer) cells (ED₅₀1.0gml^1), and 3 and 4 exhibited cytotoxic selectiv-ity for PC-3 (prostate cancer) cells but with weaker potencies (ED₅₀17–18gml^1).

The structure of the new compound, 3, was deduced from spectral evidence (Fatope et al., 1996).

● The bark extracts of A. squamosa yielded a new bioactive acetogenin, squamotacin (1), and the known compound, molvizarin, which is new to this species. Compound 1 is

identical to the potent acetogenin, bullatacin, except that the adjacent bis- THF rings and their flanking hydroxyls are shifted two carbons toward the -lactone ring.

Compound 1 showed cytotoxic activity selectively for the human prostate tumor cell line (PC-3), with a potency of over 100 million times that of Adriamycin (Hopp et al., 1997).

● Bioactivity-directed fractionation of the seeds of A. muricata L. (Annonaceae) resulted in the isolation of five new compounds: cis-annonacin, cis-annonacin-10-one, cis-goniothalamicin, arianacin and javoricin. Three of these) are among the first cis mono-THF ring acetogenins to be reported. NMR analyses of published model syn-thetic compounds, prepared cyclized formal acetals, and prepared Mosher ester derivatives permitted the determinations of absolute stereochemistries. Bioassays of the pure compounds, in the brine shrimp test, for the inhibition of crown gall tumors, and in a panel of human solid tumor cell lines for cytotoxicity, evaluated relative potencies. Compound 1 was selectively cytotoxic to colon adenocarcinoma cells (HT-29) in which it was 10,000 times the potency of adriamycin (Rieser et al., 1996).

● In a continuing activity-directed search for new antitumor compounds, using brine shrimp lethality test (BST), mixtures of three additional pairs of bis-THF ketolactone acetogenins were isolated from the ethanol extract of the bark of A. bullata Rich.

(Annonaceae). Compared with (2,4-cis and trans)-bullatacinone, these new compounds each have one more aliphatic OH group at a different position on the hydrocarbon chain and thus, were named (2,4-cis and trans)-10-hydroxybullatacinone (1 and 2), (2,4-cis and trans)-12-hydroxybullatacinone (3 and 4), and (2,4-cis and trans)-29-hydrox-ybullatacinone. These mixtures all showed potent activities in the BST and exhibited cytotoxicities comparable to those of adriamycin against human solid tumor cells in culture with selectivities exhibited especially toward the breast cancer cell line (MCF-7) (Gu et al., 1993).

● From A. bullata, three more pairs of new ketolactone Annonaceous acetogenins were isolated by bioactivity-directed isolation. They are hydroxylated adjacent bis-THF acetogenins and are named cis and trans)-32-hydroxybullatacinone (1 and 2), (2,4-cis and trans)-31-hydroxybullatacinone (3 and 4), and (2,4-(2,4-cis and trans)-30-hydroxybul-latacinone. The structures were elucidated by analysis of the ¹H- and ¹³C-NMR spectra of 1–6 and their acetates and the MS of their tri-trimethylsilyl (TMSi) deriv-atives as compared with bullatacinone. This is the first time that Annonaceous acetogenins with OH groups at successive positions near the end of the aliphatic chain have been reported. All of the new compounds showed potent activities in the BST and against human solid tumor cells in culture, with selectivities exhibited especially toward the colon cancer cell line (HT-29) (Gu et al., 1994).

● Structural work and chemical studies are reported for several cytotoxic agents from the plants Annona densicoma, Annona reticulata, Claopodium crispifolium, Polytrichum obioense, and Psorospermum febrifugum. Studies are also reported based on development of a mammalian cell culture benzo[a]pyrene metabolism assay for the detection of potential anticarcinogenic agents from natural products (Cassady et al., 1990).

References

Cassady, J.M., Baird, W.M. and Chang, C.J. (1990) Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents. J. Nat. Prod. 53(1), 23–41.

Chang, F.R., Chen, J.L., Chiu, H.F., Wu, M.J. and Wu, Y.C. (1998) Acetogenins from seeds of Annona reticulata. Phytochemistry 47(6), 1057–61.

