Farmaci Antimitotici

ULTRASTRUTTURA DEI MICROTUBULI

Heterdimers of - and -tubulin assemble to form a short microtubule nucleus. Nucleation is followed by elongation of the microtubule at both ends to form a cylinder that is composed of tubulin heterodimers arranged head-to-tail in 13 protofilaments. Each microtubule has a so-called plus (+) end, with -tubulin facing the solvent, and a minus end (-), with -tubulin facing the solvent.

time at 37 °C % tubulin subunits in microtubule polymer

a | Changes in the length of a single microtubule over time in a control cell (no drug). Microtubule ends grow and shorten stochastically over time by addition and loss of tubulin subunits from their ends. Changes in length at the plus ends are greater than at the minus ends. Microtubules also undergo phases of pause or attenuated dynamics.

. b | Life-history traces of the lengths of four individual microtubules in the absence of drug (left) and in the presence of a microtubule-targeted drug (right). The microtubules were assembled from purified bovine brain tubulin and the changes in length were traced by differential interference-contrast time-lapse microscopy. In the absence of drugs, dynamics are fast, with many length changes. In the presence of a drug such as paclitaxel, dynamics are suppressed.

c | Treadmilling microtubule c | Treadmilling microtubule. Tubulin heterodimers are added at the plus end of the microtubule at time 0, treadmill through the microtubule and are lost from the minus end of the microtubule at time 3. The length of the microtubule is unchanged. Treadmilling is brought about by the different tubulin critical concentrations at the opposite ends.

Tubulin-bound GTP is hydrolysed to tubulin–GDP and inorganic phosphate (Pi) at the time that tubulin adds to the microtubule ends, or shortly thereafter. Ultimately, the Pi dissociates from the microtubule, leaving a microtubule core consisting of tubulin with stoichiometrically bound GDP. A microtubule end containing tubulin-bound GTP or GDP–Pi is stable, or 'capped', against depolymerization. Hydrolysis of tubulin-bound GTP and the subsequent release of Pi induces conformational changes in the tubulin molecules that destabilize the microtubule polymer, resulting in catastrophe and shortening of the microtubule.

COLCHICINA Colchicum autumnale Colchicine forms complexes with tubulin dimers and copolymerizes into the microtubule lattice, suppressing microtubule dynamics. Colchicum autumnale

ALTRI COMPOSTI ATTIVI SUL SITO DI LEGAME PER LA COLCHICINA PODOFILLOTOSSINA Podophyllum peltatum

ALTRI COMPOSTI ATTIVI SUL SITO DI LEGAME PER LA COLCHICINA ROTENONE CHELERITRINA

Vinca rosea (Catharanthus roseus)

ALCALOIDI DELLA Vinca

EFFETTI DEGLI ALCALOIDI DELLA Vinca SULLA STRUTTURA DEI MICROTUBULI A few molecules of vinblastine bound to high-affinity sites at the microtubule plus end suffice to suppress microtubule dynamics.

EFFETTI TOSSICI DEGLI ALCALOIDI DELLA Vinca EMATOLOGICI (VBL >VCR) NEUROLOGICI (VCR > VBL) GASTROINTESTINALI ENDOCRINI (VCR > VBL) DERMATOLOGICI CARDIOVASCOLARI POLMONARI (VBL)

ALTRI COMPOSTI ATTIVI SUL SITO DI LEGAME PER GLI ALCALOIDI DELLA Vinca

COMPOSTI ATTIVI SUL SITO DI LEGAME PER RIZOXINA/MAYTANSINA DOLASTATINE

COMPOSTI ATTIVI SU SITI DI LEGAME DIVERSI O IGNOTI Griseofulvina Eleuterobina

COMPOSTI ATTIVI SU SITI DI LEGAME DIVERSI O IGNOTI Ecteinascidina Estramustina fosfato

Taxus brevifolia

TASSANI

MECCANISMO D’AZIONE DEI TASSANI

EFFETTI TOSSICI DEI TASSANI REAZIONI DI IPERSENSIBILITÀ EMATOLOGICI NEUROLOGICI CARDIACI (paclitaxel) DERMATOLOGICI (docetaxel > paclitaxel) RITENZIONE IDRICA (docetaxel)

MECCANISMI DI RESISTENZA AGLI ALCALOIDI DELLA Vinca E AI TASSANI alterazioni a carico di - e/o -tubulina produzione di forme di -tubulina che presentano alterazioni a livello del sito di legame per i farmaci produzione di forme di - e/o -tubulina con alterazioni a livello dei siti di legame per il GTP alterazioni dell’accumulo intracellulare overespressione di P-glicoproteina overespressione di MRP-1 (a. della Vinca > tassani)

PACLITAXEL POLIGLUMEX (XYOTAX) c | Polyglutamate– paclitaxel. d | Polyethylene glycol (PEG)–camptothecin.

Tumour targeting of long-circulating polymer therapeutics occurs passively by the 'enhanced permeability and retention' (EPR) effect. Hyperpermeable angiogenic tumour vasculature allows preferential extravasation of circulating macromolecules and polymeric micelles. Once present in the tumour interstitium, polymer therapeutics act either after endocytic internalization or extracellularly

a | Polymer–drug conjugates designed for lysosomotropic delivery of small-molecule drugs. Also shown is the use of bioresponsive, endosomolytic polymers to facilitate cytosolic access of genes and proteins from the endosome. b | Use of polymer-based systems to deliver drug within the tumour interstitium, or to destroy tumour cells following interaction with the cell membrane. Polymer-directed enzyme prodrug therapy (PDEPT) is a two-step approach that relies on activation of a polymer–drug conjugate by a complementary polymer–enzyme conjugate. Polymer–enzyme liposome therapy (PELT) relies on the liberation of drug from liposomes by the action of a polymer–phospholipase conjugate. Polymers that are conjugated to membrane active peptides or drugs that are known to activate the apoptosis pathway also have the potential to act at the level of the plasma membrane. enz, enzyme.

Figure 1. Structures of the epothilones that are furthest along in clinical development

Figure 1. Five possible outcomes of antimitotic drug treatment at the cellular level, derived from cultured cell studies. Outcome A, chronic mitotic arrest (the double-headed arrow indicates that this outcome may give rise to other outcomes or it may lead to normal cell division after withdrawal of the antimitotic drug); outcome B, mitotic death; outcome C, mitotic slippage followed by cell death; outcome D, mitotic slippage followed by senescence; outcome E, continued cycling and endoreplication after mitotic slippage (after withdrawal of drug outcome, E cells may undergo abnormal division, generating heterogeneous populations of cells with varied chromosomal content). Modified from Weaver and Cleveland (19). Yamada, H. Y. et al. Mol Cancer Ther 2006;5:2963-2969