The main agents of this group are vinblastine, vincristine, vinorelbine, docetaxel, irinotecan, paclitaxel, teniposide, topotecan, etoposide, and others.
According to the DA classification. Kharkevich, antitumor products of plant origin can be represented by the following groups:
Most alkaloids are phase-specific antitumor agents, i.e. are effective in certain phases of the cell cycle.
Alkaloids can be divided into two groups according to the point of application of the action:
Vinaalkaloids are structurally related substances, in the chemical structure of which there are two polycyclic units – vindolin and catarratin. Vinaalkaloids include vinblastine and vincristine – alkaloids isolated from the rose periwinkle plant (Vinca rosea L.), as well as vindesine and vinorelbine – semisynthetic derivatives of vinblastine. Vinorelbine differs in structure from other vinca alkaloids by the presence of an 8-membered ring of catarratin (instead of the 9-membered ring). The antitumor effect of these alkaloids is due to the effect on the cells in the M-phase of the cell cycle (mitosis phase).
In the normal (correct) course of mitosis, the formation of the achromatin spindle begins at the prophase stage, which ends in the metaphase stage. By the end of the cell division, the spindle disintegrates (the mitotic spindle is formed with each division of the eukaryotic cell and regulates the orientation and distribution of chromosomes in two daughter cells). The cytoplasmic globular protein tubulin participates in the construction of the filament spindle (microtubule) fibers.
Tubulin is a dimeric protein, consisting of two similar but not identical subunits – alpha-tubulin and beta-tubulin. Both subunits have a molecular weight of about 50 kD each (53 kD and 55 kD) and differ somewhat in the isoelectric point. Under certain conditions, depending on the needs of the cells, the dimers of tubulin polymerize and form linear chains consisting of alternating molecules of alpha-tubulin and beta-tubulin (protofilaments), from which microtubules are formed.
Microtubules form the basis of the mitotic apparatus (mitotic spindle) during cell division, and are also an important component of the cell cytoskeleton. They are necessary for the realization of many cellular functions in the interphase, incl. to maintain the spatial shape of cells, intracellular transport of organelles. In neurons, the bundles of microtubules participate in the transmission of nerve impulses.
Each microtubule is a cylinder with an outer diameter of about 24 nm and an internal channel about 15 nm in diameter, the length of the microtubule is a few microns. The walls are constructed of 13 protofilaments, arranged in the form of a spiral around the central cavity. Microtubules are dynamic polar structures with (+) – and (-) ends. Both polymerization and depolymerization of tubulin occurs at the ends of microtubules, with the greatest changes occurring at the (+) end
The antimitotic action of the vinca alkaloids is primarily mediated by the action on the microtubules: by binding to the microtubule tubulin molecules (due to pronounced affinity), they interfere with the polymerization of this protein, inhibit the formation of the fission spindle (microtubule assembly) and stop mitosis at the metaphase stage. Vinaalkaloids can also alter the metabolism of amino acids, cAMP, glutathione, the activity of calmodulin-dependent Ca2 + transport ATPase, cellular respiration, biosynthesis of nucleic acids and lipids
It is believed that there are some differences in the mechanism of action of different vinca alkaloids, which may be due to differences in their chemical structure, interaction with different parts of the tubulin molecule, and various interactions with proteins associated with microtubules. These proteins can change the nature of the interaction of alkaloids with tubuline microtubules, which as a result also determines some of the nuances in the action of different alkaloids. Thus, in vitro, vinblastine, vincristine and vinorelbine have approximately similar activity in respect of tubulin assembly in microtubules, but vinorelbine has no specific effect on the induction of spiral formation.
In an experimental comparative study, the effects of vinblastine, vincristine, and vinorelbine on microtubules of the mitotic spindle and microtubule of axons in mouse embryos at an early stage of neuronal development showed that vinorelbine acts more selectively on the microtubules of the mitotic spindle.
Natural vinca alkaloids (vincristine, vinblastine) are used to treat rapidly proliferating neoplasms. One of the widely used vinca alkaloids – vincristine is used mainly in combined chemotherapy of acute leukemia, lymphogranulomatosis, as well as other tumoral diseases (administered once a week). Neurotoxic action of vincristine may manifest as a violation of neuromuscular transmission, neurological complications, incl. paresthesia, motor disorders, loss of tendon reflexes, intestinal paresis is possible with the appearance of constipation, up to the paralytic ileus, etc.
Unlike vincristine, another vinca vinblastine alkaloid is a less neurotoxic drug, but causes myelosuppression, has a pronounced irritant effect with a risk of developing phlebitis, necrosis (with extravasal ingestion). Like vincristine, vinblastine is used in the complex therapy of a number of tumor diseases, including Hodgkin’s disease, lympho- and reticulosarcoma.
The alkaloids of the colchicum of the magnificent (Colchicum Speciosum Stev.) Family of lilacaceae (Liliaceae) include demekolcin (colchamine) and the closely related colchicine that is found in the corms of the plant.
In the Middle Ages, infusion of seeds and tubers of cesspool was used as a remedy for gout, rheumatism, neuralgia. Currently, demecolcin and colchicine are applied in a limited way.
