Cell-cycle-specific agents

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. 

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 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... 

The taxane antineoplastic agents (paditaxel and docetaxel) act by promoting formation and stabilization of microtubules. Accumulation of these polymerized microtubules may lead to mitotic arrest and cell death from nonfunctional tubules. They are considered to be cell cycle-specific agents (acting with greatest activity on cells in Gap 2 [Gj] and mitosis [M] phases). 

Topotecan and irinotecan both act by inhibiting topoisomerase I (topo I) enzymes, thereby inhibiting DNA replication. They are cell cycle-specific agents with most activity for cells in the S phase. Topotecan is used for treatment of refractory metastatic ovarian carcinoma and small cell lung cancer. It also may be useful in the treatment of head and neck cancer. Irinotecan is indicated for the treatment of metastatic carcinoma of the colon or rectum. 

So far about 72 alkaloids have been isolated from Vinca rosea Liim, genus Catharanthus roseus (Family Apocynaceae). Out of these 24 dimeric alkaloids only six possess antineoplastic activity but specifically two i.e., vincristine, vinblastine, are used clinically in human neoplasms. These are cell-cycle specific agents. 

Antimetabolites are cell-cycle specific agents which prevent synthesis of nucleotides or inhibit enzymes by mimicking nucleotides. 

Azacytidine (SED VIII, p. 961) is a pyrimidine nucleotide analogue. It is probably a cell cycle specific agent but also has an effect on resting cells. It has been found of little value in the treatment of solid tumours but has been of interest as a possible remission-inducing agent in acute non-lymphoblastic leukaemia. 

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-]. 

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

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... 

Antineoplastic agents may be teratogenic, carcinogenic, or immunosuppressant, and they exert their lethal effects on different phases of cell cycle by being either cell-cycle specific or nonspecific (Figure 8.1). 

Which one of the following agents shows cytotoxicity that is cell-cycle specific ... 

Jusko W. A pharmacodynamic model for cell cycle-specific chemotherapeutic agents. J Pharmacokinet Biopharm 1973 1 175-200. 

---