MOLLUSCS
Cone snails, Blue-ringed Octopi, Sea Hares
NOTE: The following is not intended to be a treatise on cone snails but rather an introduction to the subject through descriptions of representative molecules from a variety of species.
The cone snails contain some of the most potent neurotoxins known. The predominant peptides in the venom of the mollusc-eating snails, such as C. textile, contain 20-35 residues while the fish-eating cone snails, such as C. magus and C. striatus, the most abundant venom peptides are greater than 30-50 residues and far more bioactive towards mammals. The fish hunting cone snails simultaneously attack different areas of the neurons: the alpha-conotoxins are post-synaptic neurotoxins which bind to and inhibit the acetylcholine receptor; the mu-conotoxins directly abolish muscle action potential by binding to the muscle sodium channels; and the omega-conotoxins are presynaptic neurotoxins which decimate the release of acetylcholine by preventing the voltage activated entry of calcium into the nerve terminal (Olivera, Gray et al. 1985; Shon, Grilley et al. 1995).
The physiological effect cone alpha-toxins, such as the alpha toxins from C. magus and C. geographus, is identical to that of snake alpha-toxins, such as bungaro alpha-toxin and erabutoxin-b, consisting of high affinity specific binding to the nicontinic cholinoceptors. However there is a tremendous difference in size between the two. In addition, there is very little sequence homology, the one area of significant similarity exists is at residue 25, which interestingly enough is peripheral to the residue positions involved in the actual binding to the acetylcholine receptor (Dufton, Bladon et al. 1989).
The cone snail neurotoxins are a tremendously diverse natural pharmacology that have yielded compounds shown to have potential for therapeutic use, such as G1 and M1 which are synthetic versions of polypeptides from C. geographus and C. magus, and are likely to yield more in the future (Marshall and Harvey 1990; Olivera, Hillyard et al. 1995).
Conus geographus (Geographer cone)
C. geographus is the most dangerous specie of cone, injecting neurotoxins acting on voltage-sensitive calcium channels, sodium channels, N-methyl- D-aspartate (NMDA) receptors, acetylcholine receptors, and vasopressin receptors (Yoshiba 1984; Olivera, Rivier et al. 1990). Classes of toxins identified from this specie are: conantokin, conopressin, alpha-, mu-, and omega-conotoxins in addition to a peptide known as the 'sleeper peptide'.
Conantokin-G (CntxG), the so-called 'sleeper-peptide', is an acidic 17 amino acid polypeptide with a primary structure of Gly-Glu-Gla-Gla-Leu-Gln-Gla-Asn-Gln-Gla-Leu-Ile-Arg-Gla-Lys-Ser-Asn-NH2 (Gla equals gamma-carboxyglutamate). The secondary structure, in the presence of Ca2+, is an alpha-helical conformation in which all the gamma-carboxyglutamate residues are located on the same side, and the tertiary structure is devoid of disulphide bonds (Rivier, Galyean et al. 1987). This neurotoxin blocks the N-methyl-D-aspartate receptors (NMDAR) through specific allosteric binding, with the Gla residues at positions 3 and 4 being essential for binding (Benke, Jones et al. 1993; Zhou, Szendrei et al. 1996). This blockage results in an inhibition of N-methyl-D- aspartate (NMDA) receptor-mediated calcium influx in central nervous system neurons (Haack, Rivier et al. 1990). Studies have demonstrated that synthetic versions caused the same physiological effects as the natural peptide upon intracerebral injection into mice: a sleep-like state in young mice yet hyper-activity in older mice. These are notable differences form the typical disulphide linked, basic conotoxin and molecule has a neurochemical profile that is quite different from other described noncompetitive NMDA antagonists (Skolnick, Boje et al. 1992)..
The conopressins belong to the vasopressin-oxytocin family, a family found in organisms ranging from the hydra to humans The conopressin found in C. geographus, Lys-conopressin-G, shares a 77% sequence homology with Arg-conopressin-S from C. striatus. Both peptides containing an additional positive charge not found in in the vertebrate equivalents (Cruz, de et al. 1987). These peptides demonstrate a biological effect similar to that of vertebrate neurohypophyseal hormones when inject intracerebrally into mice, likely due to actions upon a shared brain receptor (Cruz, de et al. 1987).
