Cell-cycle specificity

In general, the mechanisms of action are not cell cycle specific, although some members of the class show greatest activity at certain phases of the cell cycle, such as S-phase (anthracyclins, mitoxantrone), Gl- and early S-phases (mitomycin C) and G2- and M-phases (bleomycins). 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

Antipyrimidine antimetabolite inhibits DNA polymerase with inhibition of DNA strand elongation and replication activated in tumor cells in triphosphate form competes with conversion of cytidine to deoxycytidine nucleotides, further blocking polymerization of DNA leads to production of short DNS strands cell-cycle specific (S phase) acts only on proliferating cells. 

HU is an inhibitor of ribonucleotide reductase, a rate-limiting enzyme which catalyzes the conversion of ribonucleotides into deoxyribonucleotides. HU is thus a cytotoxic agent as it has the ability to inhibit DNA synthesis. Consequently, H U can affect only cells that are actively synthesizing DNA and, therefore, a drug of S-phase cell-cycle specific. Moreover, HU-mediated inhibition of ribonucleotide reductase is reversible, implying that the action of HU will exhibit a relatively straight forward concentration-time course dependence [2—4-]. 

CD Fludarabine -purine analogue antimetabolite partially cell cycle specific... 

Hydroxyurea -antimetabolite inhibits ribonucleotide reductase cell cycle specific -bone marrow suppression -nausea and vomiting (uncommon at standard doses) -maculopapular rash -skin ulceration -megaloblastosis (elevated MCV)... 

In this chapter we show that topi inhibitors with apparently similar cytotoxic profile could have a specific effect of cell cycle, distinguishing the activity of classical camptothecin, such as irinotecan and SN-38, active specifically on the S phase by edotecarin active as tight binder on topi and without cell cycle specificity. The use of cytometry of solid tumors from xenograft made it possible to provide support to immunohistochemical analysis during the study of biomarkers, comparing cell cycle effects to topi modulation after treatment. 

Dividing cells in culture exposed to vinblastine or vincristine are arrested from further growth during mitosis (12,13). In fact, the antimitotic effects of this class of compounds is ubiquitous. These effects are observed at relatively low concentrations (<1 iM), and are reversible when drug is removed from the media prior to lysis of the arrested cells. The concentration of drug required to elicit an antimitotic effect is usually comparable to that required to produce a cytotoxic effect in the same cell type (14,15). Originally, this type of analysis was exceedingly laborious, but the introduction of laser- and computer-based fluoresence activated cell sorters (FACS) has rendered this type of analysis routine. Nevertheless, a cytotoxic, non-cell cycle-specific bisindole alkaloid has yet to be discovered. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

Bleomycin is a naturally occurring fermentation product of Streptomyces verticillus. It is a basic glycoprotein, complexed with Cu++. It intercalates between DNA base pairs, and it also chelates iron, generating oxygen radicals which further damage the DNA. It is the only cell-cycle specific agent among the antibiotics as it causes accumulation of cells in the G2 phase of the cell cycle. 

I 15. The tumor that is least susceptible to cell-cycle-specific (CCS) anti-cancer agents is... 

I 17. The answer is d. (Hardman, p 1236.) Cell-cycle-specific agents such as 6-MP, 5-FU, bleomycin, and vincristine have proved to be the most... 

It acts by inhibiting dihydrofolate reductase. It inhibits conversion of dihydrofolic acid to tetrahydrofolic which is essential for purine synthesis and amino acid interconversions. It primarily affects DNA synthesis but also RNA and protein synthesis. It has cell cycle specific action and kills cells in S phase. It is readily absorbed from gastrointestinal tract but larger doses are absorbed incompletely, little drug is metabolised and it is excreted largely unchanged in urine. 

The vinca alkaloids are isolated from plant Vinca rosea. They are cell cycle specific and mitotic inhibitors. 

Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs. A schematic summary of cell cycle kinetics is presented in Figure 54-2. This information is relevant to the mode of action, indications, and scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS) drugs. Agents falling into these two major classes are summarized in Table 54-1. 

Cell Cycle-Specific (CCS) Agents Cell Cycle-Nonspecific (CCNS) Agents... 

Marine sponges of the genus Haliclona contain a diverse array of active secondary metabolites, including highly potent cytotoxic macrolides, e g., halichondrin and related compounds, Fig. (56) [468], and salicylihalamides A and B, Fig. (57) [469], New macrolides chemically related to salicylihalamides, apicularens A and B, were recently isolated from the myxobacteria Chondromyces sp. [470], From marine bacteria, other cytotoxic macrolides have been isolated, such as octalactin A, Fig. (58) and B, which have been shown as a cell cycle-specific anticancer drug [471], and swinholide, Fig. (59), isolated from symbiotic cyanobacteria with the marine sponge Theonella swinhoei [472]. 

Cell-Cycle-Specific Versus Cell-Cycle-Nonspecific Drugs... 

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