Cell-cycle-specific cytotoxic agents

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-]. 

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

Mitomycin is a broad-spectrum antibiotic that also functions effectively as a monofunctional or bifunctional alkylating agent for mammalian DNA. Its activity is not considered cell-cycle specific, but maximum cytotoxic effects occur in cells in late G, and S phases. 

Cyclophosphamide is a cytotoxic (cytostatic), cell cycle non-specific, antiproliferative agent, which is used in such diverse medical problems as neoplasia, tissue transplantation, and inflammatory diseases.Chemically, it is an inert bioprecursor for a potent nitrogen mustard alkylation agent (Figure 36.32). 

Some drugs that exert their maximum cytotoxicity during the S-phase of the cycle also prevent cells from progressing through the cell cycle to the S-phase this is accomplished by sublethal inhibition of RNA and protein synthesis. The antimetabolites methotrexate, fluo-rouracU, and mercaptopurine all can inhibit RNA synthesis in Gi- and Gz-phases and inhibit DNA synthesis during S-phase. This inhibition of cell cycle progression actually may result in reduced cytotoxicity, and such agents have been termed S-phase-specific but self-limited. 

Similar to resveratrol, compounds 5b, Sf, and 6c induced a partial block of cells in S-phase and an apoptotic sub-GO-Gl peak corresponding to about 20%, suggesting that these compounds act on HL-60 cells as phase-specific cytotoxic agents. In contrast, compound 6b caused an evident sub-GO-Gl peak increase but no modification in cell cycle distribution (phases GO-Gl, S, and G2-M) compared to the control group. 

Many cancer therapies use non-S-phase-specific cytotoxic agents and the question arises whether a cell-cycle inhibitor like rhMIP-la/BB-10010 can protect normal cell from these agents. This question has been addressed using the clinically relevant non-S-phase-specific cytotoxic drug cyclophosphamide in murine chemotherapy models, which are typically less myeloablative than those described above (38). In these studies BB-10010 was administered continuously by osmotic minipump during days 0-7 at 40 pg... 

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