Alpha-conotoxin GI from C. geographus, is a 13 amino acid with two disulphide bonds, 2-7 and 3-13, is a potent reversible blocker the acetylcholine receptor at the postsynaptic neuromuscular junction, thus inhibiting neuron stimulated muscular contractions (Gray, Luque et al. 1984; McManus and Musick 1985). Alpha-conotoxin GI has a high affinity for the alpha+gamma site of the acetylcholine receptor, the same one favoured by d-tubocurarine, unlike the snake venom alpha-neurotoxins, such as neurotoxin II from the Russian cobra (Naja oxiana), which are more likely to bind to the alpha+delta site (Utkin, Kobayashi et al. 1994). Synthetic alpha-conotoxin GI retains the neuromuscular inhibiting bioactivity and is 2.5 times more potent than synthetic alpha-conotoxin MI (C. magus) (Marshall and Harvey 1990). This same study demonstrated that the bioeffects are limited to blocking neuromuscular transmission, with no effects on arterial blood pressure, heart rate, or responses to vagal and preganglionic stimulation.
Mu conotoxins in C. geographus are tissue specific sodium channel blocking neurotoxins, typified by geographutoxin II and conotoxin GIII, with GIIIA being the major toxin and stabilised by three internal disulphide bonds, structurally similar to scorpion toxins. GTX II inhibits the contractile responses of muscular tissues to electrical stimulation through the blocking of the voltage-sensitive sodium channels in the cell membranes of autonomic nerves and skeletal membranes and was the first polypeptide ligand found that is specific for receptor site 1 (Ohizumi, Minoshima et al. 1986). Studies have shown that GTX II is similar tetrodotoxin in the selective blocking of skeletal muscle sodium channels, in addition to competitively inhibiting saxitoxin binding to receptor site 1 of voltage-sensitive sodium channels (Kobayashi, Wu et al. 1986; Ohizumi, Nakamura et al. 1986). This is in direct contrast to results from the same study showing that the binding synaptosomal sodium channels by the frog toxin batrachotoxin or scorpion toxin were not not inhibited by GTX II. GTXII has been a quite useful laboratory probe of sodium channels, through studies of the effect by GTX II on sodium current on tetrodotoxin-sensitive and -insensitive sodium channels, it has been determined that there is a definitive structural difference in the region of site 1 and that the two sodium channel subtypes function in parallel (Gonoi, Ohizumi et al. 1987). The 22 amino acid GIII conotoxins, with GIIIA being the major toxin, are similar to GII in inhibiting sodium channel activation through tetrodotoxin and saxitoxin-like voltage dependent interaction upon the tetrodotoxin binding site on muscle sodium channels, with no effect upon nerve or brain sodium channels (Cruz, Gray et al. 1985; Yanagawa, Abe et al. 1986; Cruz, Kupryszewski et al. 1989).
The sodium channel inhibitor CGS (conotoxin GS) is similar to the mu-conotoxins, as well as tetrodotoxin and saxitoxin, in bioactivity but shows very limited sequence homology with the mu-conotoxins (Yanagawa, Abe et al. 1988). This lack of sequence homology yet similarity in action, is quite useful for furthering pharmacological probe studies of the sodium channels
The omega conotoxins of C. geographus are basic 27 amino acids possessing a core with three disulphide bond that are irreversible blockers of nerve stimulated release of the neurotransmitter acetylcholine, preventing the voltage-activated entry of Ca2+ into the nerve. The structure of omega-CgTx GVIA is representative of the group, having a sequence that is remarkable for containing a preponderance of hydroxylated amino acids: Cys-Lys-Ser- Hyp-Gly5-Ser-Ser-Cys-Ser-Hyp10-Thr-Ser-Tyr-Asn- Cys15-C Lys-Arg-Ser- Cys-Asn20-Hyp-Tyr-Thr-Lys-Arg25-Cys-Tyr- NH2. (Olivera, McIntosh et al. 1984). CgTx GVIA is selective for the disruption of sensory, sympathetic, or hippocampal voltage-gated, N- and L-type with only transient inhibition of T-type, Ca2+ channels, independent of calcium channel gating and having no effect upon the potassium currents (Feldman, Olivera et al. 1987; Rivier, Galyean et al. 1987). This inhibition is similar to that of omega-agatoxin-IIa from the American funnel web spider (Agelenopsis aperta )(Adams, Myers et al. 1993). These results indicate that the chemically synthesised omega-conotoxin GVIA acts exactly like the natural omega-conotoxin GVIA. Thus, the synthetic toxin can be used in place of the natural toxin as a useful probe for the voltage- sensitive Ca2+ channel in the nervous system. Trials conducted with synthetic analogs of CgTx GVIA show that the synthetic version interacts with the voltage-sensitive Ca2+ channel of the nervous system in exactly the same manner as the natural toxin (Koyano, Abe et al. 1987). These bioactivities make omega conotoxins potentially useful in furthering understanding of the presynaptic terminal (Kerr and Yoshikami 1984; McCleskey, Fox et al. 1987).