Durodola, J.I. (1975a) Viability and transplantability of developed tumour cells treated in vitro with antitumour agent C/M2 isolated from a herbal cancer remedy – of Annona senegalensis. Planta Med. 28(4), 359–62.

Durodola, J.I. (1975b) Antitumour effects against sarcoma 180 ascites of fractions of Annona senegalensis.

Planta Med. 28(1), 32–6.

Fatope, M.O., Audu, O.T., Takeda, Y., Zeng, L., Shi, G., Shimada, H. and McLaughlin, J.L. (1996) Bioactive ent-kaurene diterpenoids from Annona senegalensis. J. Nat. Prod. 59(3), 301–3.

Gu, Z.M., Fang, X.P., Hui, Y.H. and McLaughlin, J.L. (1994) 10-, 12-, and 29-hydroxybullatacinones:

new cytotoxic Annonaceous acetogenins from Annona bullata Rich (Annonaceae). Nat. Toxins. 2(2), 49–55.

Gu, Z.M., Fang, X.P., Miesbauer, L.R, Smith, D.L. and McLaughlin, J.L. (1993) 30-, 31-, and 32-hydroxybullatacinones: bioactive terminally hydroxylated annonaceous acetogenins from Annona bullata. J. Nat. Prod. 56(6), 870–6.

Hopp, D.C., Zeng, L., Gu, Z.M., Kozlowski, J.F. and McLaughlin, J.L. (1997) Novel mono-tetrahydrofuran ring acetogenins, from the bark of Annona squamosa, showing cytotoxic selectivities for the human pancreatic carcinoma cell line, PACA-2. J. Nat. Prod. 60(6), 581–6.

Hopp, D.C., Zeng, L., Gu, Z. and McLaughlin, J.L. (1996) Squamotacin: an annonaceous acetogenin with cytotoxic selectivity for the human prostate tumor cell line (PC-3). J. Nat. Prod. 59(2), 97–9.

Kim, G.S., Zeng, L., Alali, F., Rogers, L.L., Wu, F.E., Sastrodihardjo, S. and McLaughlin, J.L. (1998) Muricoreacin and murihexocin C, mono-tetrahydrofuran acetogenins, from the leaves of Annona muricata. Phytochemistry 49(2), 565–71.

Rieser, M.J., Gu, Z.M., Fang, X.P., Zeng, L., Wood, K.V. and McLaughlin, J.L. (1996) Five novel mono-tetrahydrofuran ring acetogenins from the seeds of Annona muricata. J. Nat. Prod. 59(2), 100–8.

Sonnet, P.E. and Jacobson, M. (1971) Tumor inhibitors. II. Cytotoxic alkaloids from Annona purpurea.

J. Pharm. Sci. 60(8), 1254–6.

Brucea antidysenterica (Brucea) Cytotoxic

(Simaroubaceae) (Figure 3.7) Location: China, Japan.

Part used: stem.

Active ingredients

● Cytotoxic: Bruceoside C, bruceanic acid A and its methyl ester 2 (new), bruceanic acid B, C and D.

● Quassinoid glucosides: bruceosides D, E and F, bruceantinoside C and yadanziosides G and N, bruceanic acids.

● Alkaloids: 1,11-dimethoxycanthin-6-one, 11-hydroxycanthin-6-one and canthin-6-one.

Indicative dosage and application: Tested in human carcinoma cells at:

● 250gml^1showed 42% growth inhibition.

● 500gml^1showed 56% growth inhibition.

The 50% of the results are visible after the first 7 h.

Documented target cancers: Leukemia and non-small-cell lung, colon, CNS, melanoma and ovarian cancer.

● Bruceanic acid D is cytotoxic against P-388 lymphocytic leukemia cells.

● Bruceanic acid A against KB and TE 671 tumor cells, brain metastasis, in lung cancer with radiotherapy.

● Bruceoside C is used against KB, A-549, RPMI and TE-671 tumor cells.

● The three above-mentioned alkaloids are cytotoxic and are used as anti-leukemic alkaloids.

Figure 3.7 Brucea.