Both alkaloids have antimitotic activity. The mechanism of action of colchicine is primarily due to the fact that, when it binds to tubulin, it leads to the disaggregation of the mitotic apparatus and causes the so-called. K-mitosis (colchicine mitosis) – cell division is disrupted at the stage of metaphase and subsequent anaphase, while the chromosomes can not disperse to the poles of the cell, resulting in the formation of polyploid cells. Colchicine is widely used in experimental studies as a mutagen, as well as for the production of polyploid forms of plants.
Demekolcin, which is 7-8 times less toxic than colchicine, is used mainly as an external agent (in the form of ointment) in skin tumors (inhibits the growth of tumor tissue, with direct contact causes the death of tumor cells). Colchicine is used to stop and prevent gout attacks. Colchicine, along with antimitotic activity, has the ability to inhibit the formation of amyloid fibrils and block amyloidosis, has a uricosuric effect, inhibits the development of the inflammatory process (inhibits the mitotic division of granulocytes and other mobile cells, and reduces their migration to the focus of inflammation). Assign colchicine for gout, mainly in the ineffectiveness of NSAIDs or contraindications to them.
The means, whose antimitotic activity is mainly due to the action on the microtubules of the cells, include, in addition to the vinca alkaloids and alkaloids of the cedar-free gorge, a new group of alkaloids, taxanes.
Taxanes – chemotherapeutic agents, widely used in clinical practice in the 1990’s.
Paclitaxel, the first taxane derivative with antitumor activity, was isolated in 1967 from the Pacific taxis (Taxus brevifolia), in 1971 its chemical structure was deciphered (it is a diterpenoid taxane). Currently, paclitaxel is also produced semi-synthetically and synthetically.
Docetaxel, close to paclitaxel in structure and mechanism of action, is obtained by chemical synthesis from natural raw materials – European taxis (Taxus baccata).
Taxanes belong to the class of drugs that act on microtubules. Unlike vinaalkaloids that inhibit the formation of the mitotic spindle, taxanes, binding to free tubulin, increase the rate and degree of its polymerization, stimulate the assembly of microtubules, stabilize the formed microtubules, prevent the depolymerization of tubulin and the disintegration of microtubules. Taxanes disrupt the functioning of the cell during mitosis (M-phase) and in interphase.
The formation of an excessive number of microtubules and their stabilization lead to inhibition of the dynamic reorganization of the microtubule network, which ultimately leads to disruption of the formation of the mitotic spindle and inhibition of the cell cycle in the G2 and M phases. Change of cell functioning in the interphase, incl. violation of intracellular transport, transmission of transmembrane signals, etc., is also a consequence of disturbance of the microtubular network.
Paclitaxel and docetaxel have a similar mechanism of action. However, the differences in the chemical structure determine certain nuances in the mechanism of action of these substances found in the experiment. For example, docetaxel has a more pronounced effect on activating the polymerization of tubulin and inhibiting its depolymerization (approximately twice). When acting on the paclitaxel cell, some changes in the structure of the microtubules are observed, which were not detected by the action of docetaxel. Thus, in experimental studies it was shown that microtubules formed in the presence of paclitaxel contain only 12 protofilaments (instead of 13 in norm) and have a diameter of 22 nM (in contrast to 24 in norm).
In addition, paclitaxel induces an anomalous arrangement of microtubules in the form of bundles throughout the cell cycle and the formation of multiple stellate condensations (asters) during mitosis.
The mechanisms of action of different drugs that affect microtubules are not fully understood, despite the large amount of accumulated information. It has been established that binding sites with tubulin are different for natural vinca alkaloids, vinorelbine, colchicine, taxanes. Thus, in experimental studies of paclitaxel, it has been shown that it binds predominantly to the beta subunit of tubulin, while its ability to bind to microtubules is higher than that of tubulin dimers.
Taxanes are effective for breast cancer, ovaries, non-small cell lung cancer, head and neck tumors, etc.
To antitumor agents of plant origin, podophylline (a mixture of natural substances isolated from rhizomes with the roots of the Podophyllum peltatum L. of the family of barberry (Berberidaceae), Podophyllin contains not less than 40% of podophyllotoxin, alpha and beta-peltatin. Extract from the rhizomes of the podophyll has long been used in folk medicine as a laxative for chronic constipation, as an emetic and anthelmintic remedy. Later, its cytostatic activity was shown to be manifested by blockade Oz at metaphase (by action resembles colchicine). Podophyllotoxin used topically in the treatment of warts and other skin tumors.
Semisynthetic derivatives of podophyllotoxin – epipodophyllotoxins (etoposide and teniposide) are widely used in clinical practice, according to the mechanism of action related to topoisomerase inhibitors.
Topoisomerases are enzymes directly involved in the process of DNA replication. These enzymes change the topological state of DNA: carrying out short-term ruptures and reunions of DNA sites, they promote rapid untwisting and twisting of DNA during replication. At the same time, the integrity of the chains is preserved.
Topoisomerase inhibitors, binding to the topoisomerase-DNA complex, act on the spatial (topological) structure of the enzyme, reduce its activity and thereby disrupt the DNA replication process, inhibit the cell cycle, delaying cell proliferation.