Conus imperialis (Imperial cone)
The worm hunting , C. imperialis, is the only Conus specie reported to contain high levels of serotonin in the venom (McIntosh, Foderaro et al. 1993). The alpha conotoxin from this specie, alpha-CTx-ImI, targets homomeric alpha7 neuronal neuromuscular acetylcholine receptors (Cartier, Yoshikami et al. 1996). The has a primary structure of Gly-Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg- Cys-NH2, a dramatic difference from the primary structure of alpha-conotoxins from the fish hunting species yet contains a similarly disulphide linked molecular core [2-8, 3-12] (McIntosh, Yoshikami et al. 1994). In addition, C. imperialis also contains in its venom a vasopressin homolog that is identical in structure to Lys-conopressin-G found in C. geographus (Nielsen, Dykert et al. 1994).
Conus magus
The fish hunting C. magus contains neurotoxins that have similar bioactivity to those found in C. geographus as well as the spider Agelenopsis aperta, in addition to containing in its venom a novel phospholipase A2. Conodipine-M is a phospholipase A2 made up of two polypeptide chains linked by one or more disulphide bonds and has a molecular mass of 13.6 kDa (McIntosh, Ghomashchi et al. 1995). This same study revealed that the primary structure of conodipine-M has little homology with that of other PLA2s yet, surprisingly has enzymatic activity similar to that of other 14 kDa PLA2s, such as hydrolysing the sn-2 ester of different phospholipid preparations only in the presence of calcium in a bioactive manner similar to that of snake venom PLA2s.
Alpha-conotoxin MI is a 14 amino amino acid neurotoxin with two disulphide bonds (Cys 3-Cys 8; Cys 4-Cys 14) (Gray, Rivier et al. 1983). Tests to determine the effects of synthetic MI upon neuromuscular transmission and on the cardiovascular system demonstrated that the synthetic version has the same affinity and specificity for the nicotinic acetylcholine receptors at the neuromuscular junction (Marshall and Harvey 1990). Alpha-conotoxin MII is a 16 amino acid potent blocker of alpha3beta2 nicotinic acetylcholine receptors and contains disulphide linking similar to that of other alpha-conotoxins yet with a structure that is markedly different (Cartier, Yoshikami et al. 1996).
C. magus venom contains the most major sequence variants of omega conotoxins than any other Conus specie, possessing four out of the eight (Monje, Haack et al. 1993). The omega-conotoxins MVIIA and MVIIB from magus block the neuronal Ca2+ channels. These toxins compete with omega-conotoxins from geographus for the same sites in mammalian brains but differ by having a narrower specificity in the amphibian brain in addition to differing in amino acid sequence from the omega-conotoxins from geographus (Olivera, Cruz et al. 1987). Omega-CTx MVIIC is a 26 amino acid, with three disulphide bonds, preferential blocker of P and Q type Ca2+ currents through the high affinity binding to voltage-sensitive Ca2+ channels (Farr, Miljanich et al. 1995). This neurotoxin blocks dihydropyridine- and - omega-CTX-GVIA resistant Ca channels as does omega-Aga-IVA from Agelenopsis aperta (Adams, Myers et al. 1993). Omega-conotoxin MVIID displays more pronounced discrimination against the N-type voltage-gated calcium channels than any other omega-conotoxin in addition to being able to target other voltage-gated calcium channels besides the N-type (Monje, Haack et al. 1993).
Synthetic analogs of the omega-conotoxins have demonstrated great potential as clinical analgesics, retaining the bioactivity of the natural peptide. SNX-111, derived from MVIIA, has been shown to be the most promising, with clinical trials being conducted, but SNX-230 (MVIIC) may also be shown to be therapeutically useful as a painkiller.
