Cell cycle-specific drug

FIGURE 36-1 T Phases of the cell cycle. Examples of cell-cycle-specific drugs are listed next to the phase of the cycle they act on. Examples of cell-cycle-nonspecific drugs are listed below the figure. See text for more details. 

In a patient with diffuse lymphoma, the oncologist suggests a treatment strategy that involves the initial administration of doxorubicin to obtain a significant log-kill, followed by the cell cycle-specific drugs cytarabine and vincristine. This therapeutic strategy is called... 

The cell cycle-specific drugs used in standard treatment protocols for Hodgkin s disease are bleomycin and the vinca alkaloids. Vinblastine is used in the ABVD regimen, and vincristine (Oncovin) is used in the MOPP regimen. The answer is (E). 

Antineoplastic, immunosuppressant cell cycle-specific drug that inhibits dihydrofolate reductase. Major dose reduction required in renal impairment. Tox GI distress, myelosuppression, crystalluria. Leucovorin rescue used to reduce toxicity. 

Leucovorin rescue is used in patients treated with methotrexate Methotrexate and vincristine are both cell cycle-specific drugs... 

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-]. 

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. 

Azathioprine is a phase-specific drug that is toxic to cells during nucleic acid synthesis. Phase-specific drugs are toxic during a specific phase of the mitotic cycle, usually the S-phase, when DNA synthesis is occurring, as opposed to cycle-specific drugs that kill both cycling and intermitotic cells. 

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. 

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... 

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. 

It has been shown [34,35] that the prevention of intercellular communication can lead to synchronisation of whole cultures, thus facilitating the production of cell-cycle specific metabolites of pharmaceutical importance. Perhaps a similar approach could be used in pharmacological analysis of drugs and their effects on individual cells rather than on whole tissue. 

Drugs that act on cells that are actively proliferating are cell-cycle specific (CCS)—schedule-dependent. In most cases, CCS drugs are also phase specific, as shown in Figure VIII-1 -1. 

Figure VIII-1-1. Cell-Cycle Specificity of Anticancer Drugs...

Drugs that act on proliferating cells are cell-cycle specific and are usually also cycle-phase specific. j... 

Answer A. It can help to know which anticancer drugs are cell-cycle specific and which have characteristic toxicities. Bleomycin fits both categories acting mainly in G2, it is cell cycle specific and is distinctive for causing mucocutaneous reactions and pulmonary dysfunction. Busulfan and procarbazine may also cause pulmonary toxicity, but neither drug is cell-cycle specific. 

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