Drug action, cell cycle specificity

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-]. 

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. 

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. 

Each drug is chosen to have a different cellular site of action or different cell cycle specificity. 

These drugs owe their cytotoxic action to their interactions with DNA, leading to disruption of DNA function. They are cell-cycle specific. 

Vincristine and vinblastine are generally considered to act specifically on the metaphase portion of the mitotic (M) stage of the cell cycle as a consequence of perturbations of the structure and function of tubulin. A characteristic action of the drugs is production of mitotic arrest in which the tJercentage of cells in mitosis in a given population of cells will rise from a few percent to 50% and more after treatment with a drug such as vinblastine. There are reports, however, that these drugs can interfere with other phases of the cell cycle in ways not clearly related to interference with tubulin function (5). 

Podophyllotoxin (3) is a precursor to the three cUnically used anticancer drugs, etoposide (4), teniposide (5), and etoposide phosphate (6). Its mechanism of action involves inhibition of tubuUn polymerization and disruption of mitosis during metaphase of the cell cycle. Both etoposide and teniposide are modifications of podophyllotoxin specifically designed to increase the water solubility, reduce gastric toxicity in addition to inhibiting topoisomerase II, and disrupting the cell cycle. 

Hydroxyurea (Hydrea) inhibits the enzyme ribonucleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impairment of DNA synthesis. The drug therefore is an S-phase specific agent whose action results in an accumulation of cells in the late Gj- and early S-phases of the cell cycle. 

The primary action is inhibition of enzyme ribonucleoside diphosphate reductase. The drug is specific for S phase of the cell cycle and causes cell to arrest at the Gj-S interface. 

Cell cycle (phase) specific these kill only cells that are actively cycling (often because their site of action is confined to one phase of the cell cycle, e.g. antimetabolite drugs). 

Teniposide is a podophyllotoxin derivative. Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G2 phase of the cell cycle, thus preventing cells from entering mitosis. Teniposide causes single- and double-stranded breaks in DNA and DNA protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity. The terminal half-life is 5 hours. The volume of distribution is 3 to 11 L in children and 8 to 44 L in adults. Renal elimination is 44%, fecal elimination is up to 10%, and 4 to 12% is excreted unchanged in the urine. Adult used in refractory childhood acute lymphoblastic leukemia. Pediatric used in refractory acute lymphoblastic leukemia (ALL). 

Mechanisms of action and resistance Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. The drug is activated by kinases to AraCTP, an inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the tumor cell cycle. Resistance to cytarabine can occur as a result of its decreased uptake or its decreased conversion to AraCTP. 

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