Conus marmoreus (Marbled cone)
The marbled cone, C. marmoreus, venom contains a new family of voltage dependent sodium channel ligands, the mu-O-conotoxins MrVIA and MrVIB that have amino acid sequences of ACRKKWEYCIVPIIGFIYCCPGLICGPFVCV and ACSKKWEYCIVPILGFVYCCPGLICGPFVCV, respectively, and belong to the O-superfamily of cone neurotoxins along with the delta- and omega-conotoxins. (McIntosh, Hasson et al. 1995). While the mu-O-conotoxins share little sequence homology with omega- or delta-conotoxins, the cDNA clones encoding MrVIB share a significant homology with those encoding the omega- and delta-conotoxin precursors (McIntosh, Hasson et al. 1995). The mu-O-conotoxins have the same molecule core cysteine linking as the delta- (found in C. Striatus ) and omega-conotoxins in addition to having in common with the delta-conotoxins a high amount of hydrophobic residues, having charged residues only on the first intercysteine loop (Fainzilber, van et al. 1995). The mu-O-conotoxins block not only sodium channels, including those on Aplysia neurons which other sodium channel blockers are unable to effect, but at higher doses also block the fast-inactivating calcium currents with MrVIA also slightly blocking the sustained current indicating that these neurotoxins are perhaps an evolutionary link between other variants of conotoxins targeting either sodium or calcium channels (Fainzilber, van et al. 1995).
Conus pennaceus
The molluscivorous C. pennaceus contains unique mollusc specific alpha- and mu-conotoxins. The snail acetylcholine receptor blocking alpha toxins, PnIA (GCCSLPPCAANNPDYC-NH2) and PnIB (GCCSLPPCALSNPDYC-NH2), have distinct sequences and pharmacology which results in these neurotoxins being considered novel members of the alpha-toxin family (Fainzilber, Hasson et al. 1994). The most distinctive deviation in sequence is that the loop of the C-terminal contains a single negatively charged residue, in direct contrast to the piscivorous venom alpha-conotoxins which contain a positively charged residue at this spot (Fainzilber, Hasson et al. 1994). The voltage-gated sodium channel blocking mu-conotoxins from this specie, mu-PNIVA (CCKYGWTCLLGCSPCGC) and mu-PnIVB (CCKYGWTCWLGCSPCGC), are sequentially virtually identical, differing in but one amino acid, yet PnIVB is six times as potent than PnIVA in the blockage of the mollusc sodium channel (Fainzilber, Nakamura et al. 1995). This study also showed that the cysteine framework of these toxins is different from that of all other described conotoxins, CC-----C---C--C-C, and the only charged residue is a solvent exposed Lys3 that is essential for the binding of these neurotoxins to tetrodotoxin resistant sodium channels in molluscs. All of this data taken together indicates that these novel mollusc specific toxins may provide useful data concerning mollusc neurons (Hasson, Fainzilber et al. 1995).
Conus purpurascens (Purple Cone)
C. purpurascens, a fish hunting specie, contains a new family of paralytic toxins, the alpha A-conotoxins, as well as containing a delta-conotoxin termed the 'lock-jaw peptide'. The alpha A-conotoxin PIVA targets the nicotinic acetylcholine receptor on the vertebrate postsynaptic membrane in a competitive manner to alpha-bungaro toxin from the krait Bungarus fasciatus (Hopkins, Grilley et al. 1995). The vertebrate specific delta-conotoxin PVIA, the lock-jaw peptide, has a sequence of EACYAOGTFCGIKOGLCCSEFCLPGVCFG-NH2 (O = 4-trans-hydroxyproline) and targets the voltage-sensitive sodium channels (Shon, Grilley et al. 1995). This neurotoxin is termed an excitotoxin due to its distinct production of rigid, rather than the typical flaccid, paralysis in fish.
Conus striatus (Striatus cone)
Conus striatus contains conopressins as well as alpha-, delta-, mu-, and omega-conotoxins. Arg-conopressin-S, Cys-Ile-Ile-Arg-Asn-Cys-Pro-Arg-Gly-NH2, is similar to Lys-conopressin-G found in geographus as well as in imperialis with comparable bioactivity (Cruz, de et al. 1987).
The alpha-conotoxin SI, Ile- Cys-Cys-Asn-Pro5-Ala-Cys-Gly-Pro-Lys10-Tyr-Ser-Cys-NH2, differs from other acetylcholine receptor ligands in that it has differential binding to a variety of vertebrate nicotinic acetylcholine receptors, activity that may be explained by the presence of a proline in place of a positively charged amino acid at residue 9 (Zafaralla, Ramilo et al. 1988). This notable difference widens the scope of study of vertebrate nicotinic acetylcholine receptors. Alpha-conotoxin SII, GCCCNPACGPNYGCGTSCS, has three disulphide bonds, rather than the usual two, no net positive charge and a free C-terminus (Ramilo, Zafaralla et al. 1992).