Further details Antitumor activity

● The fruit of Brucea javanica contains quassinoid glucosides, which show selective cyto-toxicity in the leukemia and non-small cell lung, colon, CNS, melanoma and ovar-ian cancer, cell lines with log GI₅₀values ranging from 4.14 to 5.72. A fruit-derived emulsion inhibited human squamous cell carcinoma cells. At a dose of 250gml^1at 96 h after drug exposure, it showed 42% growth inhibition, and at 500gml^1inhibited 56% of the cell growth. The effect of more than 50% of the growth inhibition was evident at more than 7 h after drug exposure. In the analysis of the mechanism of the drug using a flow cytometry, the arrest in G₁phase of cell cycle was found during incubation of cancer cells with drug (Fukamiya et al., 1992).

● The 10% Brucea javanica emulsion has synergetic with radiotherapy in treating brain metastasis in lung cancer. Median survival (15 months) of the patients treated was prolonged for 50% (Wang, 1992).

References

Fukamiya, N., Okano, M., Miyamoto, M., Tagahara, K. and Lee, K.H. (1992) Antitumor agents, 127.

Bruceoside C, a new cytotoxic quassinoid glucoside, and related compounds from Brucea javanica. J. Nat.

Prod. 55(4), 468–75.

Fukamiya, N., Okano, M., Aratani, T., Negoro, K., McPhail, A.T., Ju-ichi, M. and Lee, K.H. (1986) Antitumor agents, 79. Cytotoxic anti-leukemic alkaloids from Brucea antidysenterica. J. Nat. Prod. 49(3), 428–34.

Fukamiya, N., Okano, M., Tagahara, K., Aratani, T., Muramoto, Y. and Lee, K.H. (1987) Antitumor agents, 90. Bruceantinoside C, a new cytotoxic quassinoid glycoside from Brucea antidysenterica. J. Nat.

Prod. 50(6), 1075–9.

Kupchan, S.M., Britton, R.W., Ziegler, M.F. and Sigel, C.W. (1973) Bruceantin, a new potent anti-leukemic simaroubolide from Brucea antidysenterica. J. Org. Chem. 38(1), 178–9.

Lu, J.B., Shu, S.Y. and Cai, J.Q. (1994) Experimental study on effect of Brucea javanica oil emulsion on rab-bit intracranial pressure. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 14(10), 610–1.

Ohnishi, S., Fukamiya, N., Okano, M., Tagahara, K. and Lee, K.H. (1995) Bruceosides D, E, and F, three new cytotoxic quassinoid glucosides from Brucea javanica. J. Nat. Prod. 58(7), 1032–8.

Okano, M., Lee, K.H. and Hall, I.H. (1981) Antitumor agents. 39. Bruceantinoside-A and -B, novel anti-leukemic quassinoid glucosides from Brucea antidysenterica. J. Nat. Prod. 44(4), 470–4.

Phillipson, J.D. and Darwish, F.A. (1981) Bruceolides from Filjian Brucea javanica. Planta Med. 41(3), 209–20.

Phillipson, J.D. and Darwish, A. (1979) TLX-5 lymphoma cells in rapid screening for cytotoxicity in Brucea extracts. Planta Med. 35(4), 308–15.

Sakaki, T., Yoshimura, S., Tsuyuki, T., Takahashi, T. and Honda, T. (1986) Yadanzioside P, a new anti-leukemic quassinoid glycoside from Brucea javanica (L.) Merr with the 3-O-(beta-D-glucopyranosyl)bruceantin structure. Chem. Pharm. Bull. (Tokyo) 34(10), 4447–50.

Toyota, T., Fukamiya, N., Okano, M., Tagahara, K., Chang, J.J. and Lee, K.H. (1990) Antitumor agents, 118. The isolation and characterization of bruceanic acid A, its methyl ester, and the new bruceanic acids B, C, and D, from Brucea antidysenterica. J. Nat. Prod. 53(6), 1526–32.

Wang, Z.Q. (1992) Combined therapy of brain metastasis in lung cancer. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 12(10), 609–10.

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In document Una práctica de las comunidades de aprendizaje para la inclusión del alumnado con discapacidad (página 190-193)