Anticancer substances

D. auricularia is a shell-less mollusk that, therefore, initially appears to lack defenses against predators however, this is only a preliminary supposition. Accumulated evidence supports the fact that Opisthobran-chia mollusks have developed very powerful chemical defenses (Pettit et ah, 1989). Pettit et al. (1981) were the first to isolate some of these compounds the pentapeptide dolastatin 10 (Fig. 5.1) was reported to be the most active natural anticancer substance at that time with an ED50 of 4.6x 10 5pg/mL against the P388 cell line (Pettit et al., 2008). Dolastatin 10 was also shown to inhibit tubulin polymerization and tubulin-dependent GTP hydrolysis (Bai et al., 1990). 

Furocoumarins, such as xanthotoxin (20), apparently increase the sensitivity of Ehrlich tumor cells to y-rays.80 The use of phototoxic furocoumarins as anticancer substances has been investigated, but does not seem to give satisfactory results.81... 

Naturally occurring compounds with potential ionophoric properties are still being discovered, two recent examples being the antibiotic M139603100 and the remarkable anticancer substance bryostatin l.101... 

The results of this study indicated that the modification of the ester group in 7a-chloro-3-methyl-l,l-dioxoceph-3-em-4-carboxylic acid is promising in the search of new anticancer substances permitting action both on the cytotoxic effectiveness of compounds and on their selectivity in relation to cancer and normal cells [156]. 

There are few reports on the inhibitory effect of conjugated polyenes on the growth of cancer cell lines. Begin et al. (1988) reported the toxic effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on several kinds of tumor cells other polyunsaturated fatty acids, i.e., arachidonic acid (22 4n-6), a-linolenic acid (18 3n-3), and y-linolenic acid (18 3n-6) have cytotoxic action on several tumor cell lines at concentrations above 50 pM. Further, Tsuzuki et al. (2004) demonstrated that the anticarcinogenic effect of CLN are directly associated with lipid peroxidation. They transplanted human colon cancer cells (DLD-1) into nude mice, and CLA (9c, lit and lOt, 12c-18 2) and CLN (9c, lit, 13t-18 3) were administered to animals. Tumor growth was suppressed by the supplementation of CLA and CLN, and the extent of suppression was CLN >9c, llt-CLA.>10t, 12c-CLA, in that order. Furthermore, DNA fragmentation was enhanced and lipid peroxidation increased in tumor cells of the CLN-fed mouse. Thus this study indicates the possibility of seaweeds as potential sources of anticancer substances. 

Even the controversial cyanic anticancer substance known as laetrile, or amygda-lin, is thought to be detoxified by a particular enzyme or enzymes in normal cells that is not ordinarily present, or in sufficient concentrations, in cancer cells. The answer is not clear-cut, however, and laetrile remains suspect, if effective at all. More than this, there are certain other food enzymes that may cause laetrile to give off deadly hydrogen cyanide or hydrocyanic acid, or HCN, itself an enzyme inhibitor that acts against bodily processes, notably respiration. (Deadly cyanide, incidentally, is listed as an inhibitor for tyrosinase, the enzyme involved in melanoma.)... 

Incidentally, a yew-related species from China named Cephalotaxus fortunei yields a toxic anticancer substance known as harringtonine (Griggs, 1991, p. 318). A similar species in the United States is known as Cephalotaxus harringtonia, from which is derived the bioactive substance homoharringtonine. 

Some further comments include the fact that resveratrol has been extensively studied at the University of Illinois at Chicago, an institution that is said to have the broadest-based chemoprevention drug discovery program in the world. (Information about resveratrol is also provided by Hoffman, 1999a, p. 214). Some 2500 natural substances have been tested under the direction of pharmacy professor John Pezzuto (who is cited elsewhere as coauthor with Mathew Suffness of a chapter in Methods in Plant Biochemistry, Vol. 6, Assays for Bioactivity, pp. 72ff, 116). This anticancer substance (resveratrol) has been identified in over 70 plant species, notably in red-grape skins (and in red wine), but also in mulberries and peanuts. 

A particular difficulty is that apparently no one has ever bothered to figure out the optimum dosage levels and frequencies for plant-derived anticancer substances, in addition to, and in conjimction with, the purity and activity of the agent, which perforce includes composition. As it is, a plant or plant-derived substance or other substances are too often classified as toxic or nontoxic, poisonous or nonpoisonous, mostly with no in-betweens. This in-between, or gray, area may prove to be the window of opportunity. 

A molecular sieving effect of mesoporous FSM silicas with different pore diameters was reported by Hata et al. [224]. Taxol, an anticancer substance, was not adsorbed in the channels with pore sizes less than 1.6 nm. Taxol contains C=0 and OH groups and was adsorbed only from dichloromethane and toluene solution. It is not adsorbed from methanol or acetone due to the low degree of hydrophilicity of the porous materials. Reaction with trimethyl chlorosilane impeded adsorption because the surfaces are too hydrophobic. By a special adsorption-desorption procedure, Taxol could be enriched from yew needle extracts using certain FSMs. 

Section) imposes greater stereoelectronic control which leads to greater axial selectivity. Two reports have appeared on the preparation of etoposide (130) which is a clinical anticancer substance. Both use 1-thio-D-glucose compounds, but the first employs a bromine atom and the second a coordinated hydroxy group for leaving purposes. A 45% 3deld is claimed in the latter in the former report sulfoxide and sulfone analogues were described. 

Aside from the capricious result of the A. californicum research the tunicates in general represent a productive source of new antineoplastic substances (for leading references consult 23)). Indeed, during our initial (1965-1968) worldwide evaluation of marine animals as sources of new anticancer substances, we uncovered the first tunicates (e.g., Styela plicata) with such constituents (4). On our Institute s 1976 expedition to the coast of Honduras, we located a very promising [NCI confirmed active, T/C 173 (9.37 mg/kg)] tunicate of the Trididemnum genus that was later found independently by A. J. Weinheimer and colleagues to yield potent antineoplastic cyclic depsipeptides (the didemnins). 

The spiroacetal moiety is another frequently occurring structural element occurring in potent natural anticancer substances, such as spongistatin. The groups of Paterson [35,36] and Waldmann [37] have been the first to successfully synthesize Ubraries of this privileged structure using enantioselective aldol reactions—a reaction type which turned out to be difficult for implementation on sohd phase (Scheme 15). 

Gerwick, W.H. (1997) Antimutagenic, antiinflammatory, and potential anticancer substances from marine algae, in Food Factors for Cancer Prevention (ed. H. Ohigashi), Springer, Berlin, New York, pp. 342-347. 

Discovered in 2000 in an undetermined species of the genus Chondropsis harvested in Australia (Bass Island), chondropsins A, B and D are potent inhibitors of cell growth for the NCI-60 cell lines, but with the characteristic of showing no analogy with existing models. They may therefore act through a new mechanism that could make these macro-lides a new generation of anticancer substances. 

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