The delta-conotoxin VIA is selective for molluscs and slows sodium current inactivation in mollusc neurons. Delta-CTx VIA binds strongly to new sites on mollusc sodium channels and, despite a lack of toxicity towards vertebrates, this neurotoxin binds with high affinity to sodium channels in the rat central nervous systems (Fainzilber, Kofman et al. 1994). This same study that binding is voltage-independent and that the binding site is separate from other neurotoxin receptor sites and that negative allosteric modulation is produced by veratridine. These results suggest that this toxin is quite useful due to its ability to bind to the same site on receptors from different phyla yet produce different result which makes further understanding of the structural criterion determing gating variations in sodium channels.
The calcium channel omega-toxins from striatus contain the smallest natural omega-conotoxin isolated thus far. Omega-conotoxin SVIA (CRSSGSPCGVTSICCGRCYRGKCT-NH2) is a powerful paralytic toxin in lower vertebrates but less so in mammalian species (Ramilo, Zafaralla et al. 1992). Omega-conotoxin SVIB (CKLKGQSCRKTSYDCCSGSCGRSGKC- NH2) is bioactively distinct from other omega-conotoxins, being the only one lethal through intracerebral injections of mice, in addition to utilising a high-affinity binding site different from the high-affinity binding sites of the conotoxins from geographus (GVIA) or magus (MVIIA) (Ramilo, Zafaralla et al. 1992).
Another toxin of interest from striatus is the cardiotonic glycoprotein striatoxin (Kobayashi, Nakamura et al. 1982). Striatoxin slows the inactivation of inward sodium currents and enhanced residual currents, causing a prolongation of duration of the action potential with all of this resulting in an increase in Ca2+ availability in cardiac muscles thus causing an increase in contraction (Ohizumi, Kobayashi et al. 1988).
Conus textile (Textile cone; Cloth-of-Gold cone)
C. textile is a mollusc hunting cone that contains several venom proteins of interest, particularly those in the new conotoxin class 'King Kong peptides'. The King-Kong peptide (TxIA) has a primary structure of WCKQSGEMCNLLDQNCCDGYCIVLVCT while that of the homologous TxIB is WCKQSGEMCNVLDQNCCDGYCIVFVCT and TxIIA has a primary structure of that includes WGGYSTYC gamma VDS gamma CCSDNCVRSYCT, with gamma equalling gamma- carboxyglutamate (Spira, Hasson et al. 1993).
These mollusc specific paralytic neurotoxins are 27 amino acid proteins with conserved disulphide bonds which are ligands for high affinity receptors and ion channels (Woodward, Cruz et al. 1990). The disulphide linked molecule core of these toxins is similar to that of the omega-conotoxins but contain an unusual net negative charge and high content of hydrophobic residues, and one of the toxins (TxIIA) is especially unique with its uneven number of cysteine residues (Spira, Hasson et al. 1993). The King-Kong toxins induce membrane depolarisation and spontaneous repetitive firing in addition to inducing a marked prolongation of the sodium dependent action potential duration, effects distinct from blocking activities of piscivorous venom conotoxins (Fainzilber, Gordon et al. 1991). The deviations in structure and bioactivity of these toxins make them quite useful in further studies of the sodium channels.
Conus tulipa
The piscivorous C. tulipa contains a sleep inducing neurotoxin similar to that of conantokin-G. Conantokin-T is a 21 residue neurotoxin with a primary structure of Gly- Glu-Gla-Gla-Tyr-Gln-Lys-Met-Leu-Gla-Asn-Leu-Arg-Gla-Ala- Glu- Val-Lys-Lys-Asn-Ala-NH2 (Haack, Rivier et al. 1990). Like Conantokin-G, conantokin inhibits N-methyl-D- aspartate (NMDA) receptor-mediated calcium influx in central nervous system neurons produces a sleep-like state in young mice upon intracerebral injection.
For further Conus information, go to Bruce Livett's excellent cone snail page
Other important molluscs
Blue-ringed octopus Hapalochlaena maculosa
Envenomation by the blue-ringed octopus Hapalochlaena maculosa can cause acute respiratory failure through paralysis of the respiratory musculature with death as a result without early and efficient respiratory function support. The toxins also decimate neuronal transmission resulting in severe and rapid hypotension which has to be clinically countered peripherally (Flachsenberger 1986). The primary toxin from the blue-ringed octopus, maculotoxin, is in fact tetrodotoxin. This is the the first instance of tetrodotoxin being identified as a venom component (Sheumack, Howden et al. 1978).
Despite possessing some virulent toxins, poisoning by the Indian sea hare Dolabella auricularia are virtually unknown. One notable exception is a case of poisoning through ingestion of a a sea hare. The clinical pathology was primarily neurotoxic in nature, due to organic bromide compounds, with symptoms including ataxia, muscle twitching, psychomotor over-activity, and tremors.
Several compounds with extreme potential for clinical use as anticancer agents have been isolated from Dolabella auricularia (Indian Ocean sea hare) , of two primary classes: the dolabellanins and the dolastins.
The dolabellanins are anti-neoplastic factors that induce tumour lysis through recognition of a sugar moiety on the tumour cell surface. Dolabellanin A is a heat-labile 250 kDa glycoprotein of four subunits that lysis tumour necrosis factor resistant tumour cells by completely inhibiting synthesis of DNA and RNA within 1 hour (at 1-18 ng protein/ml) and causes complete cytolysis within eighteen hours. Mice bearing the syngeneic MM46 ascitic tumours have had survival time prolonged by Dolabellanin A (Yamazaki, Kisugi et al. 1989). Dolabellanin C is a 215 kDa glycoprotein composed of three 70 kDa subunits that induces cytolysis at a lower concentration than Dolabellanin A, 0.38 ng protein/ml, without affecting normal white or red blood cells (Kisugi, Kamiya et al. 1989). Dolabellanin P is a single 60 kDa polypeptide that, at 5-200 ng protein/ml, nonspecifically lyses all cells (Yamazaki, Tansho et al. 1989).
The dolastins are antineoplastic that inhibit tublin polymerisation and are potent inhibitors of normal haematopoietic progenitor cell proliferation. (Jacobsen, Ruscetti et al. 1991; Beckwith, Urba et al. 1993) Dolastatin I an extremely potent anticancer agent, with a dose of 11 microgram/kg (T/C 240, to T/C 139 at 1.37 microgram/kg) on National Cancer Institute's murine B16 melanoma having a curative response of 33% (Pettit, Kamano et al. 1981). Dolastin 10, another antimitotic peptide, inhibits tublin polymerisation and the growth of cultured LI210 murine leukaemia cells. This peptide has a very short and unusual primary structure, consisting of dolavaline, valine, dolaisoleucine, and dolaproine (three of these unique to D. auricularia) that are linked, at what would normally be the carboxyl terminus, to dolaphenine (a unique primary amine, derived from phenylalanine) (Bai, Pettit et al. 1990). The structure of dolastin 10 contains nine asymemetic carbon atoms with available isomers including alternate configurations at positions 9 and 10 in the dolaproine moiety and positions 18, 19 and 19a in the dolaisoleucine moiety; alterations of 18 and 19 resulted in loss of inhibition of tublin polymerization activity of the isomer and a tripeptide consisting of dolavaline, valine and dolaisoleucine was 30% as effective as Dolastatin 10 in inhibiting tubulin polymerisation (Bai, Pettit et al. 1990). However, the cytotoxic effects of dolastin 10 were shown to be more sensitive to structural alterations. On human lymphoma cell lines, dolastin 10 and 15 have been shown to be 3-4 logarithms more effective clinically useful, antiproliferative agent vincristine which gives further evidence that the dolastins have excellent potential for development as antineoplastic agents. (Beckwith, Urba et al. 1993).
Dolastin 15 is a seven-subunit depsipeptide structurally
homologous with dolastin 10 that also has demonstrated antimitotic and antiproliferative
activity and growth inhibition in heamatopoietic progenitor cells. (Beckwith,
Urba et al. 1993). A synthetic derivative of Dolastatin 15, LU103793 (NSC
D-669356) , disrupts microtubule organisation by depolymerising microtubules
in interphase cells and inducing development of abnormal spindles and chromosome
distribution in mitotic cells. Effects similar to that of vinblastine but
in vitro studies have shown that LU103793 does not inhibit the binding of
vinblastine to unpolymerised tubulin (de, Cocchiaro et al. 1995).
Publications relating to Molluscs
Back to Index